Cancer Therapy Advisor March/April 2015 Issue by Haymarket Media

MARCH/APRIL 2015 | VOL I, ISSUE 4

CancerTherapyAdvisor.com

CancerTherapyAdvisor

A16 CME ACTIVITY

Case Study: A 71-Year-Old Male With Relapsed CLL and an 11q Deletion

FEATURING Cancer Therapy Regimens and Oncology Drug Monographs from

1 Bone Cancer

Review the case and determine the best course of treatment

3 Brain Cancer 5 Breast Cancer 17 Endocrine Cancer

 20 Gastrointestinal Cancer

A25 FEATURE

Is Ageism Affecting Patients with Prostate Cancer? A Look At Cancer Treatment Among Age Groups

29 Genitourinary Cancer

 37 Gynecologic Cancer 42 Head and Neck Cancer

A27 IN THE CLINIC

Managing Anticoagulation in Patients with Primary or Metastatic Brain Tumors

 44 Hematologic Cancer 73 Lung Cancer

 77 Sarcoma 80 Skin Cancer

A32 VIEWPOINT MARCH/APRIL 2015 | VOL I, ISSUE 4

The Unsustainable Costs of Cancer Care: Guidelines to Alleviate Costs for Patients

84 Associated Hematological

Disorders



Regimen included

A29 EXPERT PERSPECTIVE Hot Topics From the 2015 Gastrointestinal Cancers Symposium

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A10

sponsored working group. Am J Hematol.

and deletion 17p independently predict

1988;29(3):152-163.

for worse progression-free and overall

9. Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008;111:5446-5456. 10. Gribben JG. How I treat CLL up front. Blood. 2012;115(2):187-197. 11. Gribben JG. Molecular profiling in CLL.

ANSWERS: Question 1: Correct Answer: A. Question 2: Correct Answer: A.

to first treatment in patients with

statistics, 2014. CA Cancer J Clin.

survival after allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia. Leuk Res. 2014;38(10):1165-1172. 19. Maurer C, Hallek M. Chronic lymphocytic leukemia. Dtsch Med Wochenschr. 2013;138(42):2153-2166. 20. Jones JA, Byrd JC. How will B-cell-receptor– targeted therapies change future CLL therapy? Blood. 2014;123(10):1455-1460. 21. Dighiero G, Maloum K, Desablens B, et

Hematology Am Soc Hematol Educ Program.

al. French Cooperative Group on Chronic

2008;444-449.

Lymphocytic Leukemia. Chlorambucil in

12. Quijano S, López A, Rasillo A, et al. Impact of trisomy 12, del(13q), del(17p), and del(11q) on the immunophenotype, DNA ploidy status, and proliferative rate of leukemic

indolent chronic lymphocytic leukemia. N

Engl J Med. 2998;338(21):1506-1514. 22. Shanafelt TD, Rabe KG, Hanson CA, et al. Renal Disease in Patients With Chronic

References

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Lymphocytic Leukemia (CLL).Blood.

1. Shanshal M, Haddad RY. Chronic lymphocytic

Cytometry B Clin Cytom. 2008;74B:139-149.

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leukemia. Dis Mon. 2012;58(4):153‐167. 2. Facts spring 2013. Leukemia & Lymphoma

13. Lehmann S, Ogawa S, Raynaud SD, et al.

23. Shanafelt TD, Witzig TE, Fink SR, et al.

Molecular allelokaryotyping of early-stage,

Prospective evaluation of clonal evolution

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untreated chronic lymphocytic leukemia.

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untreated early‐stage chronic lymphocytic

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leukemia. J Clin Oncol. 2006;24:4636‐4641.

resourcecenter/freeeducationmaterials/ generalcancer/pdf/facts.pdf. Accessed

al. Zeta-chain associated protein 70

September 11, 2014.

and CD38 combined predict the time

24. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and

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CME ACTIVITY cyclophosphamide in patients with chronic

31. Michallet A-S, Cazin B, Bouvet E, et al. First

43.Shanafelt TD, Geyer SM, Kay NE. Prognosis

lymphocytic leukaemia: a randomised,

immunochemotherapy outcomes in elderly

at diagnosis: integrating molecular biologic

open-label, phase 3 trial. Lancet.

patients with CLL: a retrospective analysis.

insights into clinical practice for patients

2010;376(9747):1164-1174.

J Geriatric Oncol. 2013;4:141-147.

25. Hillmen P, Gribben JG, Follows GA,

32. Eichhorst B, Goede V, Hallek M.

with CLL. Blood. 2004;103:1202-1210. 44. Rassenti LZ, Jain S, Keating MJ, et

et al. Rituximab Plus Chlorambucil

Treatment of elderly patients with chronic

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in predicting aggressive disease in

an Open-Label Phase II Study. J Clin Oncol. 2014;32(12):1236-1241. 26. Satram-Hoang S, Reyes C, Hoang KQ, et al. Treatment practice in the elderly patient with chronic lymphocytic leukemia—analysis of the combined SEER

33. Eichhorst B, Dreyling M, Robak T, et al. Chronic lymphocytic leukemia: ESMO clinical practice guidelines for diagnosis,

chronic lymphocytic leukemia. Blood. 2008;112:1923-1930. 45. Fast Stats: An interactive tool for access

treatment and follow-up. Ann Oncol.

to SEER cancer statistics. Surveillance

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Research Program, National Cancer

34. Salvi F, Miller MD, Grilli A, et al. A manual

and Medicare database. Ann Hematol.

of guidelines to score the modified

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cumulative illness rating scale and

Institute. http://seer.cancer.gov/faststats. Accessed July 18, 2013. 46. Schultz RA, Delioukina M, Gaal K, et al.

27. Gribben JG. Chronic lymphocytic leukemia:

its validation in acute hospitalized

planning for an aging population. Expert Rev

elderly patients. J Am Geriatr Soc.

by BAC-based microarray analysis. Mol

Anticancer Ther. 2010;10(9):1389-1394.

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Cytogenet. 2011;4:4.

28. Eichhorst B, Fink A-M, Busch R, et al.

35. Veliz M, Pinilla‐Ibarz J. Treatment

Evaluation of chronic lymphocytic leukemia

47. Clifford R, Schuh A. State-of-the-art

Chemoimmunotherapy With Fludarabine (F),

of relapsed or refractory chronic

Cyclophosphamide (C), and Rituximab (R)

lymphocytic leukemia. Cancer Control.

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(FCR) Versus Bendamustine and Rituximab

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Insights Oncol. 2012;6:165-178.

(BR) In Previously Untreated and Physically

36. Awan FT, Byrd JC. New strategies in

management of patients suffering from

48. Shanafelt TD, Kay NE, Rabe KG, et al.

Fit Patients (pts) With Advanced Chronic

chronic lymphocytic leukemia: shifting

Hematologist/oncologist disease-specific

Lymphocytic Leukemia (CLL): Results Of

treatment paradigms. Clin Cancer Res.

expertise and survival: lessons from chronic

a Planned Interim Analysis Of The CLL10

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lymphocytic leukemia/small lymphocytic

Trial, An International, Randomized Study Of The German CLL Study Group (GCLLSG). Presented at: 55th ASH® Annual Meeting and Exposition; December 7-10, 2013; New Orleans, LA. Abstract 526.

37. Merli M, Ferrario A, Basilico C, et al. Novel agents in indolent lymphomas. Ther Adv

Hemaol. 2013;4:133‐148. 38. ten Hacken E, Burger JA. Microenvironment dependency in Chronic Lymphocytic

lymphoma. Cancer. 2012;118(7):1827-1837. 49. Elphee EE. Caring for patients with chronic lymphocytic leukemia. Clin J Oncol Nurs. 2008;12(3):417-423. 50. Kurtin, S. Risk Analysis in the treatment of

Leukemia: The basis for new targeted

hematologic malignancies in the elderly.

To-Head Comparison Of Obinutuzumab

therapies. Pharmacol Ther. 2014

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(GA101) Plus Chlorambucil (Clb) Versus

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Rituximab Plus Clb In Patients With

pharmthera.2014.07.003

29. Goede V, Fischer K, Busch R, et al. Head-

Chronic Lymphocytic Leukemia (CLL) and Co-Existing Medical Conditions (Comorbidities): Final Stage 2 Results Of The CLL11 Trial. Presented at: 55th ASH® Annual Meeting and Exposition; December 7-10, 2013; New Orleans, LA. Abstract 6. 30. Goede V, Cramer P, Busch R, et al. Guidelines for the diagnosis and treatment

39. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics, Inc. 2014. 40. Zydelig™ (idelalisib) Prescribing Information. Gilead Sciences, Inc. 2014.

51. Dighiero G, Binet JL. When and how to treat chronic lymphocytic leukemia. N Engl J Med. 2000;343(24):1799-1801. 52. Evans J, Ziebland S, Pettitt AR. Incurable, invisible and inconclusive: watchful waiting for chronic lymphocytic leukaemia

41. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib

and implications for doctor-patient

versus ofatumumab in previously treated

communication. Eur J Cancer Care.

chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.

2012;21:67-77. 53. Koutsopoulou S, Papathanassoglou ED,

42. Furman RR, Sharman JP, Coutre SE, et

Katapodi MC, Patiraki EI. A critical review

from the International Workshop on Chronic

al. Idelalisib and rituximab in relapsed

of the evidence for nurses as information

Lymphocytic Leukemia. Haematologica.

chronic lymphocytic leukemia. N Engl J Med.

providers to cancer patients. J Clin Nurs.

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2014;370(11);997-1007.

2000;19:749-765.

of chronic lymphocytic leukemia: a report

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FEATURE

BY JOHN SCHIESZER

ew data are suggesting that some elderly oncology patients are being undertreated because of their age. The studies assert that older patients with several different tumor types (including rectal, prostate, and oropharyngeal squamous cell carcinoma) are not receiving optimal care because they are being judged by their chronologic age rather than overall level of fitness. “I think we do have a problem with ageism in treating some cancers and for prostate cancer in particular due to the perception of universally indolent, or ‘autopsy’ disease as men age,” said Judd Moul, MD, the Director of the Duke Prostate Center in Durham, NC. A recent study found that older oropharyngeal squamous cell carcinoma patients are less likely to receive surgery or radiation therapy (RT) than their younger peers.1 The researchers conducted a retrospective analysis of 14,909 patients with oropharyngeal carcinoma using the Surveillance, Epidemiology, and End Results (SEER) database. All patients were diagnosed between 2004 and 2009 and the researchers found a significant increase in the number of patients who did not receive treatment (surgery, radiation, or combined therapy) after age 55. The researchers concluded that, despite the fact that they were not

Are older patients receiving a lower quality of care because of judgments based on their chronological age rather than their overall level of fitness?

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being treated, many patients 55 and older could achieve significant benefits from aggressive treatments regardless of their older age. The researchers suggested clinicians adopt objective measures to assess patient fitness to reduce the potential for undertreatment in the elderly population. A recent study looking at preoperative radiotherapy for rectal cancer found that older patients are less likely to receive preoperative radiotherapy than younger patients, even though it is the standard of care.2 Researchers looked at 2,619 patients who underwent elective transabdominal surgery for rectal cancer in 2000 to 2010. The study showed that 1,789 patients (68.3%) received preoperative radiotherapy or chemoradiotherapy and over time the use of preoperative therapy increased. However, in a multivariable model age (80 years or older) and comorbidity (Charlson Comorbidity Index score 2 or greater) were strongly correlated to omittance of preoperative treatment. A study published this month suggested that many older men with locally advanced prostate cancer are only receiving androgen deprivation therapy (ADT) alone and not with RT even though RT could significantly improve their overall survival.3 “There is a large gap in care in older patients and it is a real health care concern,” said lead author Justin Bekelman, MD, Assistant Professor of

Is Ageism Affecting Patients with Prostate Cancer? A Look at Cancer Treatment Among Age Groups

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FEATURE Radiation Oncology, Medical Ethics and Health Policy at The University of Pennsylvania in Philadelphia, PA. “I don’t think it is a bias against radiation, but a bias against treating older patients in their late 60s, 70s, and 80s and prostate cancer is a disease of the aging.”

“There is a large gap in care in older patients with prostate cancer and it is a real health care concern.” In an interview with Cancer Therapy Advisor, Dr. Bekelman emphasized the need for communication between clinicians and their patients.“We need to have a discussion on the cure rates, the tolerability of the treatment, and [clinicians and their patients] should come to a shared decision about curative treatments and prostate cancer,” said Dr. Bekelman. Daniel Hamstra, MD, who published an accompanying editorial in the Journal of Clinical Oncology, said undertreatment of patients with high-risk prostate cancer is a very serious problem and one that will probably become much bigger in the coming years because men over the age of 65 are a fast-growing segment of the population.4 According to Dr. Hamstra, there is a general attitude that radiation will significantly harm older patients but, in an interview with Cancer Therapy Advisor, he explained that is often not case.“Radiation is better than it used to be. The side effects have improved dramatically in the last 10 to 15 years in prostate cancer. As patients get older they are a little more likely to have side effects from radiation, but I think it is

a little bit overblown. There are a lot of ways to do radiotherapy and it is better not to withhold radiation but to be a little more prudent in how you deliver it.” Dr. Moul said there is a definite age bias in the treatment of locally advanced prostate cancer.“There is the mistaken belief that all men will get prostate cancer if they live long enough and prostate cancer is a disease of old men and a waste of resources to diagnose and treat,” Dr. Moul told Cancer Therapy Advisor. “The fact is that aggressive prostate cancer is more common as men age and doctors are lulled into complacency and underdiagnose and undertreat older men.” He said the updated federal guidelines call for not screening asymptomatic men for prostate cancer. This is a mistake according to Dr. Moul, who believes it will greatly impact men 65 and older. “It may get even worse as the United States Preventive Health Services Task Force is against PSA testing in all men. If we abandon PSA screening, it will take a disproportionate toll on older men, which is very frustrating to me,” said Dr. Moul. Ruth Etzioni, PhD, of the Fred Hutchinson Cancer Research Center Public Health Sciences Division Biostatistics Program in Seattle, WA, said she thinks that both overtreatment and undertreatment are occurring in older patients with prostate cancer. “It is absolutely prudent to tailor decisions about aggressive therapy with age and life expectancies. We should not be as aggressive in older patients as younger patients. That is not a bias. The harm/ benefit tradeoffs are different. Not everyone, but in general,” Dr. Etzioni told Cancer Therapy Advisor. “In cases of treatment with aggressive therapy, the potential benefits may come later. They won’t see that benefit. They are taking on the risks immediately, but the

benefits don’t come until several years down the line. In prostate cancer, for many patients that is indeed the case.” Dr. Etzioni, who is also an Affiliate Professor of Biostat ist ics at t he University of Washington in Seattle, WA, said the primary issue is the true risk /benefit ratio from aggressive therapy in older men. Dr. Etzioni said patients with locally advanced prostate cancer definitely do better with combination therapy. However, she explained that there may be a host of reasons for men opting for only ADT and identified this as something that must be considered when reviewing the current data. “The patients may have been offered it and didn’t want it. They used Medicare data so we don’t have information on all comorbid conditions. I think the data are little biased,” said Dr. Etzioni. “[The researchers] did try to correct for selection bias, but it may be that the patients who received ADT and radiation may have been innately heathier and that is why they got aggressive therapy.” There are some cases where groups

“We should not be as aggressive in older patients as younger patients. That is not a bias.” of patients are being undertreated for a variety of reasons. Those reasons may be socioeconomic, demographic and/ or insurance-related, and identifying factors that are predisposing patients to being undertreated is an important area of research that warrants further investigation. Continued on page A28

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IN THE CLINIC | BY C. ANDREW KISTLER, MD, P

harmD,

Managing Anticoagulation in Patients with Primary or Metastatic Brain Tumors Oncologists must consider numerous factors and risks when managing anticoagulation in patients with brain cancer. When evaluating the need for anticoagulation in patients with brain cancer, numerous factors must be accounted for. Patients with a prior history of intracranial hemorrhage (ICH), platelet count less than 50,000, or increased risk of bleeding (eg, history of disseminated intravascular coagulation) are typically not anticoagulated because the risk outweighs the benefit.1 Both primary brain tumors and metastases (especially from primary melanoma,

renal cell carcinoma, or thyroid cancer) can spontaneously bleed without anticoagulation, which may make the risk of ICH too excessive. In patients who have no known history of brain metastases but have been diagnosed with cancers that frequently metastasize to the brain (eg, melanoma, lung cancer, breast cancer, and thyroid cancer), imaging may be useful prior to initiation of anticoagulation in attempts of detecting metastatic lesions. However, there are no formal guidelines on obtaining imaging in these scenarios. When imaging is being considered, MRI is typically preferred over CT when evaluating the brain for metastases. If the patient with a history of a solid tumor has neurological symptoms such as headaches, change in vision, history of seizures, or concerning findings on physical exam (focal neurological deficit), then imaging should be obtained prior to anticoagulation.

ÂŠ SPL / CUSTOM MEDICAL STOCK PHOTO

he clinical management of patients with primary or metastatic brain cancer is often challenging. As with all types of cancer, patients with brain cancer are at increased risk of deep vein thrombosis and consequently pulmonary embolism. It is common for clinicians to be faced with the question of how to safely utilize prophylactic and therapeutic anticoagulation in these patients in the setting of increased risk of intracranial bleeding from the intracranial lesions. Aside from the inherent risk of clotting secondary to malignancy itself, patients with brain cancer can be at even more risk based on resulting neurological deficits leading to decreased mobility along with any postoperative states they may experience. The incidence of venous thromboembolism (VTE) varies in studies between approximately 7.5% and approximately 25%.1,2 Risk factors associated with VTE in brain cancer patients include: gliobastomas, chemotherapy, older age, neurosurgery within last 2 months, and 3 or more chronic comorbidities.1 Patients with brain cancer diagnosed with VTE also have a higher 2-year mortality risk.1

RPh

A computed tomography scan of a pulmonary embolism. Patients with brain cancer are at an increased risk of deep vein thrombosis and consequently pulmonary embolism, making anticoagulation an important consideration during their care.

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IN THE CLINIC With respect to preventing VTE in patients with brain tumors, there is some limited data suggesting full dose aspirin may be useful although no formal recommendations have been made.3 Patients in the postoperative period are at the highest risk for VTE, therefore early ambulation and compression stockings in conjunction with enoxaparin or heparin are typically used unless there are medical contraindications to using these medications.3 Inferior vena cava (I VC) filters used to be more commonly used in patients with brain tumors, however complication rates have consistently been higher than those associated with anticoagulation.4,5 Patients with brain tumors who are anticoagulated with warfarin have been reported to have fewer complications than those with IVC filters,5 although most of the data is not derived from head-to-head

trials. Many studies evaluating warfarin have shown a similar to slightly higher risk (approximately 2% to 7%) of ICH when compared to the baseline bleeding risk of these patients.6 Low molecular weight heparin (enoxaparin) is usually the preferred agent in treating VTE in patients with cancer, however there is substantially less efficacy and safety data in patients with brain tumors. As with many decisions in patients with cancer, the choice to anticoagulate is multifactorial. A detailed risk– benefit analysis must be performed with both the patient and health care provider. The careful and delicate balance between anticoagulation and the risk for bleeding must be heavily considered. Consultation with neurosurgery, neurology, hematology, oncology, and radiology may provide useful information to help aid in the ultimate decision. ■

Feature

optimal treatment due to ageism should be a call to action. Oncologists should take away the fact that this is an area that not only needs more investigation but also greater awareness from clinicians. ■

Continued from page A26

“I think if you look at people worrying about older patients not being treated adequately you will be able to find an equal and opposite cohort of people who think that older people are being treated too much. So a lot of people think the patients would have a lot better quality of life by not having aggressive therapy,” said Dr. Etzioni. The new data suggesting that a significantly higher number of older oncology patients may not be receiving

References 1. Semrad TJ, O’Donnell R, Wun T, et al. Epidemiology of venous thromboembolism in 9489 patients with malignant glioma. J

Neurosurg. 2007;106(4):601-608. 2. Simanek R, Vormittag R, Hassler M, et al. Venous thromboembolism and survival in patients with high-grade glioma. Neuro Oncol. 2007;9(2):89-95. 3. Iorio A, Agnelli G. Low-molecular-weight and unfractionated heparin for prevention of venous thromboembolism in neurosurgery: a meta-analysis. Arch Intern Med. 2000;160(15):2327-2332. 4. Wen PY, Marks PW. Medical management of patients with brain tumors. Curr Opin Oncol. 2002;14(3):299-307. 5. Levin JM, Schiff D, Loeffler JS, et al. Complications of therapy for venous thromboembolic disease in patients with brain tumors.

Neurology. 1993;43(6):1111-1114. 6. Schiff D, DeAngelis LM. Therapy of venous thromboembolism in patients with brain metastases. Cancer. 1994;73(2):493-498.

Eur J Surg Oncol. 2014;40(12):1782-1788. 3. Bekelman JE, Mitra N, Handorf EA, et al. Effectiveness of androgen-deprivation therapy and radiotherapy for older men with locally advanced prostate cancer.

J Clin Oncol. January 5, 2015. [Epub ahead of print] doi: 10.1200/

Reference 1. Camilon PR, Stokes WA, Nguyen SA,

JCO.2014.57.2743 4. Shumway DA, Hamstra DA. Ageism in

Lentsch EJ. The elderly with oropharyngeal

the undertreatment of high-tisk prostate

carcinoma undertreated? Laryngoscope.

cancer: how long will clinical practice

2014;124(9):2057-2063.

patterns resist the weight of evidence?

2. Elliot AH, Martling A, Glimelius B, et al.

J Clin Oncol. January 5, 2015.

Preoperative treatment selection in rectal

[Epub ahed of print] doi: 10.1200/

cancer: A population-based cohort study.

JCO.2014.59.4093

Read more clinical commentary at CancerTherapyAdvisor.com

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EXPERT PERSPECTIVE | STEVEN J. COHEN, MD

Hot Topics From the 2015 Gastrointestinal Cancers Symposium Steven J. Cohen, MD, Cancer Therapy Advisor Advisory Board member highlights the key science presented at the 2015 Gastrointestinal Cancer Symposium.

or those who have never attended the Gastrointestinal Cancers Symposium, the meeting is 3 days in length and generally broken up into three components by disease: esophagogastric, hepatopancreaticobiliary, and colorectal cancer. Each day is filled with its share of oral presentations, poster presentations, and education sessions. You can generally get a good sense of “what’s hot” for each disease based on what attendees are continuing to talk about in the interactive areas of the convention center and dinners around town. Here is a sampling of which topics generated the most buzz. Esophagogastric Cancer New targets were the excitement for the first day of the meeting. Two oral presentations focused on met as a target. Kwon and colleagues reported on a prospective trial of AMG337, an oral met kinase inhibitor. Of 80 total patients enrolled in the trial, 10 had

previously treated, met-amplified gastric, esophageal, or gastroesophageal (GE) junction tumors. Of the 10, one patient had a complete response and 4 had partial responses with two having stable disease. The toxicity profile in this subset of esophagogastric cancers was comparable to that previously reported for the cohort as a whole. In contrast, Shah and colleagues reported on a randomized phase 2 study of FOLFOX with or without the antiMET antibody onartuzumab as firstline therapy for patients with metastatic esophageal or gastric cancer. While 123 patients were enrolled and randomly assigned, only 35 were met-positive by immunohistochemistry. There was no improvement in the primary endpoint of progression-free survival (PFS) in either the overall patient population or the met-positive subset. Taken in sum, the question arises as to why one met-targeting study was positive while the other was negative. Differences in targeting (small molecule vs. antibody)

could be one explanation. Certainly differences in defining “met-positive” (whether by gene amplification or IHC) could be another. In either event, met appears to be a potential target and we look forward to future presentations in the enriched patient populations. As part of a keynote address, Muro and colleagues presented data on their prospective study of the anti-PD-1 antibody pembrolizumab in patients with advanced gastric or GE junction cancer. Of 162 patients screened, 65 (40%) were positive for PD-1, as evidenced by distinctive stromal staining or at least 1% tumoral staining. Of these 65, 39 enrolled with two-thirds having received at least 2 prior regimens for advanced disease. The response rate was an impressive 22% by central review

Keynote speaker presented data on pembrolizumab in advanced gastric or GE junction cancer. and 33% by investigator review with a median response duration of 6 months. Taken together, both met and PD-1 targeting represent promising pathways to advance the care of patients with advanced esophagogastric cancer. To date, trastuzumab (anti-HER2

Read more from our Advisory Board at CancerTherapyAdvisor.com/FromTheAdvisoryBoard

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EXPERT PERSPECTIVE antibody) and ramucirumab (anti-VEGFR2 antibody) are the only two targeted agents approved to treat these diseases. We eagerly await confirmatory randomized trials to document the benefit of these new pathways. In the meantime, it is reasonable for clinicians to consider testing the tumors of their patients with advanced esophagogastric cancer for expression of these pathways as a mechanism to steer them toward targeted matched clinical trials where appropriate and available. Hepatopancreaticobiliary On the second day, there was significant discussion regarding presentations in three different tumor types within this broad category. In advanced hepatocellular cancer (HCC), Zhu and colleagues presented a subset analysis of the REACH trial, a randomized phase 3 trial of the anti-VEGFR2 antibody ramucirumab compared with placebo for patients with progressive HCC on sorafenib. The updated analysis focused on a prespecified analysis of 250/565 patients with baseline alpha-fetoprotein (AFP) 400 or greater. In this subgroup, median overall survival was 7.8 months compared with 4.2 months in the placebo group (HR 0.67, P=0.0059). For the group of patients with AFP 1.5X ULN or greater, survival was similarly improved (8.6 months vs. 5.7 months, HR 0.749, P=0.008). These provocative results suggest that tumors associated with the highest AFP levels benefit the most from ramucirumab. Whether this is a surrogate for tumors with higher angiogenic factor production or an alternative pathway is unclear. These results will likely be tested in a prospective follow-up study for patients with sorafenib-refractory HCC and elevated AFP. Phan and colleagues similarly presented a subset analysis, in this case of the CLARINET trial, which was a

randomized study of lanreotide compared with placebo for patients with gasteoenteropancreatic neuroendocrine tumors. The original presentation of the data demonstrated a significant prolongation of the primary endpoint, PFS, in the lanreotide arm. The current subset analysis focused on 91 patients with pancreatic neuroendocrine tumors, a group of patients not studied in the PROMID trial. For this group, median PFS was increased in the lanreotide arm compared to placebo at borderline statistical significance (median not reached vs. 12.1 months in placebo; HR 0.58). Given that this group of patients was not studied in the PROMID trial, the current results support use of lanreotide in pNET. Whether lanreotide is globally superior to sandostatin LAR for GEP NETs is unclear without a head to head comparison, and either is a reasonable treatment option for these patients.

Whether lanreotide is globally superior to sandostatin LAR for GEP NETs is unclear. Finally, Chen and colleagues presented an expanded analysis of the NAPOLI-1 trial, which randomly assigned patients with metastatic pancreatic cancer who were previously treated with gemcitabine to 5-fluorouracil with leucovorin (5-FU/LV), liposomal irinotecan (MM-398), or the combination. While prior presentations had focused on the intent-to-treat population, this updated analysis focused on a prespecified subgroup of patients treated with at least 80% of the target

dose in the first 6 weeks and without violating inclusion/exclusion criteria (137/417 patients). Results were quite similar, noting an improved survival in the combination arm (8.9 months vs. 5.2 months, HR 0.57, P=0.011). Thus, it is likely MM-398 will be approved for the treatment of gemcitabine-refractory pancreatic cancer with 5-FU/ LV. Since few patients had received prior irinotecan, the relative efficacy to MM-398 to irinotecan and whether it has efficacy in irinotecan-refractory patients is unclear. Colorectal Cancer Given the high prevalence of this disease, the colorectal cancer day always generates a high level of excitement. Ng and colleagues on behalf of the Alliance presented an analysis of vitamin D levels and relationship to survival from the 80405 study. The results of the study as a whole were first presented by Alan Venook at the 2014 American Society of Clinical Oncology Annual Meeting, demonstrating no difference in overall survival whether patients with KRAS wild-type metastatic colorectal cancer received cetuximab or bevacizumab with their initial chemotherapy. In the current analysis, those patients in the highest quintile of plasma 25(OH)D levels had significantly improved OS compared to those in the lowest (median 32.6 months vs. 24.5 months, HR 0.67, P=0.002). Further, increasing concentrations of 25(OH)D were associated with improved PFS (median 12.2 months vs. 10.1 months, HR 0.80, P trend=0.02). These results were consistent across patient subtypes. There was plenty of debate outside the lecture hall about whether clinicians should be checking vitamin D levels routinely and/or supplementing levels for those who are low. Continued on page A33

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Joan is more than just a patient going through

CHEMOTHERAPY We see so much more than just cancer

Joan is already busy enough with hockey practices, dance recitals, and science fair supply shopping. Now sheâ&#x20AC;&#x2122;s making room on the kitchen calendar for Q3W therapy sessions. People like Joan are at the heart of what drives Teva Oncology. With over 100 years of global pharmaceutical expertise, our mission is to develop and deliver solutions that advance cancer care and improve the lives of people affected by cancer.

We treat the person, not just the cancer

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Job Number: 20898 Revision No: 0 Date: 9/19/14

VIEWPOINT | BY DEBRA HUGHES, MS

The Unsustainable Costs of Cancer Care: Guidelines to Alleviate Costs for Patients A workshop emphasizes the importance of high-value treatment options for patients with cancer.

he high costs of cancer care are unsustainable, both for individual patients and for society. That’s the conclusion of the workshop, “Ensuring Patient Access to Affordable Cancer Drugs,” convened by the 2014 National Cancer Policy Forum of the Institute of Medicine in Washington, DC, the proceedings of which were recently published. One underlying tenet of the workshop is that “to improve cancer care, there is a need to consider patient access to appropriate cancer drugs and other treatments broadly.”1 Workshop participants noted that rising costs of cancer care could be countered by “value-based insurance design and drug pricing, episode-based reimbursements, and incentives for patients and their physicians to opt for lower cost care without compromising the quality of that care.”1 What does that mean for practicing clinicians? Specifically, they should be “empowered” and “incentivized” to use high-value treatment options. Workshop participants recommended the following:1 • Design electronic medical records to provide information on the evidence base and cost for a treatment.

• Encourage greater use of practice guidelines and more consistency among payers regarding the guidelines used. • Establish reimbursement rates based on data from relevant patient populations. • Reform reimbursement practices to replace the traditional “buy and bill” way of doing business in oncology. • Reimburse the chemotherapy administration fee separately from the drug fee. • Adequately compensate oncologists for the complex and time consuming care they offer patients. • Use bundled payments tied to metrics to incentivize efficient care. • Educate physicians on cost-cutting strategies, such as prescribing generics, offering less expensive therapeutic alternatives, and offering discount cards. • Provide guidance to eliminate care for which the evidence convincingly shows a lack of value or potential harm to patients. • Develop policies that incentivize oncologists to stay in private practice such as: —— Provide payment parity for administrative services for the hospital versus the physician office. —— Remove the sequestration cuts to Medicare Part B drugs. —— Remove prompt pay discounts from the calculation of the average sales price.

According to the proceedings, “the average monthly cost of cancer drug therapy has increased from $100 in 1965 to $10,000 in 2013.”1 Much has been written about the high cost of cancer drugs, from Kantarjian and colleagues on the “just price of agents” to the “financial toxicity” many patients experience when being treated for their cancers.2 At the recent 56th Annual Meeting of the American Society of Hematology, for example, 183 abstracts had the word “cost” in their title, and a special symposium on the topic of quality concluded with a sometimes contentious discussion focusing, in part, on who should make decisions regarding cost and access: the patient, the physician, or the insurer?

“The average monthly cost of cancer drug therapy has increased from $100 in 1965 to $10,000 in 2013.” During the symposium, S. Yousuf Zarar, MD, MHS, of Duke Cancer Institute in Durham, NC, reported on a survey of 300 patients with an 86% response rate in which patients who discussed costs with their doctors “believed the conversations helped reduce their expenses.” The survey identified two key research areas of barriers that need to be overcome “to deliver high-value, patient-centered care,” he said. The first is the need to “identify patients who

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VIEWPOINT might desire or benefit from a cost discussion,” and the second is to “validate practice-based interventions to reduce out-of-pocket costs.” He noted that in the United States and Europe, cancer treatment now costs more than $100 billion annually.3 Writing recently in the Journal of Clinical Oncology, Reshma Jagsi, MD, DPhil, of the University of Michigan in Ann Arbor, MI, agreed. “As oncologists begin to appreciate how cancer care can cause substantial long-term fi nancial burdens and deprivation among the very patients we intend to serve, we

may also begin to recognize that discussions of the costs of care and fi nancial consequences of treatment decisions with patients can help us to fulfill our duty not only to society but also to the patients before us,” she said.4 ■

Expert Perspective

c olore c t a l c a nc er. O ver 1,0 0 0 patients were randomly assigned. The results demonstrated improved clinical outcome for the addition of ramucirumab in terms of the primary endpoint of overall survival (median 13.3 months vs. 11.7 months for placebo, HR 0.84, P=0.02) and PFS (median 5.7 months vs. 4.5 months for placebo, HR 0.79, P=0.0005). Response rates were similar at approximately 12% to 13%. As expected, grade 3 or higher neutropenia and hypertension were increased in the ramucirumab arm. A lively discussion ensued regarding the potential place for this agent in the armamentarium of second-line mCRC. To date,

Continued from page A30

At the current time, there are no prospective data regarding vitamin D supplementation and trials are ongoing. While the data clearly tell us that higher vitamin D levels are associated with better outcomes in patients with metastatic colorectal cancer receiving initial chemotherapy, cause and effect is unclear. Finally, Dr. Tabernero presented dat a f rom t he R A ISE st udy, a randomized phase 3 comparison of FOLFIRI plus ramucirumab vs. FOLFIRI plus placebo as second-line therapy for patients with metastatic

2. Kantarjian HM, Fojo T, Mathisen M, Zwelling LA. Cancer drugs in the United States: Justum Pretium – the just price. J Clin Oncol. 2013;31(28):3600-3604. Epub May 6, 2013. 3. Zafar SY. Financial toxicity: how the cost of medical care affects our patients. Presentation at the 56th Annual Meeting of the American

References

Society of Hematology. December 6, 2014.

1. Nass SJ, Patlak M. National Cancer Policy

Available at: https://ash.confex.com/

Forum; Board on Health Care Services; Institute of Medicine. Ensuring Patient Access to Affordable Cancer Drugs:

ash/2014/webprogram/Paper66432.html. Accessed December 11, 2014. 4. Jagsi R. Debating the oncologist’s role in

Workshop Summary. 2014. Available at:

defining the value of cancer care: we have

http://www.nap.edu/catalog.php?record_

a duty to society. J Clin Oncol. Published

id=18956. Accessed December 2, 2014.

ahead of print on November 24, 2014.

bevacizumab beyond progression has demonstrated a similar improvement in survival in the second-line and is commonly used in the clinic. The antiVEGF fusion molecule ziv-aflibercept has also shown benefit, although it is less commonly used in the clinic since its approval is also in secondline where bevacizumab is commonly utilized. Now, we have similar data with ramucirumab. On balance, most left the session acknowledging that ramucirumab is active in second-line mCRC, but wondering if there is a niche for it given the widespread use of bevacizumab in this setting. Cost considerations of the agents may also be a factor in choosing therapy. ■

Review oncology treatment regimens and gain access to an extensive range of current and concise drug information.

CancerTherapyAdvisor.com

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REGIMEN & MONOGRAPH INDEX CANCER THERAPY REGIMENS & DRUG MONOGRAPHS

Bone Cancer

3 Brain Cancer 5 Breast Cancer 17 Endocrine Cancer 20 Gastrointestinal Cancer

 Colon Cancer Treatment Regimens

29 Genitourinary Cancer 37 Gynecologic Cancer  Uterine Sarcoma

42 Head and Neck Cancer 44 Hematologic Cancer

 Non-Hodgkin Lymphoma (NHL):

Burkitt Lymphoma  Hodgkin Lymphoma

73 Lung Cancer 77 Sarcoma

 Gastrointestinal Stromal Tumor (GIST)

80 Skin Cancer 84

Associated Hematological Disorders

To view the complete collection of cancer treatment regimens for all cancer types visit CancerTherapyAdvisor.com/TreatmentRegimens. To view the complete collection of drug monographs visit CancerTherapyAdvisor.com/DrugMonographs.

IMPORTANT INFORMATION FOR ALL READERS CANCER THERAPY ADVISOR (CTA) is an up-to-date guide to commonly prescribed pharmaceuticals, as well as certain OTC products. It has been produced to provide an easily accessible reminder of basic information useful to review when prescribing medications, such as specific indications for use, dosage, and a checklist of precautions, interactions, and adverse drug reactions. Reference should always be made to each drug being coadmin istered. The information it contains is intended solely for use by the medical profession. IT IS NOT INTENDED FOR LAY READERS. This reference has been assembled and edited by an experienced staff of pharmacists uti lizing information available from FDA-approved labeling. Distinctions have not necessarily been made between those reactions that are well-documented and/or clinically significant, and those that carry only a theoretical risk. A renowned board of consulting medical specialists has also independently reviewed the product references. However, although every effort is made to assure accuracy, the information in CTA is not necessarily reviewed by the supplier of a particular drug. If any questions arise about information in CTA, the physician should verify it against labeling or by contacting the company marketing the drug. The publisher and editors do not warrant or guarantee any of the products described or the information describing them. THE PUBLISHER AND EDITORS DO NOT ASSUME, AND HEREBY EXPRESSLY DISCLAIM ANY LIABILITY WHATSOEVER FOR ANY ERRORS OR OMISSIONS IN SUCH INFORMATION OR FOR ANY USE OF ANY OF THE PRODUCTS LISTED. No prescription drug should be used except on the advice of, and as directed by, a physician. The training and experience of a physician are essential to forming any opinion on the appropriateness of a specific drug for a specific patient. The information in this publication is not by itself sufficient for a lay person—or even a physician—to evaluate the risks and benefits of taking any particular drug. In reaching professional judgments on whether to prescribe a pharmaceutical, which to prescribe, and under what regimen, the physician should thoroughly understand the options available for any clinical application, the potential effectiveness of each product, and the associated risks and side effects. This knowledge should be considered in light of the special circumstances of the patient, for each patient is unique. No single reference can substitute for medical training and experience. The physician must be familiar with the full product labeling, provided by the manufacturer or distributor of the drug, of every product he or she prescribes, as well as the relevant medical literature. Certain additional qualifications are important in using this book. First, CTA has been deliberately kept concise, with a standardized format, so that it could be a convenient reference tool. This means that lengthy and detailed explanations about certain aspects of drugs commonly found in labeling are omitted or condensed. Second, by revising and reprinting quarterly, CTA should be one of the most up-to-date guides to prescription drugs now available in print. Only the current issue should be used. The prescribing decision is ultimately the responsibility of the physician. CTA is offered to assist physicians in this area. © 2015 Haymarket Media, Inc.

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DRUG MONOGRAPHS

BONE CANCER Methotrexate injection

℞

Bedford

Folic acid antagonist. Methotrexate 25mg/mL; soln for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free. ℞ Also: Methotrexate for injection Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free. Indications: Non-metastatic osteosarcoma in patients who have undergone surgical resection or amputation for the primary tumor (high-dose therapy with leucovorin rescue). Adults: Initially 12g/m2 IV infusion over 4 hours; may be increased to 15g/m2; see literature for leucovorin rescue dosing with high-dose methotrexate. Children: See literature. Contraindications: Pregnancy (Cat.X). Nursing mothers. Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration). Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer. Ulcerative colitis. Infection. Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated. Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin).

Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome). How supplied: Soln (2mL, 4mL, 8mL, 10mL)–10 (single-use vials); pwd (1 gram)–1 (single-use vial)

VOTRIENT GlaxoSmithKline

℞

Kinase inhibitor. Pazopanib 200mg; tabs. Indications: Advanced soft tissue sarcoma in patients who have received prior chemotherapy. Limitation of use: not for treating adipocytic soft tissue sarcoma or gastrointestinal stromal tumors. Adults: Take on an empty stomach. Swallow whole. 800mg once daily. Dose adjustments: see full labeling. Hepatic impairment: moderate: 200mg once daily; severe: not recommended. Concomitant strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin): avoid and consider alternate drug; if warranted, reduce dose of pazopanib to 400mg; may reduce further if toxicity occurs. Concomitant strong CYP3A4 inducers (eg, rifampin): avoid and consider alternate drug. Children: Not established (increased toxicity in developing organs). Warnings/Precautions: Not indicated for use in combination with other cancer agents. Risk of severe and fatal hepatotoxicity. Monitor liver tests before starting and at Weeks 3, 5, 7, and 9, thereafter at Months 3 and 4, then periodically. If ALT between 3×ULN and 8×ULN continue therapy with weekly monitoring until ALT returns to Grade 1 or baseline. If ALT >8×ULN interrupt therapy until ALT returns to Grade 1 or baseline; may consider reintroducing at a reduced dose, measure liver tests weekly for 8 weeks; if ALT>3×ULN recurs, permanently discontinue. Permanently discontinue if ALT>3×ULN and bilirubin >2×ULN. Gilbert’s syndrome (see full labeling). History of QT prolongation. Cardiac dysfunction risk: evaluate LVEF at baseline and periodically; monitor for CHF. Monitor ECG, electrolytes (eg, calcium, magnesium, potassium), thyroid. History of hemoptysis, cerebral, or clinically significant GI hemorrhage in the past 6 months: not recommended. Risk of arterial thrombotic events (within previous 6 months: not recommended). Monitor for VTE, PE, infection, proteinuria (reduce dose if 24-hour urine protein ≥3g), thrombotic microangiopathy, GI perforation or fistula. Monitor BP and

manage hypertension promptly. Discontinue if severe and persistent hypertension (despite antihypertensives and dose reduction), if repeat episodes of proteinuria (despite dose reductions), thrombotic microangiopathy, or serious infection occurs. Stop therapy at least 7 days before surgery; discontinue in patients with wound dehiscence. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: See Adult dosing: Potentiated by strong CYP3A4 inhibitors, grapefruit juice. Avoid concomitant strong Pgp or BCRP inhibitors. Antagonized by strong CYP3A4 inducers. Concomitant drugs with narrow therapeutic windows metabolized by CYP3A4, CYP2D6, or CYP2C8: not recommended. Increased risk of ALT elevations with concomitant simvastatin; caution and monitor closely; follow dosing guidelines or consider alternatives to pazopanib, or discontinuing simvastatin if develops. Separate antacids by several hours. Caution with concomitant drugs that prolong QT interval (eg, antiarrhythmics). Adverse reactions: Diarrhea, hypertension, hair color changes, nausea, anorexia, vomiting, fatigue, decreased weight, decreased appetite, tumor pain, musculoskeletal pain, headache, dysgeusia, dyspnea, skin hypopigmentation; hepatoxicity, QT prolongation, hemorrhagic events, arterial thrombotic events (eg, MI, angina, ischemic stroke, TIA), venous thrombotic events (eg, VTE, PE), GI perforation or fistula, impaired wound healing, hypothyroidism, proteinuria, infection, reversible posterior leukoencephalopathy syndrome (discontinue if occurs). How supplied: Tabs–120

XGEVA Amgen

℞

Osteoclast inhibitor (RANKL inhibitor). Denosumab 120mg/vial (70mg/mL); soln for SC inj; preservative-free. Indications: Treatment of adults and skeletallymature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. Adults: Give by SC inj into upper arm, upper thigh, or abdomen. 120mg once every 4 weeks with additional 120mg doses on Days 8 and 15 of the 1st month of therapy. Children: Not established (interferes with bone growth and dentition). Contraindications: Pre-existing hypocalcemia. Warnings/Precautions: Correct hypocalcemia before starting; ensure adequate daily calcium, magnesium, and Vit.D intake, esp. in renal impairment (CrCl <30mL/min). Monitor calcium,

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DRUG MONOGRAPHS

BONE CANCER phosphorus, magnesium levels in susceptible patients (eg, severe renal impairment, receiving dialysis). Monitor for osteonecrosis of the jaw. Perform oral exam and preventive dentistry before and regularly during therapy. Maintain good oral hygiene. Avoid invasive dental procedures during treatment. Evaluate for atypical fractures if thigh/groin pain develops; consider withholding therapy until risk/benefit

assessment. Pregnancy (Cat.D); use highly effective contraception during therapy, and for at least 5 months after last dose. Nursing mothers: avoid (may impair mammary gland development/ lactation). Interactions: Concomitant other denosumabcontaining products (eg, Prolia): not recommended. Concomitant drugs that can lower calcium levels; monitor.

Adverse reactions: Fatigue, asthenia, hypophosphatemia, nausea, arthralgia, headache, back pain, pain in extremity, dyspnea, decreased appetite, peripheral edema, vomiting, anemia, constipation, diarrhea; osteonecrosis of jaw, severe hypocalcemia (may be fatal), anaphylactic reactions (discontinue if occurs). How supplied: Single-use vial (1.7mL)–1

EMETOGENIC POTENTIAL OF ANTINEOPLASTIC AGENTS High Risk (>90% frequency without antiemetics) AC combination: Doxorubicin or Epirubicin (Ellence) + Cyclophosphamide (Cytoxan) IV Altretamine (HMM, Hexalen) oral Carmustine (BCNU, BiCNU) IV: >250mg/m2

Cisplatin (CDDP) IV Cyclophosphamide (CTX, Cytoxan) IV: >1,500mg/m2 Dacarbazine (DTIC, DTIC-Dome) IV Doxorubicin IV: >60mg/m2

Epirubicin (Ellence) IV: >90mg/m2 Ifosfamide (Ifex) IV: ≥2g/m2 per dose Mechlorethamine (Mustargen) IV Procarbazine (Matulane) oral Streptozocin (Zanosar) IV

Moderate Risk (30–90% frequency without antiemetics) Aldesleukin (IL-2, Proleukin) IV: >12–15 million IU/m2 Amifostine (Ethyol) IV: >300mg/m2 Arsenic trioxide (As2O3, Trisenox) IV Azacitidine (Vidaza) IV Bendamustine (Treanda) IV Busulfan (Busulfex) IV; oral: >4mg/day Carboplatin IV Carmustine (BCNU, BiCNU) IV: ≤250mg/m2 Clofarabine (Clolar) IV

Cyclophosphamide (CTX, Cytoxan) IV: ≤1,500mg/m2 Cyclophosphamide (CTX) oral ≥100mg/m2/day Cytarabine (ARA-C) IV: >200mg/m2 Dactinomycin (Cosmegen) IV Daunorubicin (Cerubidine) IV Doxorubicin IV: ≤60mg/m2 Epirubicin (Ellence) IV: ≤90mg/m2 Estramustine (Emcyt) oral Etoposide (VP-16) oral

Idarubicin (Idamycin) IV Ifosfamide (Ifex) IV: <2g/m2 Interferon alpha (IFN-alfa, Intron A) IV: ≥10 million IU/m2 Irinotecan (CPT-11, Camptosar) IV Lomustine (CCNU, CeeNU) oral Melphalan (L-PAM, Alkeran) IV Methotrexate (MTX) IV: ≥250mg/m2 Oxaliplatin (Eloxatin) IV Temozolomide (Temodar) IV; oral >75mg/ m2/day

Low Risk (10–30% frequency without antiemetics) Aldesleukin (IL-2, Proleukin) IV: ≤12 million IU/m2 Amifostine (Ethyol) IV: ≤300mg Bexarotene (Targretin) oral Cabazitaxel (Jevtana) IV Capecitabine (Xeloda) oral Cyclophosphamide (CTX) oral <100mg/m2/day Cytarabine (ARA-C) IV: 100–200mg/m2 Docetaxel (Taxotere) IV Doxorubicin liposomal (Doxil) IV

Eribulin (Halaven) IV Etoposide (VP-16, Etopophos) IV Floxuridine IV Fludarabine (Fludara) oral Fluorouracil (5-FU) IV Gemcitabine (Gemzar) IV Interferon alpha (IFN-alfa, Intron A) IV: >5–<10 million IU/m2 Ixabepilone (Ixempra) IV Methotrexate (MTX) IV: >50mg/m2 to <250mg/m2

Mitomycin (MTC) IV Mitoxantrone (DHAD) IV Paclitaxel (Taxol) IV Paclitaxel albumin (Abraxane) IV Pemetrexed (Alimta) IV Pentostatin IV Pralatrexate (Folotyn) IV Romidepsin (Istodax) IV Thiotepa IV Topotecan (Hycamtin) IV, oral

Minimal Risk (<10% frequency without antiemetics) Alemtuzumab (Campath) IV Bevacizumab (Avastin) IV Bleomycin IV Bortezomib (Velcade) IV Busulfan (Busulfex) oral: <4mg/day Cetuximab (Erbitux) IV Chlorambucil (Leukeran) oral Cladribine (2-CdA) IV Cytarabine (ARA-C) IV: <100mg/m2 Dasatinib (Sprycel) oral Decitabine (Dacogen) IV Denileukin diftitox (Ontak) IV Dexrazoxane (Totect, Zinecard) IV Erlotinib (Tarceva) oral Everolimus (Afinitor, Zortress) oral Fludarabine (Fludara) IV

Hydroxyurea (Hydrea) oral Imatinib (Gleevec) oral Interferon alpha (IFN-alfa, Intron A) IV: ≤5 million IU/m2 Ipilimumab (Yervoy) IV Lapatinib (Tykerb) oral Lenalidomide (Revlimid) oral Melphalan (L-PAM, Alkeran) oral Mercaptopurine (Purinethol) oral Methotrexate (MTX) IV: ≤50mg/m2; oral Nelarabine (Arranon) IV Niltoinib (Tasigna) oral Ofatumumab (Arzerra) IV Panitumumab (Vectibix) IV Pazopanib (Votrient) oral Pegasparagase (Oncaspar) IV

Peginterferon IV Rituximab (Rituxan) IV Sorafenib (Nexavar) oral Sunitinib (Sutent) oral Temsirolimus (Torisel) IV Temozolamide (Temodar) oral: ≤75mg/m2/day Thalidomide (Thalomid) oral Thioguanine (6-TG, Tabloid) oral Trastuzumab (Herceptin) IV Tretinoin (Vesanoid) oral Valrubicin (Valstar) IV Vandetanib (Caprelsa) oral Vinblastine (VLB) IV Vincristine (VCR) IV Vinorelbine (Navelbine) IV Vorinostat (Zolinza) oral

Daily use of antiemetics is not recommended based on clinical experience.

References

Adapted from: 1. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update 2006. J Clin Oncol 2006;24:2932–2947. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology; v.1.2012: Antiemesis. (Rev. 6/2014) Available at: http://www.nccn.org/professionals/physician_gls/PDF/antiemesis.pdf. Accessed August 8, 2012.

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DRUG MONOGRAPHS

BRAIN CANCER AFINITOR Novartis

℞

mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs. ℞ Also: AFINITOR DISPERZ Everolimus 2mg, 3mg, 5mg; tabs for oral susp. Indications: Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) in adults and children who require therapeutic intervention but are not candidates for curative surgical resection. Adults and Children: <1yr: not recommended. Swallow tabs whole with water or use Disperz tabs administered as a suspension only. Take at the same time each day either consistently with or without food. Prepare suspension using 5mL of water in an oral syringe or 25mL of water in a drinking glass; max 10mg dose per syringe or glass. ≥1yrs: initially 4.5mg/m2 once daily. Do not combine the 2 dosage forms to achieve the desired total dose. Use therapeutic drug monitoring to guide subsequent dosing. Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5–15ng/mL (see full labeling). Severe hepatic impairment: initiate at 2.5mg/m2 once daily. Concomitant strong CYP3A4/PgP inhibitors: avoid; moderate CYP3A4/PgP inhibitors: initiate at 2.5mg/m2 once daily, if CYP3A4/PgP inhibitor discontinued, after 2–3 days, return to dose used prior to initiating moderate inhibitor. Concomitant strong CYP3A4 inducers: avoid, if required, then initiate at 9mg/m2 once daily; if discontinued, then return to dose used prior to initiating strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions, or others: see full labeling. Contraindications: Allergy to other rapamycin derivatives. Warnings/Precautions: Monitor for new or worsening respiratory symptoms. Increased risk of infections; some may be severe or fatal; monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines. Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg,

ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used. Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid. Adverse reactions: Pneumonitis (interrupt, reduce dose and/or manage with corticosteroids; if severe, discontinue; may reintroduce daily dose at approx. 50% lower than previously administered), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with non-alcoholic, non-peroxide mouthwash), diarrhea, nausea, abdominal pain, rash, fatigue, edema, fever, asthenia, cough, headache, decreased appetite; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; proteinuria, renal failure, others (see full labeling). How supplied: Tabs, Disperz–28 (4 blister cards × 7 tabs)

AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free. Indications: Glioblastoma, as a single agent for patients with progressive disease following prior therapy. Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins. 10mg/kg every 2 weeks. Children: Not established. Warnings/Precautions: Risk of GI perforations, surgery and wound healing complications, and hemorrhage. Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). Do not administer if recent history of hemoptysis of ≥ ½-teaspoon of red blood. Permanently discontinue if GI perforation, tracheoesophageal fistula, any grade 4 fistula, or grade 4 venous thromboembolic event. Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior reversible encephalopathy syndrome, or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe

proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction. History of arterial thromboembolism. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection. Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis; GI perforation and fistulae, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure, neutropenia, and infection. How supplied: Single-use vial–1

TEMODAR Merck

℞

Alkylating agent. Temozolomide 5mg, 20mg, 100mg, 140mg, 180mg, 250mg; caps. ℞ Also: TEMODAR INJECTION Temozolomide 100mg; per vial; lyophilized pwd for IV infusion after reconstitution; contains mannitol. Indications: Newly diagnosed glioblastoma multiforme. Refractory anaplastic astrocytoma. Adults: See full labeling for monitoring and dose adjustment guidelines. IV: Infuse over 90 mins. Oral caps: Swallow whole with water; take on empty stomach at bedtime to reduce nausea, pretreat with antiemetics. Glioma: Concomitant phase, for newly diagnosed: 75mg/m2 daily for 42 days with focal radiotherapy; Maintenance phase, Cycle 1: 150mg/m2 once daily for 5 consecutive days, then 23 days off; for Cycles 2 through 6: increase to 200mg/m2 once daily for 5 consecutive days if tolerated, then 23 days off. Anaplastic astrocytoma: 150mg/m2 once daily for 5 consecutive days per 28-day treatment cycle; increase dose in subsequent cycles to 200mg/m2 if tolerated; continue until disease progression, discontinue if minimum dose not tolerated. Children: Not established. Contraindications: Hypersensitivity to dacarbazine. Warnings/Precautions: Myelosuppression (higher risk in women or elderly, esp. in 1st cycle). Do not begin therapy unless hematology (ANC and platelets) is acceptable. Do CBC prior to treatment initiation and on Day 22 of each cycle or within 48 hours of that day; repeat weekly

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DRUG MONOGRAPHS

BRAIN CANCER until recovery if ANC or platelets fall below acceptable limits. Perform LFTs at baseline, midway through Cycle 1, prior to each subsequent cycle, and 2–4wks after last dose. Glioblastoma: monitor for and provide prophylaxis against P. carinii pneumonia (PCP). Severe renal or hepatic impairment. Avoid inhalation, and skin/ mucous membrane contact, of capsule contents.

Elderly. Pregnancy (Cat.D), nursing mothers: not recommended. See full labeling. Interactions: Valproic acid may increase temozolomide levels. Concomitant carbamazepine, phenytoin, sulfamethoxazole/trimethoprim may complicate myelosuppression assessment. Adverse reactions: Alopecia, fatigue, nausea, vomiting, anorexia, constipation, headache,

convulsions, rash, hemiparesis, diarrhea, asthenia, fever, dizziness, abnormal coordination, viral infection, amnesia, insomnia, edema; myelosuppression (may be dose-limiting; see full labeling), hepatotoxicity; others. How supplied: Caps 5mg, 20mg, 100mg, 140mg 180mg–5, 14; 250mg–5; Single-use vials–1

HIGH-ALERT MEDICATIONS High-alert medications are drugs that bear a heightened risk of causing significant patient harm when they are used in error. Although mistakes may or may not be more common with these drugs, the consequences of an error are clearly more devastating to patients. This list may be used to determine which medications require special safeguards to reduce the risk of errors. This may include strategies such as standardizing the ordering, storage, preparation, and administration of these products;

improving access to information about these drugs; limiting access to high-alert medications; using auxiliary labels and automated alerts; and employing redundancies such as automated or independent doublechecks when necessary. (Note: manual independent double-checks are not always the optimal error-reduction strategy and may not be practical for all of the medications on the list).

SPECIFIC MEDICATIONS Epinephrine, subcutaneous

Oxytocin, IV

Epoprostenol (Flolan), IV

Nitroprusside sodium for injection

Insulin U-500 (special emphasis)

Potassium chloride for injection concentrate

Magnesium sulfate injection

Potassium phosphates injection

Methotrexate, oral, non-oncologic use

Promethazine, IV

Opium tincture

Vasopressin, IV or intraosseous

CLASSES/CATEGORIES OF MEDICATIONS Adrenergic agonists, IV (eg, epinephrine, phenylephrine, norepinephrine) Adrenergic antagonists, IV (eg, propranolol, metoprolol, labetalol) Anesthetic agents, general, inhaled and IV (eg, propofol, ketamine) Antiarrhythmics, IV (eg, lidocaine, amiodarone) Antithrombotic agents, including: • Anticoagulants (eg, warfarin, low-molecular-weight heparin, IV unfractionated heparin) • Factor Xa inhibitors (eg, fondaparinux, apixaban, rivaroxaban)

• Direct thrombin inhibitors (eg, argatroban, bivalirudin, dabigatran etexilate) • Thrombolytics (eg, alteplase, reteplase, tenecteplase) • Glycoprotein IIb/IIIa inhibitors (eg, eptifibatide)

Cardioplegic solutions Chemotherapeutic agents, parenteral and oral Dextrose, hypertonic, (20% or greater) Dialysis solutions, peritoneal and hemodialysis Epidural or intrathecal medications Hypoglycemics, oral Inotropic medications, IV (eg, digoxin, milrinone) Insulin, subcutaneous and IV Liposomal forms of drugs (eg, liposomal amphotericin B) and conventional counterparts (eg, amphotericin B desoxycholate) Moderate sedation agents, IV (eg, dexmedetomidine, midazolam) Moderate sedation agents, oral, for children (eg, chloral hydrate) Narcotics/opioids IV, transdermal, oral (including liquid concentrates, immediate and sustained-release forms) Neuromuscular blocking agents (eg, succinylcholine, rocuronium, vecuronium) Parenteral nutrition preparations Radiocontrast agents, IV Sterile water for injection, inhalation, and irrigation (excluding pour bottles) in containers of 100mL or more Sodium chloride for injection, hypertonic, greater than 0.9% concentration Notes Based on error reports submitted to the Institute of Safe Medication Practices (ISMP) National Medication Errors Reporting Program, reports of harmful errors in the literature, and input from practitioners and safety experts, ISMP created and periodically updates a list of potential high-alert medications. During May and June 2014, practitioners responded to an ISMP survey designed to identify which medications were most frequently considered high-alert drugs by individuals and organizations. Further, to assure relevance and completeness, the clinical staff at ISMP, members of the ISMP advisory board, and safety experts throughout the US were asked to review the potential list. This list of drugs and drug categories reflects the collective thinking of all who provided input. References Source: Institute for Safe Medication Practices. High-Alert Medications. 2014. Available at: http://www.ismp.org/Tools/institutionalhighAlert.asp

(Rev. 11/2014)

4 CANCER THERAPY ADVISOR | MARCH/APRIL 2015 | CancerTherapyAdvisor.com

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DRUG MONOGRAPHS

BREAST CANCER ABRAXANE Celgene

℞

Taxane antimicrotubule. Paclitaxel [bound to albumin (human)] 100mg/vial; pwd for IV infusion after reconstitution; solvent-free. Indications: Treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy (prior therapy should have included an anthracycline unless clinically contraindicated). Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3. 260mg/m2 by IV infusion over 30 minutes every 3 weeks. If severe neutropenia (neutrophil <500 cells/mm3 for ≥1week) or severe sensory neuropathy occurs: reduce subsequent doses to 220mg/m2; reduce to 180mg/m2 if severe neutropenia or sensory neuropathy recurs. If grade 3 sensory neuropathy occurs, suspend use until resolution to grade 1 or 2; reduce subsequent doses. Hepatic impairment: see full labeling. Avoid extravasation. Children: Not evaluated. Contraindications: Baseline neutrophil count <1,500 cells/mm3. Prior severe hypersensitivity reaction (do not rechallenge). Warnings/Precautions: Do not substitute for, or with, other paclitaxel products (due to formulation differences). Do frequent complete blood cell counts. Monitor for sensory neuropathy, sepsis, or pneumonitis. Hepatic or renal dysfunction. Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: May potentiate or be potentiated by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir). Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events. How supplied: Single-use vial–1

AFINITOR Novartis mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs. Indications: Postmenopausal women with advanced hormone receptor-positive, HER2-

℞

negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated. Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risk. Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor. Concomitant strong CYP3A4/PgP inducers: consider doubling the daily dose by increments of 5mg or less. If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions, or others: see full labeling. Children: Not recommended. Contraindications: Allergy to other rapamycin derivatives. Warnings/Precautions: Monitor for new or worsening respiratory symptoms. Increased risk of infections; some may be severe or fatal; monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines. Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used. Antagonized by

strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid. Adverse reactions: Pneumonitis (interrupt, reduce dose and/or manage with corticosteroids; if severe, discontinue; may reintroduce daily dose at approx. 50% lower than previously administered), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with non-alcoholic, non-peroxide mouthwash), diarrhea, nausea, abdominal pain, rash, fatigue, edema, fever, asthenia, cough, headache, decreased appetite; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; proteinuria, renal failure, others (see full labeling). How supplied: Tabs–28 (4 blister cards × 7 tabs)

ARIMIDEX AstraZeneca

℞

Aromatase inhibitor. Anastrozole 1mg; tabs. Indications: In postmenopausal women: adjuvant treatment of hormone receptor-positive early breast cancer; first-line treatment of hormone receptor-positive or unknown locally advanced or metastatic breast cancer; advanced breast cancer with disease progression after tamoxifen therapy. Adults: 1mg once daily. Advanced disease: continue until tumor progression. Children: Not applicable. Contraindications: Women who are or may become pregnant. Pregnancy (Cat.X). Warnings/Precautions: Pre-existing ischemic heart disease. Severe hepatic impairment. Monitor bone mineral density, cholesterol. Nursing mothers: not recommended. Interactions: Antagonized by tamoxifen, estrogens; do not give concomitantly. Adverse reactions: Hot flashes, asthenia, arthritis, pain, arthralgia, pharyngitis, hypertension, depression, nausea, vomiting, rash, osteoporosis, fractures, back pain, insomnia, headache, peripheral edema, lymphedema, dyspnea, dizziness, paresthesia, vaginal bleeding, cough, hypercholesterolemia. How supplied: Tabs–30

AROMASIN Pfizer

℞

Aromatase inactivator. Exemestane 25mg; tabs. Indications: In postmenopausal women: adjuvant treatment of estrogen-receptor positive early breast cancer after 2–3yrs of tamoxifen therapy to complete a total of 5yrs of hormonal therapy; advanced breast cancer with disease progression after tamoxifen therapy.

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DRUG MONOGRAPHS

BREAST CANCER Adults: Give after a meal. 25mg once daily. Concomitant strong CYP3A4 inducers (see Interactions): 50mg once daily. Children: Not established. Contraindications: Pregnancy (Cat.X). Premenopausal women. Warnings/Precautions: Hepatic or renal insufficiency. Osteoporosis; assess bone mineral density (BMD) at start of treatment. Monitor all patients for BMD loss and treat as appropriate. Perform routine assessment of Vit. D levels prior to initiation; supplement if deficient. Nursing mothers: not recommended. Interactions: Antagonized by strong CYP3A4 inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort). Adverse reactions: Hot flashes, fatigue, arthralgia, headache, insomnia, increased sweating, nausea, increased appetite; reductions in bone mineral density. How supplied: Tabs–30

ESTRACE Warner Chilcott

℞

Estrogen. Estradiol 0.5mg, 1mg, 2mg+; scored tabs; +contains tartrazine. Indications: Palliative treatment of metastatic breast cancer in select patients (see literature). Adults: 10mg 3 times daily for at least 3 months. Children: Not applicable. Contraindications: Thrombophlebitis. Thromboembolic disorders. Cerebrovascular disorders. Abnormal undiagnosed genital bleeding. Estrogen-depended neoplasias. Liver dysfunction or disease. Pregnancy (Cat.X). Warnings/Precautions: Asthma (2mg tabs). Hepatic dysfunction. Conditions aggravated by fluid retention. Cardiovascular disorders, arterial vascular disease, and risks factors (eg, hypertension, diabetes, obesity, SLE). Familial hyperlipoprotenemia. Monitor BP. Discontinue if jaundice occurs and before prolonged immobilization (eg, surgery). Nursing mothers. Adverse reactions: See literature. GI upset, headache, hypertension, edema, hypercalcemia, gallbladder or thromboembolic disease, gynecomastia, impotence, impaired glucose tolerance. How supplied: Tabs–100

EVISTA Lilly

℞

Selective estrogen receptor modulator (SERM). Raloxifene HCl 60mg; tabs. Indications: Reduction in risk of invasive breast cancer in postmenopausal women: with osteoporosis and/or at high risk for invasive breast cancer. Adults: 60mg once daily. Children: Not recommended. Contraindications: Active or history of venous thromboembolic events. Nursing mothers. Pregnancy (Cat.X). Women who may become pregnant.

Warnings/Precautions: Not for use in premenopausal women. Concomitant systemic estrogen therapy: not recommended. Discontinue 72 hours before, and during prolonged immobilization; resume when fully ambulatory. Coronary heart disease or risk of coronary event (increased risk of death due to stroke). Hepatic dysfunction. Moderate to severe renal impairment. Interactions: May antagonize warfarin; monitor. Avoid concomitant cholestyramine, other anion exchange resins. Caution with other highly protein-bound drugs (eg, diazepam, diazoxide, lidocaine). Adverse reactions: Hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, sweating; rare: venous thromboembolic events. How supplied: Tabs–30, 100, 2000

FASLODEX AstraZeneca

℞

Estrogen receptor antagonist. Fulvestrant 50mg/mL; soln for IM inj. Indications: Hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Adults: Give by IM inj slowly (1–2 mins/ injection). 500mg (as two 5mL injections, one in each buttock) on days 1, 15, 29, then once per month thereafter. Moderate hepatic impairment: 250mg (as one 5mL injection) on days 1, 15, 29, then once per month thereafter. Children: Not applicable. Warnings/Precautions: Bleeding diatheses, thrombocytopenia, or anticoagulant use. Moderate to severe hepatic impairment. Pregnancy (Cat.D; avoid); exclude pregnancy before starting. Nursing mothers: not recommended. Adverse reactions: Inj site pain, GI upset, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, constipation; increased hepatic enzymes, hypersensitivity reactions. How supplied: Prefilled syringe kit (2 × 5mL)–1

FEMARA Novartis

℞

Aromatase inhibitor. Letrozole 2.5mg; tabs. Indications: In postmenopausal women: Adjuvant treatment of hormone receptor positive early breast cancer; Extended adjuvant treatment of early breast cancer after 5 years of adjuvant tamoxifen therapy; First-line treatment of hormone receptor positive or unknown, locally advanced or metastatic breast cancer; Treatment of advanced breast cancer with disease progression following antiestrogen therapy. Adults: 2.5mg once daily. Continue until tumor progression is evident. Adjuvant or extended adjuvant therapy: treat for at least 24 months (see literature). Severe hepatic impairment or cirrhosis: 2.5mg every other day. Children: Not applicable.

Contraindications: Women of premenopausal endocrine status. Pregnancy (Cat.X). Warnings/Precautions: Severe renal or hepatic impairment. Monitor bone mineral density, serum cholesterol. Nursing mothers. Adverse reactions: Pain (bone, musculoskeletal, and others), hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, sweating increased, GI upset, fatigue, dyspnea, cough, insomnia, hypertension, alopecia, anorexia, weight changes, hypercalcemia, pleural effusion, vertigo; thromboembolic or cardio- or cerebrovascular events (rare). How supplied: Tabs–30

Fluorouracil (various)

℞

Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj. Indications: Palliative management of carcinoma of the breast. Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs. Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/ week. Poor risk patients: see literature for dose adjustments. Children: Not recommended. Contraindications: Poor nutritional state. Depressed bone marrow function. Potentially serious infections. Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of highdose pelvic irradiation. Previous use of alkylating agents. Widespread involvement of bone marrow by metastatic tumors. Renal or hepatic impairment. Discontinue if signs of toxicity appear (eg, stomatitis, esophagopharyngitis, leukopenia, intractable vomiting, diarrhea, GI ulceration or bleeding, thrombocytopenia, hemorrhage). Monitor WBCs with differential before each dose. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Potentiated by leucovorin. Adverse reactions: Stomatitis, esophagopharyngitis, GI upset, anorexia, leukopenia, alopecia, dermatitis, hand-foot syndrome; others. Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase). How supplied: Contact supplier.

HALAVEN Eisai

℞

Non-taxane microtubule dynamics inhibitor. Eribulin mesylate 0.5mg/mL, soln for IV inj. Indications: Treatment of metastatic breast cancer in patients who have previously received

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NOW APPROVED

FDA-approved for Use in the First-line Setting IBRANCE is a kinase inhibitor indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

For more information, please visit www.IbranceHCP.com

Important Safety Information Neutropenia: Neutropenia is frequently reported with IBRANCE therapy. In the randomized phase II study, Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole. Febrile neutropenia can occur. Monitor complete blood count prior to starting IBRANCE and at the beginning of each cycle, as well as Day 14 of the ﬁrst two cycles, and as clinically indicated. For patients who experience Grade 3 neutropenia, consider repeating the complete blood count monitoring 1 week later. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Infections: Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole (55%) compared with letrozole alone (34%). Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole vs no patients treated with letrozole alone. Monitor patients for signs and symptoms of infection and treat as medically appropriate.

Pulmonary embolism (PE): PE has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone. Monitor patients for signs and symptoms of PE and treat as medically appropriate. Pregnancy and lactation: Based on the mechanism of action, IBRANCE can cause fetal harm. Advise females with reproductive potential to use effective contraception during therapy with IBRANCE and for at least 2 weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with IBRANCE. Advise women not to breastfeed while on IBRANCE therapy because of the potential for serious adverse reactions in nursing infants from IBRANCE. Additional hematologic abnormalities: Decreases in hemoglobin (83% vs 40%), leukocytes (95% vs 26%), lymphocytes (81% vs 35%), and platelets (61% vs 16%) occurred at a higher rate in patients treated with IBRANCE plus letrozole vs letrozole alone.

Please see additional Important Safety Information and Brief Summary on the following pages.

Art: Palbociclib-Now-Approved-Corner-Curve_WB_4C_RW.ai (Up to Date), Palbociclib-Now-Approved-Corner-Curve_CW_4C_RW.ai (Up to Date), IBRANCE_LOGO_No_Icon_4C.ai (Up to Date)

CODE: IBR-15-3

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SAP #: S.TEMP.02585

BLEED: 8.5” x 11.125”

ADVERSE REACTIONS Clinical Studies Experience. Because clinical trials are conducted under varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. The safety of IBRANCE (125 mg/day) plus letrozole (2.5 mg/day) versus letrozole alone was evaluated in Study 1. The data described below reflect exposure to IBRANCE in 83 out of 160 patients with ER-positive, HER2-negative advanced breast cancer who received at least 1 dose of treatment in Study 1. The median duration of treatment for palbociclib was 13.8 months while the median duration of treatment for letrozole on the letrozole-alone arm was 7.6 months. Dose reductions due to an adverse reaction of any grade occurred in 38.6% of patients receiving IBRANCE plus letrozole. No dose reduction was allowed for letrozole in Study 1. Permanent discontinuation due to an adverse event occurred in 7 of 83 (8%) patients receiving IBRANCE plus letrozole, and in 2 of 77 (3%) patients receiving letrozole alone. Adverse reactions leading to discontinuation for those patients receiving IBRANCE plus letrozole included neutropenia (6%), asthenia (1%), and fatigue (1%). The most common adverse reactions (≥10%) of any grade reported in patients in the IBRANCE plus letrozole arm were neutropenia, leukopenia, fatigue, anemia, upper respiratory infection, nausea, stomatitis, alopecia, diarrhea, thrombocytopenia, decreased appetite, vomiting, asthenia, peripheral neuropathy, and epistaxis. The most frequently reported serious adverse reactions in patients receiving IBRANCE plus letrozole were pulmonary embolism (3 of 83; 4%) and diarrhea (2 of 83; 2%). An increased incidence of infections events was observed in the palbociclib plus letrozole arm (55%) compared to the letrozole alone arm (34%). Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases were observed in Study 1. Grade ≥3 neutropenia was managed by dose reductions and/or dose delay or temporary discontinuation consistent with a permanent discontinuation rate of 6% due to neutropenia [see Dosage and Administration]. The following table presents adverse drug reactions (≥10%) reported in patients who received IBRANCE plus letrozole or letrozole alone. Adverse Reactions* (≥10%) in Study 1 IBRANCE + Letrozole (N=83) Letrozole Alone (N=77) System Organ Class All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Any Adverse Drug Reaction (%) (%) (%) (%) (%) (%) Infections and infestations URIa 31 1 0 18 0 0 Blood and lymphatic system disorders Neutropenia 75 48 6 5 1 0 Leukopenia 43 19 0 3 0 0 Anemia 35 5 1 7 1 0 Thrombocytopenia 17 2 0 1 0 0 Metabolism and nutrition disorders Decreased appetite 16 1 0 7 0 0 Nervous system disorders b Peripheral neuropathy 13 0 0 5 0 0 Respiratory, thoracic, and mediastinal disorders Epistaxis 11 0 0 1 0 0 Gastrointestinal disorders c Stomatitis 25 0 0 7 1 0 Nausea 25 2 0 13 1 0 Diarrhea 21 4 0 10 0 0 Vomiting 15 0 0 4 1 0 Skin and subcutaneous tissue disorders Alopecia 22d N/A N/A 3e N/A N/A General disorders and administration site conditions Fatigue 41 2 2 23 1 0 Asthenia 13 2 0 4 0 0

*Adverse Reaction rates reported in the table include all reported events regardless of causality. Grading according to CTCAE Version 3.0. CTCAE=Common Terminology Criteria for Adverse Events; N=number of subjects; N/A=not applicable; URI=Upper respiratory infection. a URI includes: Influenza, Influenza like illness, Laryngitis, Nasopharyngitis, Pharyngitis, Rhinitis, Sinusitis, Upper respiratory tract infection. b Peripheral neuropathy includes: Neuropathy peripheral, Peripheral sensory neuropathy. c Stomatitis includes: Aphthous stomatitis, Cheilitis, Glossitis, Glossodynia, Mouth ulceration, Mucosal inflammation, Oral pain, Oropharyngeal discomfort, Oropharyngeal pain, Stomatitis. d Grade 1 events - 21%; Grade 2 events - 1%. e Grade 1 events - 3%. Laboratory Abnormality for Patients in Study 1 Laboratory Abnormality White blood cells decreased Neutrophils decreased Lymphocytes decreased Hemoglobin decreased Platelets decreased N=number of patients.

IBRANCE + Letrozole (N=83) Letrozole Alone (N=77) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%) 95 44 0 26 0 0 94 57 5 17 3 0 81 17 1 35 3 0 83 5 1 40 3 0 61 3 0 16 3 0

DRUG INTERACTIONS Effect of CYP3A Inhibitors. Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%. Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, verapamil, and voriconazole). Avoid grapefruit or grapefruit juice during IBRANCE treatment. If

Art: PFZ- Pfizer Oncology-POS.ai (Up to Date), PFZ- Pfizer-POS.ai (Up to Date)

coadministration of IBRANCE with a strong CYP3A inhibitor cannot be avoided, reduce the dose of IBRANCE [see Dosage and Administration and Clinical Pharmacology]. Effect of CYP3A Inducers. Coadministration of a strong CYP3A inducer (rifampin) decreased the plasma exposure of palbociclib in healthy subjects by 85%. Avoid concomitant use of strong CYP3A inducers (e.g., phenytoin, rifampin, carbamazepine and St John’s Wort) [see Clinical Pharmacology]. Coadministration of moderate CYP3A inducers may also decrease the plasma exposure of IBRANCE. Avoid concomitant use of moderate CYP3A inducers (e.g., bosentan, efavirenz, etravirine, modafinil, and nafcillin) [see Clinical Pharmacology]. Drugs That May Have Their Plasma Concentrations Altered by Palbociclib. Coadministration of midazolam with multiple doses of IBRANCE increased the midazolam plasma exposure by 61%, in healthy subjects, compared with administration of midazolam alone. The dose of the sensitive CYP3A substrate with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus and tacrolimus) may need to be reduced as IBRANCE may increase their exposure [see Clinical Pharmacology]. USE IN SPECIFIC POPULATIONS Pregnancy. Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology]. In animal studies, palbociclib was teratogenic and fetotoxic at maternal exposures that were ≥4 times the human clinical exposure based on AUC at the recommended human dose. There are no available human data informing the drug-associated risk. Advise pregnant women of the potential risk to a fetus. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies. Lactation. There are no data on the presence of palbociclib in human milk, the effects of IBRANCE on the breastfed child, or the effects of IBRANCE on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from IBRANCE, advise a nursing woman to discontinue breastfeeding during treatment with IBRANCE. Females and Males of Reproductive Potential. Advise females of reproductive potential to use effective contraception during treatment with IBRANCE and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Use in Specific Populations]. Based on findings in animals, male fertility may be compromised by treatment with IBRANCE [see Carcinogenesis, Mutagenesis, Impairment of Fertility]. Pediatric Use. The safety and efficacy of IBRANCE in pediatric patients have not been studied. Geriatric Use. Of 84 patients who received IBRANCE in Study 1, 37 patients (44%) were ≥65 years of age and 8 patients (10%) were ≥75 years of age. No overall differences in safety or effectiveness of IBRANCE were observed between these patients and younger patients but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment. Based on a population pharmacokinetic analysis that included 183 patients, where 40 patients had mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with moderate or severe hepatic impairment (total bilirubin >1.5 × ULN and any AST) [see Clinical Pharmacology]. Renal Impairment. Based on a population pharmacokinetic analysis that included 183 patients, where 73 patients had mild renal impairment (60 mL/min ≤ CrCl <90 mL/min) and 29 patients had moderate renal impairment (30 mL/min ≤ CrCl <60 mL/min), mild and moderate renal impairment had no effect on the exposure of palbociclib. The pharmacokinetics of palbociclib have not been studied in patients with severe renal impairment [see Clinical Pharmacology]. OVERDOSAGE There is no known antidote for IBRANCE. The treatment of overdose of IBRANCE should consist of general supportive measures. PATIENT COUNSELING INFORMATION • Advise patients to immediately report any signs or symptoms of myelosuppression or infection, such as fever, chills, dizziness, shortness of breath, weakness or any increased tendency to bleed and/or to bruise [see Warnings and Precautions]. • Advise patients to immediately report any signs or symptoms of pulmonary embolism, such as shortness of breath, chest pain, tachypnea, and tachycardia [see Warnings and Precautions]. • Advise patients to take IBRANCE with food and swallow IBRANCE capsules whole. • IBRANCE may interact with grapefruit. Patients should not consume grapefruit products while on treatment with IBRANCE. • Inform patients to avoid strong CYP3A inhibitors and strong CYP3A inducers. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact. • Advise females of reproductive potential to use effective contraception during IBRANCE therapy and for at least two weeks after the last dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with IBRANCE [see Warnings and Precautions and Use in Specific Populations]. Rx only Issued: February 2015 ULN=upper limit of normal. 678307-01 © 2015 Pfizer Inc. All rights reserved. February 2015

U.S. Pharmaceuticals

CODE: IBR-15-2

Delivery Support: 212.237.7000

PRODUCTION: Roseann Panariello

LIVE: 7” x 10”

DESCRIPTION: Ibrance Now Approved 3 Page Journal Ad

PUB/POST: Ibrance Now Approved 3 Page

WORKORDER #: 007130

TRIM: 7.75” x 10.5”

FILE: 02A-007130-01C-819867-IBRANCE-JOURNAL-ADS.indd

SAP #: S.TEMP.02585

BLEED: 8.5” x 11.125”

Important Safety Information (cont.) Adverse reactions: The most common all causality adverse reactions (≥10%) of any grade reported in patients treated with IBRANCE® (palbociclib) plus letrozole vs letrozole alone in the phase II study included neutropenia (75% vs 5%), leukopenia (43% vs 3%), fatigue (41% vs 23%), anemia (35% vs 7%), upper respiratory infection (31% vs 18%), nausea (25% vs 13%), stomatitis (25% vs 7%), alopecia (22% vs 3%), diarrhea (21% vs 10%), thrombocytopenia (17% vs 1%), decreased appetite (16% vs 7%), vomiting (15% vs 4%), asthenia (13% vs 4%), peripheral neuropathy (13% vs 5%), and epistaxis (11% vs 1%). Grade 3/4 adverse reactions reported (≥10%) occurring at a higher incidence in the IBRANCE plus letrozole vs letrozole alone group include neutropenia (54% vs 1%) and leukopenia (19% vs 0%). The most frequently reported serious adverse events in patients receiving IBRANCE were pulmonary embolism (4%) and diarrhea (2%). General dosing information: The recommended dose of IBRANCE is 125 mg taken orally once daily for 21 days followed by 7 days off treatment in 28-day cycles. IBRANCE should be taken with food and in combination with letrozole 2.5 mg once daily continuously. Patients should be encouraged to take their dose at approximately the same time each day. Capsules should be swallowed whole. No capsule should be ingested if it is broken, cracked, or otherwise not intact. If a patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. Management of some adverse reactions may require temporary dose interruption/delay and/or dose reduction, or permanent discontinuation. Dose modiﬁcation of IBRANCE is recommended based on individual safety and tolerability. Drug interactions: Avoid concurrent use of strong CYP3A inhibitors. If patients must be administered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg/day. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor. Grapefruit or grapefruit juice may increase plasma concentrations of IBRANCE and should be avoided. Avoid concomitant use of strong and moderate CYP3A inducers. The dose of the sensitive CYP3A substrates with a narrow therapeutic index may need to be reduced as IBRANCE may increase their exposure. Hepatic and renal impairment: IBRANCE has not been studied in patients with moderate to severe hepatic impairment or in patients with severe renal impairment (CrCl <30 mL/min). Brief Summary of Prescribing Information

Dose Modification and Management – Non-Hematologic Toxicities

IBRANCE (palbociclib) capsules Initial US Approval: 2015

CTCAE Grade Grade 1 or 2

INDICATIONS AND USAGE IBRANCE is indicated in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as initial endocrine-based therapy for their metastatic disease. This indication is approved under accelerated approval based on progression-free survival (PFS) [see Clinical Studies]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. DOSAGE AND ADMINISTRATION General Dosing Information. The recommended dose of IBRANCE is a 125 mg capsule taken orally once daily for 21 consecutive days followed by 7 days off treatment to comprise a complete cycle of 28 days. IBRANCE should be taken with food in combination with letrozole 2.5 mg once daily given continuously throughout the 28-day cycle. [see Clinical Pharmacology]. Patients should be encouraged to take their dose at approximately the same time each day. If the patient vomits or misses a dose, an additional dose should not be taken that day. The next prescribed dose should be taken at the usual time. IBRANCE capsules should be swallowed whole (do not chew, crush or open them prior to swallowing). No capsule should be ingested if it is broken, cracked, or otherwise not intact. Dose Modification. Dose modification of IBRANCE is recommended based on individual safety and tolerability. Management of some adverse reactions [see Warnings and Precautions] may require temporary dose interruptions/delays and/or dose reductions, or permanent discontinuation. If dose reduction is required the first recommended dose reduction is 100 mg/day and the second dose reduction is 75 mg/day. If further dose reduction below 75 mg/day is required, discontinue the treatment. Dose Modification and Managementa – Hematologic Toxicities CTCAE Grade

Dose Modifications

Grade 1 or 2

No dose adjustment is required.

Grade 3b

No dose adjustment is required. Consider repeating complete blood count monitoring one week later. Withhold initiation of next cycle until recovery to Grade ≤2.

Grade 3 ANC (<1000 to 500/mm3) + Fever ≥38.5ºC and/or infection

Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2 (≥1000/mm3). Resume at next lower dose

Grade 4b

Withhold IBRANCE and initiation of next cycle until recovery to Grade ≤2. Resume at next lower dose.

Grading according to CTCAE Version 4.0. ANC=absolute neutrophil count; CTCAE=Common Terminology Criteria for Adverse Events. a Monitor complete blood count prior to the start of IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. b Except lymphopenia (unless associated with clinical events, e.g., opportunistic infections).

Art: None

Grade ≥3 non-hematologic toxicity (if persisting despite medical treatment)

Dose Modifications No dose adjustment is required. Withhold until symptoms resolve to: • Grade ≤1; • Grade ≤2 (if not considered a safety risk for the patient) Resume at the next lower dose.

See manufacturer’s prescribing information for the coadministered product, letrozole, dose adjustment guidelines in the event of toxicity and other relevant safety information or contraindications. Dose Modifications for Use With Strong CYP3A Inhibitors. Avoid concomitant use of strong CYP3A inhibitors and consider an alternative concomitant medication with no or minimal CYP3A inhibition. If patients must be coadministered a strong CYP3A inhibitor, reduce the IBRANCE dose to 75 mg once daily. If the strong inhibitor is discontinued, increase the IBRANCE dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor [see Drug Interactions and Clinical Pharmacology]. DOSAGE FORMS AND STRENGTHS 125 mg capsules: opaque hard gelatin capsules, size 0, with caramel cap and body, printed with white ink “Pfizer” on the cap, “PBC 125” on the body. 100 mg capsules: opaque hard gelatin capsules, size 1, with caramel cap and light orange body, printed with white ink “Pfizer” on the cap, “PBC 100” on the body. 75 mg capsules: opaque hard gelatin capsules, size 2, with light orange cap and body, printed with white ink “Pfizer” on the cap, “PBC 75” on the body. CONTRAINDICATIONS: None WARNINGS AND PRECAUTIONS Neutropenia. Decreased neutrophil counts have been observed in clinical trials with IBRANCE. Grade 3 (57%) or 4 (5%) decreased neutrophil counts were reported in patients receiving IBRANCE plus letrozole in the randomized clinical trial (Study 1). Median time to first episode of any grade neutropenia per laboratory data was 15 days (13-117 days). Median duration of Grade ≥3 neutropenia was 7 days [see Adverse Reactions]. Febrile neutropenia events have been reported in the IBRANCE clinical program, although no cases of febrile neutropenia have been observed in Study 1. Monitor complete blood count prior to starting IBRANCE therapy and at the beginning of each cycle, as well as on Day 14 of the first two cycles, and as clinically indicated. Dose interruption, dose reduction or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia [see Dosage and Administration]. Infections. Infections have been reported at a higher rate in patients treated with IBRANCE plus letrozole compared to patients treated with letrozole alone in Study 1. Grade 3 or 4 infections occurred in 5% of patients treated with IBRANCE plus letrozole whereas no patients treated with letrozole alone experienced a Grade 3 or 4 infection. Monitor patients for signs and symptoms of infection and treat as medically appropriate. Pulmonary Embolism. Pulmonary embolism has been reported at a higher rate in patients treated with IBRANCE plus letrozole (5%) compared with no cases in patients treated with letrozole alone in Study 1. Monitor patients for signs and symptoms of pulmonary embolism and treat as medically appropriate. Embryo-Fetal Toxicity. Based on findings in animals and mechanism of action, IBRANCE can cause fetal harm. IBRANCE caused embryo-fetal toxicities in rats and rabbits at maternal exposures that were greater than or equal to 4 times the human clinical exposure based on area under the curve (AUC). Advise females of reproductive potential to use effective contraception during therapy with IBRANCE and for at least two weeks after the last dose [see Use in Specific Populations and Clinical Pharmacology].

DRUG MONOGRAPHS

BREAST CANCER at least two chemotherapeutic regimens for metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting. Adults: Give by IV injection over 2–5mins. 1.4mg/m2 on Days 1 and 8 of a 21-day cycle. Mild hepatic impairment (Child-Pugh A) or moderate renal impairment (CrCl 30–50mL/min): 1.1mg/m2 on Days 1 and 8 of a 21-day cycle. Moderate hepatic impairment (Child-Pugh B): 0.7mg/m2 on Days 1 and 8 of a 21-day cycle. Hold dose for ANC <1000/mm3, platelets <75000/mm3, or grade 3 or 4 non-hematological toxicities. Delay or reduce dose according to toxicities; see full labeling. Do not re-escalate dose after it is reduced. Children: <18yrs: not established. Warnings/Precautions: Monitor CBCs; increase frequency of monitoring if grade 3 or 4 cytopenias develop, delay and reduce subsequent doses if febrile neutropenia or grade 4 neutropenia lasting >7 days develops. Monitor for peripheral neuropathy; withhold dose if grade 3 or 4 peripheral neuropathy develops until resolution to grade 2 or less. Congenital long QT syndrome: avoid. CHF, bradyarrhythmias, electrolyte abnormalities: monitor ECG for prolonged QT interval. Correct electrolyte abnormalities (K+, Mg+) before treatment; monitor. Severe hepatic impairment (Child-Pugh C) or severe renal impairment (CrCl<30mL/min): insufficient data. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Caution with other drugs that prolong QT interval (eg, Class IA and III antiarrhythmics); monitor. Adverse reactions: Neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, constipation, febrile neutropenia; possible QT prolongation, elevated liver enzymes. Note: Do not mix with dextrose-containing solutions. Do not administer in same line as other drugs or fluids. How supplied: Single-use vial (2mL)–1

HERCEPTIN Genentech

℞

Human epidermal growth factor receptor (HER2) inhibitor. Trastuzumab 440mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free. Indications: HER2-overexpressing metastatic breast cancer as a single agent in patients who have received one or more chemotherapy regimens; or in combination with paclitaxel in patients who have not received chemotherapy. Adjuvant treatment in HER2-overexpressing, node-positive or node-negative breast cancer

(as a single agent following multi-modality anthracycline based therapy; in combination with doxorubicin, cyclophosphamide, and either paclitaxel or docetaxel; or in combination with docetaxel and carboplatin). Adults: Give as IV infusion. Initially 4mg/kg over 90 mins, followed by 2mg/kg over 30 mins weekly; administer until tumor progression. Adjuvant treatment (administer trastuzumab weekly for 52 weeks); In combination therapy: with doxorubicin and cyclophosphamide, followed by either paclitaxel or docetaxel; or with docetaxel/carboplatin: initially 4mg/kg over 90 mins, followed by 2mg/kg over 30 mins once weekly for the 1st 12 weeks (concurrently w. paclitaxel or docetaxel) or 1st 18 weeks (concurrently w. docetaxel/carboplatin). One week after the last trastuzumab weekly dose, give trastuzumab 6mg/kg over 30–90 mins every 3 weeks. Following multi-modality anthracycline based therapy: initially 8mg/kg over 90 mins, then 6mg/kg over 30–90 mins every 3 weeks. Infusion reactions or cardiomyopathy: see full labeling. Children: Not established. Warnings/Precautions: Increased risk of cardiomyopathy. Conduct cardiac assessment (eg, history, physical exam, LVEF) at baseline, every 3 months during and after therapy or every 6 months for ≥2yrs after therapy (if adjuvant); repeat LVEF at 4 week intervals if dose is withheld due to significant left ventricular cardiac dysfunction. Interrupt therapy if dyspnea or significant hypotension occurs; consider discontinuing permanently if severe infusion reactions, CHF, pulmonary toxicity, or significant left ventricular myocardial dysfunction develops. Symptomatic intrinsic lung disease. Extensive tumor involvement of the lungs. Test for HER2 protein overexpression and HER2 gene amplification using FDA-approved tests for specific tumor type (breast or gastric/ gastroesophageal adenocarcinoma). Elderly. Pregnancy (Cat.D); use adequate contraception during and at least 6 months after therapy. Nursing mothers: not recommended. Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy. Increased toxicity with other myelosuppressives. Potentiated by paclitaxel. Adverse reactions: Fever, diarrhea, nausea, chills, infections, increased cough, headache, CHF, insomnia, fatigue, dyspnea, rash, neutropenia, anemia, myalgia, thrombosis/ embolism; severe infusion reactions, febrile neutropenia/exacerbation of chemotherapyinduced neutropenia, pulmonary toxicity (eg,

interstitial pneumonitis), cardiomyopathy (eg, left ventricular myocardial dysfunction); pregnant women (2nd & 3rd trimesters): possible oligohydramnios (monitor). Note: Enroll pregnant women with breast cancer who are using trastuzumab in the MotHER-the Herceptin Pregnancy Registry (800) 690-6720. Testing considerations: HER2 protein overexpression How supplied: Vial–1 (w. diluent)

IXEMPRA Bristol-Myers Squibb

℞

Epothilone microtubule inhibitor. Ixabepilone 15mg/vial, 45mg/vial; pwd for IV infusion after constitution and dilution; diluent contains alcohol, polyoxyethylated castor oil. Indications: Metastatic or locally advanced breast cancer: In combination with capecitabine after failure of an anthracycline and a taxane; and as monotherapy after failure of an anthracycline, a taxane, and capecitabine. Adults: Pretreat with both H1 and H2 blockers 1hr before infusion; and with steroid if previous hypersensitivity reaction occurred. 40mg/m2 by IV infusion over 3hrs, once every 3wks. Use max body surface area (BSA) of 2.2m2 to calculate dose if BSA >2.2m2. Moderate hepatic impairment (as monotherapy): initially 20mg/m2 per dose; max 30mg/m2 per dose (see literature). Neuropathy, myelosuppression, concomitant strong CYP3A4 inhibitors: reduce dose. Concomitant strong CYP3A4 inducers: consider gradual dose increases. See literature. Children: Not recommended. Contraindications: Baseline neutrophils <1500cells/mm3 or platelets <100,000cells/mm3. AST or ALT >2.5×ULN or bilirubin >1×ULN (in combination with capecitabine). Warnings/Precautions: Monitor CBC and liver function at baseline, then periodically. Hepatic impairment (ALT or AST >10×ULN or bilirubin >3×ULN: not recommended; ALT or AST >5×ULN: limited data, use caution). Diabetes. Neuropathy. Cardiac disease (discontinue if cardiac ischemia or cardiac dysfunction occurs). Monitor for signs/ symptoms of neuropathy, neutropenia. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Potentiated by strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, certain macrolides, nefazodone, grapefruit juice); avoid. Caution with mild or moderate CYP3A4 inhibitors; consider alternative agents. Antagonized by strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, dexamethasone, phenobarbital); avoid. Avoid St. John’s wort.

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CTA_Mar-Apr15_MB.indd 7

2/24/15 7:12 AM

DRUG MONOGRAPHS

BREAST CANCER Adverse reactions: Peripheral sensory neuropathy, fatigue, asthenia, myalgia, arthralgia, alopecia, GI upset, stomatitis, mucositis, musculoskeletal pain, palmarplantar erythrodysesthesia syndrome, anorexia, abdominal pain, nail disorder, constipation; myelosuppression (neutropenia, leukopenia, anemia, thrombocytopenia); hypersensitivity reactions; others. How supplied: Kit–1 vial (w. diluent)

KADCYLA Genentech

Adverse reactions: Fatigue, nausea, musculoskeletal pain, thrombocytopenia, headache; increased transaminases, constipation. How supplied: Single-use vial–1

Progestin. Megestrol acetate 20mg, 40mg; scored tabs. Indications: Palliative treatment of advanced breast carcinoma. Adults: 40mg 4 times daily. Children: Not applicable. Warnings/Precautions: History of thromboembolic disease. Diabetes. Monitor for adrenal insufficiency. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: May increase insulin requirements. Decreases indinavir levels. Adverse reactions: Weight gain, thromboembolic events, heart failure, GI upset, edema, breakthrough menstrual bleeding, dyspnea, tumor flare, hyperglycemia, alopecia, hypertension, carpal tunnel syndrome, mood changes, hot flashes, malaise, asthenia, lethargy, sweating, rash. How supplied: Contact supplier.

arrythmia requiring treatment or a cumulative prior anthracycline exposure to >360mg/m2 of doxorubicin or its equivalent: not studied. Assess LVEF at baseline and at regular intervals (eg, every 3 months in metastatic setting, and every 6 weeks in the neoadjuvant setting) during treatment; if LVEF is <45%, or is 45% to 49% with a ≥10% absolute decrease below the pretreatment value, withhold (pertuzumab + trastuzumab) and repeat LVEF within 3 weeks; discontinue if LVEF has not improved. Monitor for signs/symptoms of infusion reactions; slow or interrupt infusion and treat if occurs; discontinue if severe. Test and confirm for HER2 protein overexpression using FDA-approved tests by labs with demonstrated proficiency. Pregnancy (Cat.D); use adequate contraception during and at least 6 months after therapy. Nursing mothers: not recommended. Adverse reactions: Diarrhea, alopecia, neutropenia, nausea, fatigue, rash, peripheral neuropathy; hypersensitivity (monitor), decreases in LVEF; pregnant women: possible oligohydramnios (monitor). Note: Encourage women who are exposed to Perjeta during pregnancy to enroll in the MotHER Pregnancy Registry: (800) 690-6720. How supplied: Single-use vial–1

PERJETA Genentech

PREMARIN Pfizer

Megestrol acetate (various)

℞

HER2-targeted antibody-drug conjugate. Adotrastuzumab emtansine 100mg, 160mg; per vial; powder; for IV infusion after reconstitution. Indications: Treatment in patients with HER2positive (+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease or developed disease recurrence during or within 6 months of completing adjuvant therapy. Adults: Give by IV infusion only over 90 minutes 3.6mg/kg max every 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. Subsequent infusions may be given over 30 minutes if previously tolerated. Monitor closely for possible SC infiltration during infusion. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Do not substitute for or with trastuzumab. Hepatotoxicity; monitor serum transaminases and bilirubin prior to starting and to each dose; reduce dose or discontinue if occurs. Risk of left ventricular dysfunction. Assess LVEF prior to initiation and every 3 months during treatment; interrupt and discontinue as appropriate. Risk of embryofetal toxicity. Permanently discontinue if interstitial lung disease or pneumonitis occurs. Monitor for signs/symptoms of extravasation, infusion-related or hypersensitivity reactions; if significant, slow or interrupt infusion; discontinue if life-threatening. Monitor platelets at baseline and prior to each dose; if platelets <50,000/mm3, delay dose until recovery to ≥75,000/mm3; if platelets <25,000/mm3, delay until recovery to ≥75,000/mm3 and reduce dose. If thrombocytopenia occurs <100,000/mm3 and concomitant anticoagulants, monitor closely. Monitor for neurotoxicity; withhold temporarily if Grade 3 or 4 peripheral neuropathy occurs. Test for HER2 protein overexpression or gene amplification using FDA-approved tests by labs with demonstrated proficiency. Pregnancy (Category D); use adequate contraception during and at least 6 months after last dose. Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin, atazanavir, indinavir, ritonavir, nefazodone, nelfinavir, saquinavir, telithromycin); if unavoidable, consider delaying therapy (see full labeling).

℞

Human epidermal growth factor receptor (HER2) dimerization inhibitor. Pertuzumab 420mg/14mL (30mg/mL); soln for IV infusion; preservative-free. Indications: In combination with trastuzumab and docetaxel: to treat patients with HER2-positive metastatic breast cancer (MBC) who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease; for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either >2cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. Limitations of use: not established as part of a doxorubicin-containing regimen. Not established in administration for >6 cycles for early breast cancer. Adults: In combination with trastuzumab and docetaxel: initially 840mg IV over 60 minutes, followed every 3 weeks thereafter by a dose of 420mg IV over 30–60 minutes. Pertuzumab should be withheld or discontinued if trastuzumab is withheld or discontinued. If docetaxel is discontinued, treatment with pertuzumab and trastuzumab may continue. Neoadjuvant treatment: give every 3 weeks for 3 to 6 cycles as part of one of the treatment regimens for early breast cancer: see full labeling. Dose modification (missed dose, LVEF, or infusion reactions): see full labeling. Children: Not established. Warnings/Precautions: Risk of embryo-fetal toxicity. Pretreatment LVEF value of ≤50%, history of CHF, decreases in LVEF to <50% during prior trastuzumab therapy, uncontrolled hypertension, recent MI, serious cardiac

℞

Estrogen. Conjugated estrogens 0.3mg, 0.45mg, 0.625mg, 0.9mg, 1.25mg; tabs. Indications: Treatment of breast cancer (for palliation only) in appropriately selected women and men with metastatic disease. Adults: 10mg 3 times daily for at least 3 months. Children: Not applicable. Contraindications: Known, suspected, or history of breast cancer, except in appropriately selected patients being treated for metastatic disease. Known or suspected estrogen-dependent neoplasia. Undiagnosed abnormal genital bleeding. Pulmonary embolism/DVT (active or history of). Arterial thromboembolism (eg, stroke, MI; active or history of). Liver dysfunction or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Known or suspected pregnancy (Cat.X). Warnings/Precautions: Not for prevention of cardiovascular disease. Use for shortest duration consistent with treatment goals and risks. Reevaluate periodically. Patients with an intact uterus should almost always receive a progestin with systemic estrogens to avoid endometrial hyperplasia. Discontinue if cardiovascular events occur or are suspected; if jaundice occurs; and during immobilization or at least 4–6 weeks before surgery associated with thromboembolism. Hepatic dysfunction. Conditions aggravated by fluid retention. Gallbladder disease. Bone disease associated with hypercalcemia. Hereditary angioedema. Do initial complete physical and repeat annually (include BP, mammogram, PAP smear). Adolescents. Nursing mothers: not recommended.

8 CANCER THERAPY ADVISOR | MARCH/APRIL 2015 | CancerTherapyAdvisor.com

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• NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend pertuzumab (PERJETA) + trastuzumab (Herceptin) + docetaxel as a (category 1) preferred option for the first-line treatment of patients with HER2+ MBC1

NCCN®=National Comprehensive Cancer Network®; HER2=human epidermal growth factor receptor 2 ; ASCO®=American Society of Clinical Oncology®.

Indication

PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin® (trastuzumab) and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease.

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• ASCO® Clinical Oncology Practice Guidelines recommend pertuzumab + trastuzumab + docetaxel as first-line therapy for advanced HER2+ breast cancer 2

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity Cosmos Communications C

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PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for eﬀective contraception. Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages.

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Treatment guidelines recommend PERJETA-based therapy as the preferred first-line option

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JOB#: 40680 CLIENT: Genentech DESC: Journal Ad 3-pg FILE NAME: GNH_HER_Q40680_JA_D03.indd PG: CordobaR/MerinoR AD: R Vetrano-Pyke x4077 PM: B Fu x4416 AE: K McGinty x3950 TRIM: 15.5” x 10.5” BLEED: 17.5” x 11.5” SAFETY: 14.75” x 9.875” PROD: M Haight x4245 FONTS: Myriad Pro (Bold, Regular, Light), Helvetica Neue LT Std (45 Light) IMAGES: 40680_JA_1_fn.tif (CMYK; 300 ppi; 100%), 40680_glow_fn.psd (CMYK; 300 ppi; 100%), Perjeta_US_MBC_NEO_4C.eps (69.5%) Cyan, Magenta, Yellow, Black INKS: DOC PATH: Macintosh HD:Users:cordobar:De...sk_prep:GNH_HER_Q40680_JA_D03.indd NOTES: None

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Significantly extend progression-free survival (PFS) in first-line HER2+ metastatic breast cancer Combining PERJETA with Herceptin + docetaxel added 6 months median PFS3

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Additional Important Safety Information

PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

Left Ventricular Dysfunction (LVD)

• In Study 1, for patients with MBC, PERJETA in combination with Herceptin and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in left ventricular ejection fraction (LVEF) compared with placebo in combination with Herceptin and docetaxel • Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and in 8.3% of patients in the placebo-treated group • Symptomatic LVSD (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and in 1.8% of patients in the placebo-treated group • Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months in the metastatic setting) during treatment to ensure that LVEF is within your institution’s normal limits • If LVEF is <45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and Herceptin and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further, unless benefits for the individual patient outweigh the risks

Infusion-Associated Reactions

• PERJETA has been associated with infusion reactions • In Study 1, for patients with MBC, on the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group, with the majority being mild to moderate. The most common infusion reactions (≥1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting • During the second cycle, when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

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• The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy 3

median line

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At the second interim analysis (30 months median follow-up, 1 year after the first interim analysis), the HR and P value for OS crossed the predefined efficacy stopping boundary (HR ≤0.739, P≤0.0138). OS improvement with PERJETA + trastuzumab + docetaxel was statistically significant at the second interim analysis (HR=0.66, P=0.0008).3 The final analysis was performed when 221 patient deaths occurred in the placebo-treated group and 168 in the PERJETA-treated group. The statistically significant OS benefit in favor of the PERJETA-treated group was maintained (HR=0.68, P=0.0002).4

• In the second interim analysis, PERJETA improved both PFS and OS when combined with Herceptin + docetaxel in patients, including the visceral metastasis subgroup5,6 — There was an inability to show an OS benefit with PERJETA in patients with nonvisceral metastases (n=178; HR=1.42 [95% CI: 0.71-2.84])3 • Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions

Hypersensitivity Reactions/Anaphylaxis

• In Study 1, the overall frequency of hypersensitivity/anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grades 3-4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebo-treated group according to NCICTCAE (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis • Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients

HER2 Testing

• Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown • Patients were required to have evidence of HER2 overexpression, defined as 3+ IHC or FISH amplification ratio ≥2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH but did not demonstrate protein overexpression by IHC

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• Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized

Most Common Adverse Reactions

• In MBC, the most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI-CTCAE (version 3) Grade 3-4 adverse reactions (>2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue You may report side effects to the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at 1-888-835-2555. For more information about PERJETA, contact your local representative or visit www.PERJETA.com/hcp. Please see Brief Summary of PERJETA full Prescribing Information including Boxed WARNINGS for additional Important Safety Information on the following pages. References: 1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.3.2014. © National Comprehensive Cancer Network, Inc. 2014. All rights reserved. Accessed May 12, 2014. To view the most recent and complete version of the guideline, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 2. Giordano SH, Temin S, Kirshner JJ, et al. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32(19):2078-2099. 3. PERJETA Prescribing Information. Genentech, Inc. September 2013. 4. Data on file. Genentech, Inc. 5. Swain SM, Kim S-B, Cortes J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013;14:461-471. 6. Baselga J, Cortés J, Kim S-B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119.

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• PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function • Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception —Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant —If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 —Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known

• At the final analysis, the OS benefit was maintained (HR=0.68, 95% CI: 0.56-0.84; P=0.0002) and the median was reached in the PERJETA + Herceptin + docetaxel arm (56.5 months vs 40.8 months in the Herceptin + docetaxel arm)4

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HR=0.68 95% CI: 0.56-0.84 P=0.0002

Select Important Safety Information: Discontinue/Interrupt/Withhold Withhold PERJETA and Herceptin and repeat left ventricular ejection fraction assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if LVEF has not improved or has declined further. If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Consider permanent discontinuation in patients with severe infusion reactions. PERJETA treatment should be withheld or discontinued if Herceptin treatment is withheld or discontinued. Advise nursing mothers receiving PERJETA to discontinue treatment, taking into account the importance of the drug to the mother.

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• At the first interim analysis, PFS events occurred in 191 (47.5%) patients treated with PERJETA + Herceptin + docetaxel and 242 (59.6%) patients treated with Herceptin + docetaxel3

HR=hazard ratio; CI=confidence interval. Median PFS was reached at the first interim analysis.3 Results of the phase III, randomized, double-blind, placebo-controlled CLEOPATRA trial in patients (N=808) with HER2+ locally recurrent, unresectable, or metastatic breast cancer previously untreated with a biologic or chemotherapy for metastatic disease. Patients received PERJETA + Herceptin + docetaxel or placebo + Herceptin + docetaxel every 3 weeks until progression or unacceptable toxicity. Primary endpoint: PFS, assessed by independent review.3

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity

• In the second interim analysis, there was a statistically significant improvement in OS (secondary endpoint)3 — Median not yet reached in the PERJETA-containing arm vs 37.6 months with Herceptin + docetaxel (HR=0.66; 95% CI: 0.52-0.84; P=0.0008)

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JOB#: 40680 CLIENT: Genentech DESC: Journal Ad 3-pg FILE NAME: GNH_HER_Q40680_JA_D03.indd DATE: 11-21-2014 6:50 PM ROUND: 3 PG: CordobaR/MerinoR AD: R Vetrano-Pyke x4077 PM: B Fu x4416 AE: K McGinty x3950 CW: L Gibbons Last Saved: 11-21-2014 6:50 PM TRIM: 15.5” x 10.5” BLEED: 17.5” x 11.5” SAFETY: 14.75” x 9.875” PROD: M Haight x4245 INK Spec: 4C PRINT SCALE: 82.94% FONTS: Myriad Pro (Regular, Bold, Condensed, Condensed Italic, Bold Condensed) IMAGES: 40680_JA_2_fn.tif (CMYK; 300 ppi; 100%), Genentech_AMOTRG_4C.eps (96.6%), Perjeta_US_MBC_NEO_4C.eps (65%), 40680_KMchart_v5.eps (100%), 40680_40062_oschartREV_v3.eps (100%) Cyan, Magenta, Yellow, Black INKS: DOC PATH: Macintosh HD:Users:cordobar:De...sk_prep:GNH_HER_Q40680_JA_D03.indd NOTES: None C

Placebo + Herceptin + docetaxel

PERJETA demonstrated an OS improvement when combined with Herceptin + docetaxel at the final analysis4

15.7-month improvement in median OS in the final analysis (secondary endpoint)4

6.1-month improvement in median PFS by independent review (primary endpoint)3

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PERJETA + Herceptin (trastuzumab) + docetaxel

Significantly extend progression-free survival (PFS) in first-line HER2+ metastatic breast cancer Combining PERJETA with Herceptin + docetaxel added 6 months median PFS3

SIGNOFF

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60 50

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10 267 209

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AE/AS ED PROD

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PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients.

Left Ventricular Dysfunction (LVD)

Infusion-Associated Reactions

56.5 MONTHS

70 60

• The most common adverse reactions (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy 3

median line

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HER2 Testing

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Most Common Adverse Reactions

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• At the first interim analysis, PFS events occurred in 191 (47.5%) patients treated with PERJETA + Herceptin + docetaxel and 242 (59.6%) patients treated with Herceptin + docetaxel3

Boxed WARNINGS: Cardiomyopathy and Embryo-Fetal Toxicity

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PERJETA demonstrated an OS improvement when combined with Herceptin + docetaxel at the final analysis4

15.7-month improvement in median OS in the final analysis (secondary endpoint)4

6.1-month improvement in median PFS by independent review (primary endpoint)3

Cosmos Communications 29452a

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Overall survival (OS) data

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: CARDIOMYOPATHY and EMBRYO-FETAL TOXICITY Cardiomyopathy PERJETA administration can result in subclinical and clinical cardiac failure. Evaluate left ventricular function in all patients prior to and during treatment with PERJETA. Discontinue PERJETA treatment for a confirmed clinically significant decrease in left ventricular function. (2.2, 5.2, 6.1) Embryo-Fetal Toxicity Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE 1.1 Metastatic Breast Cancer (MBC) PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 1.2 Neoadjuvant Treatment of Breast Cancer PERJETA is indicated for use in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer (either greater than 2 cm in diameter or node positive) as part of a complete treatment regimen for early breast cancer. This indication is based on demonstration of an improvement in pathological complete response rate. No data are available demonstrating improvement in event-free survival or overall survival [see Clinical Studies (14.2) and Dosage and Administration (2.1)]. Limitations of Use: • The safety of PERJETA as part of a doxorubicin-containing regimen has not been established. • The safety of PERJETA administered for greater than 6 cycles for early breast cancer has not been established. 4 CONTRAINDICATIONS PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In Study 1, for patients with MBC, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebo-treated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF.

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In patients receiving neoadjuvant treatment in Study 2, the incidence of LVSD was higher in the PERJETA-treated groups compared to the trastuzumab- and docetaxeltreated group. An increased incidence of LVEF declines was observed in patients treated with PERJETA in combination with trastuzumab and docetaxel. In the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 1.9% of patients treated with neoadjuvant trastuzumab and docetaxel as compared to 8.4% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and docetaxel. Symptomatic LVSD occurred in 0.9% of patients treated with neoadjuvant PERJETA in combination with trastuzumab and no patients in the other 3 arms. LVEF recovered to ≥ 50% in all patients. In patients receiving neoadjuvant PERJETA in Study 3, in the overall treatment period, LVEF decline > 10% and a drop to less than 50% occurred in 6.9% of patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel, 16.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, and 10.5% of patients treated with PERJETA in combination with TCH. Symptomatic LVSD occurred in 4.0% of patients treated with PERJETA plus trastuzumab and docetaxel following FEC, 1.3% of patients treated with PERJETA in combination with TCH, and none of the patients treated with PERJETA plus trastuzumab and FEC followed by PERJETA plus trastuzumab and docetaxel. LVEF recovered to ≥ 50% in all but one patient. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months in the metastatic setting and every six weeks in the neoadjuvant setting) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 45%, or is 45% to 49% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Related Reactions PERJETA has been associated with infusion reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in Study 1 as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction, or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETAtreated group and 9.8% in the placebo-treated group. Less than 1% were Grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In Study 2 and Study 3, PERJETA was administered on the same day as the other study treatment drugs. Infusion reactions were consistent with those observed in Study 1, with a majority of reactions being National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0) Grade 1 – 2. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-related reaction occurs, slow or interrupt the infusion, and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 Hypersensitivity Reactions/Anaphylaxis In Study 1, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2.0% in the PERJETA-treated group and 2.5% in the placebotreated group according to NCI - CTCAE v3.0. Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis.

In Study 2 and Study 3, hypersensitivity/anaphylaxis events were consistent with those observed in Study 1. In Study 2, two patients in the PERJETA- and docetaxel-treated group experienced anaphylaxis. In Study 3, the overall frequency of hypersensitivity/anaphylaxis was highest in the PERJETA plus TCH treated group (13.2%), of which 2.6% were NCICTCAE (version 3) Grade 3 – 4. Patients should be observed closely for hypersensitivity reactions. Severe hypersensitivity, including anaphylaxis, has been observed in clinical trials with treatment of PERJETA [see Clinical Trials Experience (6.1)]. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. PERJETA is contraindicated in patients with known hypersensitivity to pertuzumab or to any of its excipients [see Contraindications (4)]. 5.5 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. Patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC or FISH amplification ratio ≥ 2.0 in the clinical studies. Only limited data were available for patients whose breast cancer was positive by FISH, but did not demonstrate protein overexpression by IHC. Assessment of HER2 status should be performed by laboratories using FDA-approved tests with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of sub-optimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Related Reactions [see Warnings and Precautions (5.3)] • Hypersensitivity Reactions/Anaphylaxis [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Metastatic Breast Cancer (MBC) The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in Study 1. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients in the PERJETA-treated group. The safety profile of PERJETA remained unchanged with an additional year of follow-up (median total follow-up of 30 months) in Study 1. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%).

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Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in Study 1 PERJETA Placebo + trastuzumab + trastuzumab + docetaxel + docetaxel n=407 n=397 Body System/ Adverse Reactions Frequency rate, % Frequency rate, % All Grades All Grades Grades, % 3–4, % Grades, % 3–4, %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 3.3 Asthenia 26.0 2.5 30.2 1.5 Edema peripheral 23.1 0.5 30.0 0.8 Mucosal inflammation 27.8 1.5 19.9 1.0 Pyrexia 18.7 1.2 17.9 0.5 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 0.3 Rash 33.7 0.7 24.2 0.8 Nail disorder 22.9 1.2 22.9 0.3 Pruritus 14.0 0.0 10.1 0.0 Dry skin 10.6 0.0 4.3 0.0 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 5.0 Nausea 42.3 1.2 41.6 0.5 Vomiting 24.1 1.5 23.9 1.5 Constipation 15.0 0.0 24.9 1.0 Stomatitis 18.9 0.5 15.4 0.3 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 45.8 Anemia 23.1 2.5 18.9 3.5 Leukopenia 18.2 12.3 20.4 14.6 Febrile neutropenia* 13.8 13.0 7.6 7.3 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 2.0 Headache 20.9 1.2 16.9 0.5 Dysgeusia 18.4 0.0 15.6 0.0 Dizziness 12.5 0.5 12.1 0.0 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 0.8 Arthralgia 15.5 0.2 16.1 0.8 Infections and infestations Upper respiratory tract 16.7 0.7 13.4 0.0 infection Nasopharyngitis 11.8 0.0 12.8 0.3 Respiratory, thoracic, and mediastinal disorders Dyspnea 14.0 1.0 15.6 2.0 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 1.5 Eye disorders Lacrimation increased 14.0 0.0 13.9 0.0 Psychiatric disorders Insomnia 13.3 0.0 13.4 0.0 *In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group in Study 1: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the PERJETA-treated group vs. 3.5% in the placebotreated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebo-treated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebo-treated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In Study 1, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). Neoadjuvant Treatment of Breast Cancer (Study 2) In Study 2, the most common adverse reactions seen with PERJETA in combination with trastuzumab and docetaxel administered for 4 cycles were similar to those seen in the PERJETA-treated group in Study 1. The most common adverse reactions (> 30%) were alopecia, neutropenia, diarrhea, and nausea. The most common NCI – CTCAE v3.0 Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, and diarrhea. In this group, one patient permanently discontinued neoadjuvant treatment due to an adverse event. Table 2 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 2.

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Table 2 Summary of Adverse Reactions Occurring in ≥ 10% in the Neoadjuvant Setting for Patients Receiving PERJETA in Study 2

Body System/ Adverse Reactions

PERJETA PERJETA PERJETA Trastuzumab + trastuzumab + docetaxel + trastuzumab + docetaxel + docetaxel n=108 n=108 n=107 n=107 Frequency rate Frequency rate Frequency rate Frequency rate % % % % All Grades All Grades All Grades All Grades Grades 3–4 Grades 3–4 Grades 3–4 Grades 3–4 % % % % % % % %

General disorders and administration site conditions Fatigue 27.1 0.0 26.2 0.9 12.0 0.0 25.5 1.1 Asthenia 17.8 0.0 20.6 1.9 2.8 0.0 16.0 2.1 Edema 10.3 0.0 2.8 0.0 0.9 0.0 5.3 0.0 peripheral Mucosal 21.5 0.0 26.2 1.9 2.8 0.0 25.5 0.0 inflammation Pyrexia 10.3 0.0 16.8 0.0 8.3 0.0 8.5 0.0 Skin and subcutaneous tissue disorders Alopecia 66.4 0.0 65.4 0.0 2.8 0.0 67.0 0.0 Rash 21.5 1.9 26.2 0.9 11.1 0.0 28.7 1.1 Gastrointestinal disorders Diarrhea 33.6 3.7 45.8 5.6 27.8 0.0 54.3 4.3 Nausea 36.4 0.0 39.3 0.0 13.9 0.0 36.2 1.1 Vomiting 12.1 0.0 13.1 0.0 4.6 0.0 16.0 2.1 Stomatitis 7.5 0.0 17.8 0.0 4.6 0.0 9.6 0.0 Blood and lymphatic system disorders Neutropenia 63.6 58.9 50.5 44.9 0.9 0.9 64.9 57.4 Leukopenia 21.5 11.2 9.3 4.7 0.0 0.0 13.8 8.5 Nervous system disorders Headache 11.2 0.0 11.2 0.0 13.9 0.0 12.8 0.0 Dysgeusia 10.3 0.0 15.0 0.0 4.6 0.0 7.4 0.0 Peripheral 12.1 0.9 8.4 0.9 1.9 0.0 10.6 0.0 Sensory Neuropathy Musculoskeletal and connective tissue disorders Myalgia 22.4 0.0 22.4 0.0 9.3 0.0 21.3 0.0 Arthralgia 8.4 0.0 10.3 0.0 4.6 0.0 9.6 0.0 Metabolism and nutrition disorders Decreased 6.5 0.0 14.0 0.0 1.9 0.0 14.9 0.0 appetite Psychiatric disorders Insomnia 11.2 0.0 8.4 0.0 3.7 0.0 8.5 0.0 The following adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment and occurred more frequently in PERJETA-treated groups in Study 2: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel) Blood and lymphatic system disorders: Anemia (6.5% in the T+D arm, 2.8% in the Ptz+T+D arm, 4.6% in the Ptz+T arm and 8.5% in the Ptz+D arm), Febrile neutropenia (6.5% in the T+D arm, 8.4% in the Ptz+T+D arm, 0.0% in the Ptz+T arm and 7.4% in the Ptz+D arm) Immune system disorders: Hypersensitivity (1.9% in the T+D arm, 5.6% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 5.3% in the Ptz+D arm) Nervous system disorders: Dizziness (3.7% in the T+D arm, 2.8% in the Ptz+T+D arm, 5.6% in the Ptz+T arm and 3.2% in the Ptz+D arm) Infections and infestations: Upper respiratory tract infection (2.8% in the T+D arm, 4.7% in the Ptz+T+D arm, 1.9% in the Ptz+T arm and 7.4% in the Ptz+D arm) Respiratory, thoracic and mediastinal disorders: Dyspnea (3.7% in the T+D arm, 4.7% in the Ptz+T+D arm, 2.8% in the Ptz+T arm and 2.1% in the Ptz+D arm) Cardiac disorders: Left ventricular dysfunction (0.9% in the T+D arm, 2.8% in the Ptz+T+D arm, 0.0% in the Ptz+T arm, and 1.1% in the Ptz+D arm) including symptomatic left ventricular dysfunction (CHF) (0.9% in the Ptz+T arm and 0.0% in the T+D arm, Ptz+T+D arm, and Ptz+D arm) Eye disorders: Lacrimation increased (1.9% in the T+D arm, 3.7% in the Ptz+T+D arm, 0.9% in the Ptz+T arm, and 4.3% in the Ptz+D arm) Neoadjuvant Treatment of Breast Cancer (Study 3) In Study 3, when PERJETA was administered in combination with trastuzumab and docetaxel for 3 cycles following 3 cycles of FEC, the most common adverse reactions (> 30%) were diarrhea, nausea, alopecia, neutropenia, vomiting, and fatigue. The most common NCI-CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, leukopenia, febrile neutropenia, diarrhea, left ventricular dysfunction, anemia, dyspnea, nausea, and vomiting. Similarly, when PERJETA was administered in combination with docetaxel, carboplatin, and trastuzumab (TCH) for 6 cycles, the most common adverse reactions (> 30%) were diarrhea, alopecia, neutropenia, nausea, fatigue, vomiting, anemia, and thrombocytopenia. The most common NCICTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, anemia, leukopenia, diarrhea, thrombocytopenia, vomiting, fatigue, ALT increased, hypokalemia, and hypersensitivity. The rates of adverse events resulting in permanent discontinuation of any component of neoadjuvant treatment were 6.7% for patients receiving PERJETA in combination with trastuzumab and docetaxel following FEC and 7.9% for

patients receiving PERJETA in combination with TCH. Table 3 reports the adverse reactions that occurred in patients who received neoadjuvant treatment with PERJETA for breast cancer in Study 3. Table 3 Summary of Adverse Reactions Occurring in ≥ 10% of Patients Receiving Neoadjuvant Treatment with PERJETA in Study 3

Body System/ Adverse Reactions

PERJETA + trastuzumab PERJETA + FEC followed + trastuzumab by PERJETA + docetaxel + trastuzumab following FEC PERJETA + TCH + docetaxel n=75 n=76 n=72 Frequency rate, % Frequency rate, % Frequency rate, % All Grades Grades 3 – 4 % %

All Grades All Grades Grades 3 – 4 Grades 3 – 4 % % % %

General disorders and administration site conditions Fatigue 36.1 0.0 36.0 0.0 42.1 3.9 Asthenia 9.7 0.0 14.7 1.3 13.2 1.3 Edema peripheral 11.1 0.0 4.0 0.0 9.2 0.0 Mucosal 23.6 0.0 20.0 0.0 17.1 1.3 inflammation Pyrexia 16.7 0.0 9.3 0.0 15.8 0.0 Skin and subcutaneous tissue disorders Alopecia 48.6 0.0 52.0 0.0 55.3 0.0 Rash 19.4 0.0 10.7 0.0 21.1 1.3 Dry skin 5.6 0.0 9.3 0.0 10.5 0.0 Palmar-Plantar Erythrodysaesthesia 6.9 0.0 10.7 0.0 7.9 0.0 Syndrome Gastrointestinal disorders Diarrhea 61.1 4.2 61.3 5.3 72.4 11.8 Dyspepsia 25.0 1.4 8 0.0 22.4 0.0 Nausea 52.8 0.0 53.3 2.7 44.7 0.0 Vomiting 40.3 0.0 36.0 2.7 39.5 5.3 Constipation 18.1 0.0 22.7 0.0 15.8 0.0 Stomatitis 13.9 0.0 17.3 0.0 11.8 0.0 Blood and lymphatic system disorders Neutropenia 51.4 47.2 46.7 42.7 48.7 46.1 Anemia 19.4 1.4 9.3 4.0 38.2 17.1 Leukopenia 22.2 19.4 16.0 12.0 17.1 11.8 Febrile 18.1 18.1 9.3 9.3 17.1 17.1 neutropenia Thrombocytopenia 6.9 0.0 1.3 0.0 30.3 11.8 Immune system disorders Hypersensitivity 9.7 2.8 1.3 0.0 11.8 2.6 Nervous system disorders Neuropathy 5.6 0.0 1.3 0.0 10.5 0.0 peripheral Headache 22.2 0.0 14.7 0.0 17.1 0.0 Dysgeusia 11.1 0.0 13.3 0.0 21.1 0.0 Dizziness 8.3 0.0 8.0 1.3 15.8 0.0 Musculoskeletal and connective tissue disorders Myalgia 16.7 0.0 10.7 1.3 10.5 0.0 Arthralgia 11.1 0.0 12.0 0.0 6.6 0.0 Respiratory, thoracic, and mediastinal disorders Cough 9.7 0.0 5.3 0.0 11.8 0.0 Dyspnea 12.5 0.0 8.0 2.7 10.5 1.3 Epistaxis 11.1 0.0 10.7 0.0 15.8 1.3 Oropharyngeal 8.3 0.0 6.7 0.0 11.8 0.0 pain Metabolism and nutrition disorders Decreased 20.8 0.0 10.7 0.0 21.1 0.0 appetite Eye disorders Lacrimation 12.5 0.0 5.3 0.0 7.9 0.0 increased Psychiatric disorders Insomnia 11.1 0.0 13.3 0.0 21.1 0.0 Investigations ALT increased 6.9 0.0 2.7 0.0 10.5 3.9 FEC=5-fluorouracil, epirubicin, cyclophosphamide, TCH=docetaxel, carboplatin, trastuzumab The following selected adverse reactions were reported in < 10% of patients receiving neoadjuvant treatment in Study 3: (Ptz=pertuzumab; T=trastuzumab; D=docetaxel; FEC=fluorouracil, epirubicin, and cyclophosphamide; TCH=docetaxel, carboplatin, and trastuzumab) Skin and subcutaneous tissue disorders: Nail disorder (9.7% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/ Ptz+T+D arm, and 9.2% in the Ptz+TCH arm), Paronychia (0% in the Ptz+T+FEC/Ptz+T+D and 1.3% in both the FEC/Ptz+T+D and Ptz+TCH arms), Pruritis (2.8% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 3.9% in the Ptz+TCH arm) Infections and infestations: Upper respiratory tract infection (8.3% in the Ptz+T+FEC/Ptz+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm), Nasopharyngitis (6.9% in the Ptz+T+FEC/Ptz+T+D arm, 6.7% in the FEC/Ptz+T+D arm, and 7.9% in the Ptz+TCH arm)

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Respiratory, thoracic, and mediastinal disorders: Pleural effusion (1.4% in the Ptz+T+FEC/Ptz+T+D arm and 0% in the FEC/Ptz+T+D and Ptz+TCH arm) Cardiac disorders: Left ventricular dysfunction (5.6% in the Ptz+T+FEC/PTZ+T+D arm, 4.0% in the FEC/Ptz+T+D arm, and 2.6% in the Ptz+TCH arm) including symptomatic left ventricular systolic dysfunction (CHF) (2.7% in the FEC/Ptz+T+D arm and 0% in the Ptz+T+FEC/Ptz+T+D and Ptz+TCH arms) 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in Study 1 were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/hypersensitivity reactions that were clearly related to the anti-therapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading. 7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to

20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryofetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights, and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use Of 402 patients who received PERJETA in Study 1, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety

of PERJETA were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

PERJETA® (pertuzumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No. 1048

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DRUG MONOGRAPHS

BREAST CANCER Adverse reactions: See literature. Increased risk of cardiovascular events, estrogen-dependent carcinoma, gallbladder disease, thromboembolic disorders, hepatic tumors. GI upset, breakthrough bleeding, edema, weight changes, mastodynia, hypertension, depression, anaphylactic reactions, angioedema, intolerance to contact lenses. How supplied: Tabs 0.3mg, 0.625mg, 1.25mg–100, 1000; 0.45mg, 0.9mg–100

SOLTAMOX ORAL

SOLUTION DARA BioSciences

℞

Antiestrogen. Tamoxifen (as citrate) 10mg/5mL; licorice and aniseed flavors; sugar-free; contains alcohol. Indications: Treatment of metastatic breast cancer in men and women. Axillary node-positive breast cancer in postmenopausal women after surgery + irradiation. Axillary node-negative breast cancer in women after surgery + irradiation. Reduction in risk of invasive breast cancer in women with ductal carcinoma in situ (DCIS) after surgery + radiation. Reduction in breast cancer incidence in high-risk women. Adults: Treatment: 20–40mg/day; give doses >20mg in divided doses (AM and PM). Reduction of incidence in high-risk women or DCIS: 20mg once daily for 5 years. Children: Not recommended. Contraindications: For reduction in incidence in high-risk women and women with DCIS: concomitant coumarin anticoagulants, history of deep vein thrombosis or pulmonary embolism. Warnings/Precautions: See literature. Do gynecological exam at least annually. DCIS and risk reduction: consider increased risk of uterine cancer (endometrial adenocarcinoma, uterine sarcoma), stroke and pulmonary embolism. Women with advanced disease: discontinue if severe hypercalcemia occurs. Monitor blood, lipids, liver function, for thromboembolism symptoms (eg, leg swelling, unexplained shortness of breath), and for uterine changes/ cancer (eg, pelvic pain or pressure); promptly investigate any abnormal vaginal bleeding. Breast cancer treatment: history of thromboembolic events. Pregnancy (Cat.D); avoid. Premenopausal: use effective nonhormonal contraception during and within 2 months of discontinuing therapy; begin therapy during menses or, if irregular menses, obtain (−) B-hCG pregnancy test first. Nursing mothers: not recommended. Interactions: See Contraindications. May potentiate oral anticoagulants; if co-administered, monitor PT. Concomitant anastrozole: not recommended. Antagonizes letrozole. Plasma

℞

Interactions: May potentiate oral anticoagulants (see Contraindications). Antagonizes anastrozole (avoid concomitant use); letrozole. Plasma levels reduced by CYP3A4 inducers (eg, rifampin). Cytotoxic drugs increase risk of thrombotic events. Potentiated by bromocriptine. Adverse reactions: Hot flashes, vaginal discharge, altered menses, rash, headache, nausea, cough, edema, fatigue, abdominal cramps, bone and tumor pain (in advanced disease), local disease flare, hypercalcemia, thrombotic events, ovarian cysts, uterine fibroids or cancer (endometrial adenocarcinoma, uterine sarcoma), endometrial or visual changes, jaundice, hypertriglyceridemia, blood dyscrasias, hair loss. How supplied: Contact supplier.

Antiestrogen. Tamoxifen (as citrate) 10mg, 20mg; tabs. Indications: Treatment of metastatic breast cancer in men and women. Axillary node-positive breast cancer in postmenopausal women after surgery + irradiation. Axillary node-negative breast cancer in women after surgery + irradiation. Reduction in risk of invasive breast cancer in women with ductal carcinoma in situ (DCIS) after surgery + radiation. Reduction in breast cancer incidence in high-risk women. Adults: Treatment: 20–40mg/day; give doses >20mg in divided doses (AM and PM). Reduction of incidence in high-risk women or DCIS: 20mg once daily for 5 years. Children: McCune-Albright Syndrome, precocious puberty: see literature. Contraindications: For risk reduction: concomitant coumarin anticoagulants, history of deep vein thrombosis or pulmonary embolism, planned pregnancy. Pregnancy (Cat.D). Nursing mothers. Warnings/Precautions: See literature. Do gynecological exam at least annually. DCIS and risk reduction: consider increased risk of uterine cancer (endometrial adenocarcinoma, uterine sarcoma) and thrombotic events. Women with advanced disease: discontinue if severe hypercalcemia occurs. Monitor blood, lipids, liver function, for thromboembolism symptoms (eg, leg swelling, unexplained shortness of breath), and for uterine changes/cancer (eg, pelvic pain or pressure); promptly investigate any abnormal vaginal bleeding. Breast cancer treatment: history of thromboembolic events. Premenopausal: use effective non-hormonal contraception during and within 2 months of discontinuing therapy; begin therapy during menses or, if irregular menses, obtain (−) B-hCG pregnancy test first.

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. Also: Methotrexate injection Bedford ℞ Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free. Also: Methotrexate for injection Bedford ℞ Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free. Indications: Breast cancer. Adults: See literature. Children: Not established. Contraindications: Pregnancy (Cat.X). Nursing mothers. Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration). Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer. Ulcerative colitis. Infection. Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated.

levels reduced by CYP3A4 inducers (eg, rifampin, aminoglutethimide). Cytotoxic drugs increase risk of thrombotic events. Potentiated by bromocriptine. Adverse reactions: Hot flashes, vaginal discharge, altered menses, oligomenorrhea, nausea, cough, edema, fatigue, abdominal cramps, bone and tumor pain (in advanced disease), local disease flare, hypercalcemia, thrombotic events, ovarian cysts, uterine fibroids or cancer (endometrial adenocarcinoma, uterine sarcoma), endometrial or visual changes, liver abnormalities, hypertriglyceridemia, blood dyscrasias, hair loss. How supplied: Soln–150mL

Tamoxifen (various)

TREXALL Teva

℞

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DRUG MONOGRAPHS

BREAST CANCER Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin). Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome). How supplied: Tabs–30; soln (2mL, 4mL, 8mL, 10mL)–10 (single-use vials); pwd (1 gram)–1 (single-use vial)

TYKERB GlaxoSmithKline

℞

Tyrosine kinase inhibitor. Lapatinib 250mg; tabs. Indications: In combination with capecitabine, for the treatment of patients with advanced or metastatic breast cancer whose tumors overexpress HER2 and who have received prior therapy including an anthracycline, a taxane, and trastuzumab. Limitation of use: patients should have disease progression on trastuzumab before initiating Tykerb in combination with capecitabine. In combination with letrozole for the treatment of postmenopausal women with hormone receptor positive metastatic breast cancer that overexpresses HER2 for whom hormonal therapy is indicated. Adults: Take 1hr before or 1hr after a meal (capecitabine should be taken with food or within 30mins after food). HER2 metastatic breast cancer: 1250mg (5 tabs) once daily on Days 1–21 continuously in combination with capecitabine 2000mg/m2/day (administered orally in 2 doses approx. 12hrs apart) on Days 1–14 in a repeating 21 day cycle; continue until disease progression or unacceptable toxicity occurs. After recovery from left ventricular ejection fraction (LVEF) decrease: 1000mg/day. Severe hepatic dysfunction (Child-Pugh Class C): 750mg/day (no clinical data for this dose adjustment). Concomitant potent CYP3A4 inducers: may titrate up to 4500mg/day (no clinical data for this dose adjustment). Hormone receptor positive, HER2 positive metastatic breast cancer: 1500mg (6 tabs) once daily continuously in combination with letrozole 2.5mg once daily. After recovery from LVEF decrease: 1250mg/day. Severe hepatic dysfunction: 1000mg/day (no clinical data for this dose adjustment). Concomitant potent CYP3A4 inducers: may titrate up to 5500mg/day (no clinical data for this dose

adjustment). For both: Concomitant potent CYP3A4 inhibitors: 500mg/day (no clinical data for this dose adjustment). Interrupt if diarrhea is NCI CTC grade 3, or grade 1 or 2 with complicating features develop; may restart at lower dose (reduced from 1250mg/day to 1000mg/day or from 1500mg/day to 1250mg/day) when resolves ≤ grade 1; permanently discontinue if diarrhea is grade 4. Other toxicities: discontinue if ≥grade 2 NCI CTC toxicity occurs; may restart at 1250mg/day if toxicity improves to grade 1; if recurs, may restart at 1000mg/day (with capecitabine); 1250mg/day (w. letrozole). Children: Not established. Warnings/Precautions: Confirm normal LVEF before starting. Discontinue if ≥grade 2 decrease in LVEF occurs, or if LVEF falls below institution’s lower limit of normal; may restart after at least 2 weeks at reduced dose if asymptomatic and LVEF recovers. Conditions that impair left ventricular function, or risk factors for QT prolongation (eg, hypokalemia, hypomagnesemia, congenital long QT syndrome, concomitant antiarrhythmics, cumulative high dose anthracyclines); correct electrolyte disturbances before starting. Monitor for interstitial lung disease or pneumonitis; discontinue if pulmonary symptoms ≥grade 3 (NCI CTCAE). Monitor liver function tests before, every 4–6 weeks during therapy and as indicated; discontinue if hepatotoxicity occurs; do not retreat. Severe hepatic impairment: consider dose reduction. Diarrhea: promptly treat with anti-diarrheal agents; if severe, may require fluids, electrolytes, antibiotics and therapy interruption/ discontinuation. Monitor ECG. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Avoid potent CYP3A4 inhibitors (eg, ketoconazole), grapefruit; reduce dose if unavoidable. Avoid potent CYP3A4 inducers (eg, carbamazepine); slowly titrate dose up if unavoidable. May affect drugs that are affected by p-glycoprotein, CYP2C8, CYP3A4. Adverse reactions: Diarrhea (may be severe), nausea, vomiting, hand/foot syndrome, rash, fatigue; decreased LVEF, QT prolongation, interstitial lung disease, pneumonitis, hepatotoxicity (may be fatal). Testing considerations: HER2 protein overexpression How supplied: Tabs–150

XELODA Roche

℞

Fluoropyrimidine. Capecitabine (prodrug of 5-fluorouracil) 150mg, 500mg; tabs. Indications: Metastatic breast cancer resistant to both paclitaxel and an anthracyclinecontaining chemotherapy regimen or resistant to paclitaxel when further anthracycline therapy is not indicated (eg, prior cumulative doses of 400mg/m2 of doxorubicin or its equivalents). With docetaxel for metastatic breast cancer after failure of prior anthracycline-containing regimen.

Adults: See literature. Give cyclically (2 weeks on, 1 week off). Take with water within 30 minutes after AM & PM meals. ≥18yrs: 1250mg/m2 twice daily. Combination therapy: give with docetaxel 75mg/m2 IV infused over 1 hour every 3 weeks. Interrupt, adjust dose, and/or treat symptoms if toxicity occurs (eg, hyperbilirubinemia, diarrhea, nausea, vomiting, hand-and-foot syndrome, stomatitis) (see literature); do not increase dose afterwards. Renal impairment (CrCl 51–80mL/min): monitor carefully; (CrCl 30–50mL/min): reduce capecitabine dose to 75% of starting dose (ie, 950mg/m2 twice daily). Children: <18yrs: not recommended. Contraindications: Severe renal impairment (CrCl <30mL/min). Dihydropyrimidine dehydrogenase deficiency. Pregnancy (Cat.D), nursing mothers: not recommended. Warnings/Precautions: Hepatic or renal dysfunction. Coronary artery disease. Elderly (≥80years). Interactions: Potentiated by leucovorin. Monitor warfarin, other CYP2C9 substrates, phenytoin. Adverse reactions: Diarrhea, lymphopenia, necrotizing enterocolitis, hand-and-foot syndrome, GI upset, stomatitis, fatigue, dermatitis, anorexia, cardiotoxicity, bone marrow suppression, blood dyscrasias, hyperbilirubinemia, paresthesias, eye irritation, fever, headache, edema, dizziness, insomnia, myalgia, dehydration, nail disorder, limb pain, skin discoloration, alopecia. Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase) How supplied: Tabs 150mg–60; 500mg–120

CARE OF DRUGS Patients should be advised that all drug preparations require careful storage.

DOSAGE Recommended adult dosage and, where appropriate, the dosage for children. Doses are given for children <12 years of age unless stated otherwise. Assume the adult dosage for children ≥12 years. Dosages for children are presented in ascending age order.

SEE LITERATURE Consult the manufacturer’s labeling for full prescribing information.

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DRUG MONOGRAPHS

ENDOCRINE CANCER ABRAXANE Celgene

℞

Taxane antimicrotubule. Paclitaxel [bound to albumin (human)] 100mg/vial; pwd for IV infusion after reconstitution; solvent-free. Indications: First-line treatment of metastatic adenocarcinoma of the pancreas, in combination with gemcitabine. Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3. 125mg/m2 IV over 30–40 minutes on Days 1, 8, and 15 of each 28-day cycle. Dose reductions for hematologic and neurologic adverse reactions, hepatic impairment: see full labeling. Avoid extravasation. Children: Not evaluated. Contraindications: Baseline neutrophil count <1,500 cells/mm3. Prior severe hypersensitivity reaction (do not rechallenge). Warnings/Precautions: Do not substitute for, or with, other paclitaxel products (due to formulation differences). Do frequent complete blood cell counts. Monitor for sensory neuropathy, sepsis, or pneumonitis. Hepatic or renal dysfunction. Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: May potentiate or be potentiated by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir). Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events. How supplied: Single-use vial–1

AFINITOR Novartis

℞

mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs. Indications: Progressive neuroendocrine tumors of pancreatic origin (PNET) in adults with unresectable, locally advanced or metastatic disease. Not for treating functional carcinoid tumors. Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic

impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated. Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risk. Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor. Concomitant strong CYP3A4/PgP inducers: consider doubling the daily dose by increments of 5mg or less. If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions, or others: see full labeling. Children: Not recommended. Contraindications: Allergy to other rapamycin derivatives. Warnings/Precautions: Monitor for new or worsening respiratory symptoms. Increased risk of infections; some may be severe or fatal; monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines. Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/ PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used. Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid. Adverse reactions: Pneumonitis (interrupt, reduce dose and/or manage with corticosteroids; if severe, discontinue; may reintroduce daily dose at approx. 50% lower than previously administered), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with nonalcoholic, non-peroxide mouthwash), diarrhea, nausea, abdominal pain, rash, fatigue, edema, fever, asthenia, cough, headache, decreased

appetite; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; proteinuria, renal failure, others (see full labeling). How supplied: Tabs–28 (4 blister cards × 7 tabs)

CAPRELSA AstraZeneca

℞

Kinase inhibitor. Vandetanib 100mg, 300mg, tabs. Indications: Symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease. Adults: Do not crush tabs. May disperse tabs in 2oz noncarbonated water for oral or NGT administration; avoid contact of dispersion with skin, mucous membranes. 300mg once daily. Renal impairment (CrCl<50mL/min): initially 200mg once daily. Dose adjustments for adverse reactions: see full labeling. Do not take a missed dose within 12hrs of the next dose. Children: Not established. Contraindications: Congenital long QT syndrome. Warnings/Precautions: Hypocalcemia, hypokalemia, hypomagnesemia, QTcF interval >450msec, history of torsades de pointes, bradyarrhythmias, uncompensated heart failure, recent hemoptysis: not recommended. Ventricular arrhythmias. Recent MI. Monitor electrolytes (esp. K+, Ca++, Mg++), TSH, and ECG for QT prolongation at baseline, 2–4 weeks and 8–12 weeks after starting, then every 3 months, and after dose reductions or dose interruptions >2 weeks; reduce dose as needed. Correct electrolyte disturbances before starting. Maintain serum K+ at least 4mEq/mL. Hepatic impairment (Child-Pugh B or C): not recommended. Interrupt therapy and follow-up if acute or worsening pulmonary symptoms, QTcF >500msec, or CTCAE Grade ≥3 toxicity occurs. Monitor for heart failure; consider discontinuing if occurs. Discontinue if confirmed interstitial lung disease, severe ischemic cerebrovascular event, hemorrhage, uncontrolled hypertension, or posterior leukoencephalopathy symptoms (RPLS) occur. Avoid sun, UV light. Elderly. Pregnancy (Cat.D) (may cause fetal harm; use appropriate effective contraception during and for 4 months after stopping therapy), nursing mothers: not recommended. Interactions: Avoid strong CYP3A4 inducers (eg, rifampicin, St. John’s Wort). Avoid other drugs that can prolong QT interval (eg, amiodarone, disopyramide, procainamide, sotalol, dofetilide, chloroquine, clarithromycin, dolasetron, granisetron, haloperidol, pimozide, methadone, moxifloxacin). Potentiates OCT2 transporters (eg, metformin), digoxin; monitor. Adverse reactions: Diarrhea/colitis (suspend if severe), rash, acneiform dermatitis, nausea,

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DRUG MONOGRAPHS

ENDOCRINE CANCER hypertension, headache, upper respiratory tract infections, decreased appetite, abdominal pain, hypocalcemia, hypoglycemia, increased ALT; QT prolongation, torsades de pointes, sudden death, severe skin reactions (eg, Stevens-Johnson syndrome; discontinue if occurs). Note: Prescribers and pharmacies must enroll in the Caprelsa REMS program by calling (800) 2369933 or visit www.caprelsarems.com. How supplied: Tabs–30

COMETRIQ Exelixis

℞

Kinase inhibitor. Cabozantinib 20mg, 80mg; caps. Indications: Treatment of progressive, metastatic medullary thyroid cancer (MTC). Adults: Swallow whole. 140mg daily. Do not eat at least 2 hours before or 1 hour after dose. Continue until disease progression or unacceptable toxicity. Withhold for Grade 4 hematologic adverse reactions, ≥Grade 3 non-hematologic reactions or intolerable Grade 2 reactions. Upon improvement to Grade 1 or to baseline, reduce dose as follows: previously on 140mg daily, resume at 100mg daily; previously on 100mg daily, resume at 60mg daily; previously on 60mg daily, resume at 60mg if tolerated, otherwise discontinue. Concomitant strong CYP3A4 inhibitor: reduce daily dose by 40mg; resume dose used prior to starting inhibitor 2–3 days after discontinuation of inhibitor. Concomitant strong CYP3A4 inducers: increase daily dose by 40mg; resume dose used prior to starting inducer 2–3 days after discontinuation of inducer. Max daily dose: 180mg. Children: Not studied. Warnings/Precautions: Permanently discontinue if the following occurs: GI or non-GI perforation/fistula formation, severe hemorrhage, serious arterial thromboembolic events (eg, MI, cerebral infarction), nephrotic syndrome, malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management, osteonecrosis of the jaw, reversible posterior leukoencephalopathy syndrome. Moderate to severe hepatic impairment: not recommended. Recent history of hemorrhage, hemoptysis: avoid. Stop treatment at least 28 days prior to scheduled surgery (including invasive dental procedures); withhold dose if dehiscence or wound healing complications require medical intervention. Monitor for bleeding, hypertension, proteinuria (measure urine protein regularly). Use effective contraception during and up to 4 months after completion of therapy. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole, grapefruit or grapefruit juice) and strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort): see Adult dose. Adverse reactions: Diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome,

decreased weight/appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, constipation, increased AST, ALT, alkaline phosphatase, lymphopenia, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, hyperbilirubinemia. How supplied: 140mg daily-dose carton–4 blister cards (each: 7×80mg and 21×20mg caps); 100mg daily-dose carton–4 blister cards (each: 7×80mg and 7×20mg caps); 60mg daily-dose carton–4 blister cards (each: 21×20mg caps)

Fluorouracil (various)

℞

Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj. Indications: Palliative management of carcinoma of the pancreas. Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs. Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/week. Poor risk patients: see literature for dose adjustments. Children: Not recommended. Contraindications: Poor nutritional state. Depressed bone marrow function. Potentially serious infections. Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of highdose pelvic irradiation. Previous use of alkylating agents. Widespread involvement of bone marrow by metastatic tumors. Renal or hepatic impairment. Discontinue if signs of toxicity appear (eg, stomatitis, esophagopharyngitis, leukopenia, intractable vomiting, diarrhea, GI ulceration or bleeding, thrombocytopenia, hemorrhage). Monitor WBCs with differential before each dose. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Potentiated by leucovorin. Adverse reactions: Stomatitis, esophagopharyngitis, GI upset, anorexia, leukopenia, alopecia, dermatitis, hand-foot syndrome; others. Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase). How supplied: Contact supplier.

LYSODREN Bristol-Myers Squibb

℞

Adrenal cytotoxic agent. Mitotane 500mg; scored tabs. Indications: Inoperable adrenal cortical carcinoma. Adults: 2–6g/day in divided doses (3–4 times/day). Doses may be increased incrementally to 9–10g/day. Max: 18–19g/day. Continue as long as clinical benefit observed. Children: Not established. Warnings/Precautions: Discontinue temporarily following shock or severe trauma. Hepatic disease. Remove any tumor tissues from metastatic masses prior to therapy to minimize possible infarction

and hemorrhage. Long-term administration of high doses: assess behavioral and neurological function. May need concomitant steroid replacement; measure free cortisol and ACTH levels. Surgery. Pregnancy (Cat.D); use effective contraception during and after discontinuation until mitotane levels are undetectable. Nursing mothers: not recommended. Interactions: Concomitant oral anticoagulants, CYP3A4 substrates; monitor for change in dose requirements. Adverse reactions: Anorexia, nausea, vomiting, diarrhea, lethargy, somnolence, dizziness, vertigo, rash; prolonged bleeding. How supplied: Tabs–100

NEXAVAR Bayer and Onyx

℞

Multikinase inhibitor. Sorafenib 200mg; tabs. Indications: Locally recurrent or metastatic, progressive, differentiated thyroid carcinoma refractory to radioactive iodine treatment. Adults: Take on an empty stomach. 400mg twice daily. If toxicity occurs, may reduce dose to 400mg and 200mg 12hrs apart (either dose can come first); if second reduction is required, may reduce dose to 200mg twice daily; if third reduction is required, may reduce to 200mg once daily (see full labeling). Concomitant strong CYP3A4 inducers: consider increasing dose, monitor for toxicity. Children: Not established. Contraindications: Concomitant carboplatin/ paclitaxel in patients with squamous cell lung cancer. Warnings/Precautions: Avoid in congenital long QT syndrome. Monitor patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, electrolyte abnormalities. Discontinue if severe dermatologic toxicity, hypertension, GI perforation, hemorrhage, cardiac ischemia, MI occurs. Suspend therapy before major surgery. Monitor BP weekly during the first 6 weeks and thereafter. Monitor hepatic function regularly; discontinue if transaminases significantly elevated. Severe hepatic impairment (Child-Pugh C) or on dialysis. Monitor TSH levels monthly and adjust thyroid therapy. Use effective contraception during and for 2 weeks after stopping treatment. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: See Contraindications. Avoid strong CYP3A4 inducers (eg, St. John’s Wort, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampin, phenobarbital) and neomycin; may decrease sorafenib levels. May potentiate warfarin (monitor PT & INR), other drugs metabolized by UGT1A1 or UGT1A9 pathway, or substrates of CYP2B6, CYP2C8, CYP2C9, P-gp. Concomitant Class Ia and III antiarrhythmics; may prolong QT interval. Adverse reactions: Dermatologic toxicity (eg, rash, hand-foot skin reaction, alopecia, pruritus, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis), fatigue, weight loss, diarrhea, anorexia, abdominal pain, hypertension, hemorrhage, electrolyte abnormalities; druginduced hepatitis, QT prolongation. How supplied: Tabs–120

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DRUG MONOGRAPHS

ENDOCRINE CANCER SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 50mg; gelatin caps. Indications: Progressive, well-differentiated pancreatic neuroendocrine tumors (pNET) in patients with unresectable locally advanced or metastatic disease. Adults: 37.5mg once daily continuously without a scheduled off-treatment period. May adjust dose in increments or decrements of 12.5mg. Concomitant strong CYP3A4 inhibitors (see Interactions): may reduce dose to 25mg daily. Concomitant strong CYP3A4 inducers (see Interactions): may increase to max 62.5mg daily. Children: Not established. Warnings/Precautions: Hepatotoxicity; may be severe or fatal. Monitor liver function tests before starting, during each cycle of treatment and as clinically needed; interrupt if Grade 3 or 4 hepatic adverse events occur and discontinue if no resolution; if severe liver function changes or signs/ symptoms of failure, do not restart. Cardiovascular disease: monitor LVEF at baseline and periodically thereafter; interrupt or reduce dose if LVEF <50% and >20% below baseline; discontinue if CHF occurs. History of QT prolongation or proarrythmic conditions (eg, bradycardia, electrolyte disturbances); perform periodic ECG, monitor electrolytes. Monitor BP. Suspend therapy if severe hypertension, seizures, or pancreatitis develops. Obtain CBCs, platelets, serum chemistries at start of each cycle. Concomitant exposure to risk factors (eg, IV bisphosphonates therapy or dental disease) may increase the risk of osteonecrosis of the jaw; avoid or consider preventive dentistry prior to treatment. Risk of tumor lysis syndrome: monitor closely in RCC and GIST patients with high tumor burden. Monitor for thyroid dysfunction; obtain baseline levels prior to treatment. Undergoing major surgery. Stress (monitor for adrenal insufficiency). Renal or hepatic impairment. Pregnancy (Cat.D; avoid). Nursing mothers: not recommended. Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole); grapefruit. May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); St. John’s wort: not recommended. Adverse reactions: Fatigue, asthenia, fever, diarrhea, nausea, vomiting, mucositis/stomatitis, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, handfoot syndrome, skin discoloration, dry skin, hair

color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, bleeding; hepatotoxicity, left ventricular dysfunction, QT prolongation, hemorrhage, hypertension, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing, others (see full labeling). How supplied: Caps–28 ℞

disorders (eg, conjunctivitis, keratitis, corneal ulceration/perforation), MI/ischemia, hemolytic anemia, cerebrovascular accidents, interstitial lung disease; hepatic or renal failure and hepatorenal syndrome (may be fatal); bullous, blistering and exfoliative skin conditions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis). Testing considerations: K-RAS mutation analysis, EGFR amplification analysis How supplied: Tabs–30

Human epidermal growth factor receptor type 1/ epidermal growth factor receptor tyrosine kinase inhibitor. Erlotinib (as HCl) 25mg, 100mg, 150mg; tabs. Indications: In combination with gemcitabine: first-line treatment of locally advanced, unresectable or metastatic pancreatic cancer. Adults: Take on empty stomach. 100mg once daily + gemcitabine (see literature). Use until disease progression or unacceptable toxicity occurs. Diarrhea unresponsive to loperamide, severe skin reactions, strong CYP3A4 inhibitors (see Interactions), hepatic impairment: reduce in 50mg decrements. CYP3A4 inducers (see Interactions): consider increased dose (see literature). Children: Not recommended. Warnings/Precautions: Discontinue if interstitial lung disease, hepatic failure, or GI perforation occurs; interrupt or discontinue therapy in patients with dehydration at risk for renal failure, or with severe bullous, blistering or exfoliative skin conditions, or with acute/worsening ocular disorders. Hepatic impairment. Monitor liver function tests periodically; if tests worsen, consider withholding or reducing dose; interrupt or discontinue therapy if severe changes (eg, total bilirubin >3×ULN, and/or transaminases >5×ULN) occur. Monitor renal function, serum electrolytes, pulmonary function, INR, prothrombin time. History of peptic ulcers or diverticular disease. Pregnancy (Cat.D); use adequate contraception (see literature). Nursing mothers: not recommended. Interactions: Potentiated by CYP3A4 inhibitors (eg, clarithromycin, ritonavir, ketoconazole). Plasma levels decreased by CYP3A4 inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort), proton pump inhibitors or H2 blockers, and smoking. Antagonizes midazolam. Increased risk of GI perforation with concomitant anti-angiogenic agents, steroids, NSAIDs, taxane-based chemotherapy. Monitor for bleeding with oral anticoagulants, NSAIDs. Adverse reactions: Rash, diarrhea, GI upset, anorexia, fatigue, elevated LFTs, unexplained pulmonary symptoms (eg, dyspnea, cough, fever; discontinue and follow-up if occurs), stomatitis, infection; rare: GI perforation (may be fatal), ocular

Thyroid stimulating hormone (recombinant). Thyrotropin alfa 1.1mg/vial; lyophilized pwd for IM inj after reconstitution; contains mannitol. Indications: Adjunctive diagnostic tool for serum thyroglobin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer. Adjunctive treatment for radioiodine ablation of thyroid tissue remnants in patients who have undergone a near-total or total thyroidectomy for welldifferentiated thyroid cancer and who do not have evidence of metastatic thyroid cancer. Adults: ≥16yrs: Give by IM inj into the buttock. 0.9mg, followed by a second 0.9mg injection 24 hours later. For radioiodine imaging or remnant ablation, give radioiodine 24 hours after the second Thyrogen injection. Children: <16yrs: not established. Warnings/Precautions: See full labeling. Reports of death in patients who are not thyroidectomized or with distant metastatic thyroid cancer wthin 24hrs after administration. Heart disease, extensive metastatic disease, or other serious underlying illnesses; increased risk of Thyrogen-induced hyperthyroidism, consider hospitalization for administration and postadministration observation. Caution patients regarding possible neurologic symptoms. Consider pretreatment with glucocorticoids in those whose tumor expansion may compromise vital anatomic structures (eg, trachea, CNS, lung metastases). Thyroglobulin (Tg) antibodies may render Tg levels uninterpretable; consider further evaluation with thyroid hormone withdrawal scan. Previous bovine TSH treatment. Residual thyroid tissue. End-stage renal disease. Elderly (increased risk of cardiac effects). Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Nausea, headache, fatigue, influenza-like symptoms; death (in nonthyroidectomized or with distant metastatic thyroid cancer), stroke and other neurologic events, sudden rapid tumor enlargement in distant metastatic thyroid cancer. How supplied: 2-vial kit–2 vials of Thyrogen; 4-vial kit–2 vials of Thyrogen + 2 vials of diluent

TARCEVA Genentech

THYROGEN Genzyme

℞

Access Cancer Therapy Advisor treatment regimens in a user-friendly format. CancerTherapyAdvisor.com/TreatmentRegimens.

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CANCER TREATMENT REGIMEN

GASTROINTESTINAL CANCER Colon Cancer Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Advanced or Metastatic Disease1 Note: All recommendations are Category 2A unless otherwise indicated

REGIMEN

DOSING

mFOLFOX6

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours Day 1: Leucovorin 400mg/m2* IV over 2 hours Days 1–3: 5-FU 400mg/m2 IV bolus on day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† IV continuous infusion. Repeat cycle every 2 weeks.

mFOLFOX6 + Bevacizumab3,5

mFOLFOX6 + Panitumumab3,6

CapeOX2

Day 1: Oxaliplatin 130mg/m2 IV over 2 hours Days 1–14: Capecitabine 850–1,000mg/m2‡ twice daily PO. Repeat cycle every 3 weeks.

CapeOX + Bevacizumab2,7

Day 1: Oxaliplatin 130mg/m2 IV over 2 hours Days 1–14: Capecitabine 850–1,000mg/m2‡ PO twice daily Day 1: Bevacizumab 7.5mg/kg IV. Repeat cycle every 3 weeks.

FOLFIRI8

FOLFIRI8 + Bevacizumab9

Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes Day 1: Leucovorin 400mg/m2* IV infusion to match duration of irinotecan infusion Days 1–3: 5-FU 400mg/m2 IV bolus day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† IV continuous infusion Day 1: Bevacizumab 5mg/kg IV. Repeat cycle every 2 weeks.

FOLFIRI8 + Cetuximab11

Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes Day 1: Leucovorin 400mg/m2* IV infusion to match duration of irinotecan infusion Days 1–3: 5-FU 400mg/m2 IV bolus day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† IV continuous infusion, plus Days 1 and 8: Cetuximab 400mg/m2 IV over 2 hours first infusion, then 250mg/m2 IV over 60 minutes.10 OR Day 1: Cetuximab 500mg/m2 IV over 2 hours. Repeat cycle every 2 weeks

2-4

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GASTROINTESTINAL CANCER Advanced or Metastatic Disease1 (continued) REGIMEN

DOSING

FOLFIRI8 + Panitumumab12

FOLFIRI + ziv-aflibercept13

Day 1: Irinotecan 180mg/m2 IV over 30–90 minutes Day 1: Leucovorin 400mg/m2* IV infusion to match duration of irinotecan infusion Days 1–3: 5-FU 400mg/m2 IV bolus day 1, then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† continuous infusion Day 1: Ziv-aflibercept 4mg/kg IV over 1 hour. Repeat cycle every 2 weeks.

Capecitabine14

Days 1–14: 850–1,250mg/m2 PO twice daily. Repeat cycle every 3 weeks.

Capecitabine14 + Bevacizumab7

Days 1–14: Capecitabine 850–1,250mg/m2 PO twice daily Day 1: Bevacizumab 7.5mg/kg IV. Repeat cycle every 3 weeks.

Bolus or infusional 5-FU/leucovorin Roswell Park regimen15

Days 1, 8, 15, 22, 29, and 36: Leucovorin 500mg/m2 IV over 2 hours Days 1, 8, 15, 22, 29, and 36: 5-FU 500mg/m2 IV bolus 1 hour after start of leucovorin. Repeat cycle every 8 weeks.

Simplified biweekly infusional 5-FU/ LV (sLV5FU2)8

Day 1: Leucovorin 400mg/m2* IV over 2 hours Days 1–3: 5-FU bolus 400mg/m2 and then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46–48 hours)† continuous infusion. Repeat cycle every 2 weeks.

Weekly infusional LV5FU216, 17

Day 1: Leucovorin 20mg/m2 IV over 2 hours Day 1: 5-FU 500mg/m2 IV bolus injection 1 hour after the start of leucovorin Day 1: 5-FU 2,600mg/m2 by 24-hour infusion plus leucovorin 500mg/m2 Repeat cycle every week.

IROX18

Day 1: Oxaliplatin 85mg/m2 IV over 2 hours, followed by irinotecan 200mg/m2 IV over 30 or 90 minutes. Repeat cycle every 3 weeks.

FOLFOXIRI ± bevacizumab19, 20

Day 1: Irinotecan 165mg/m2 IV, plus oxaliplatin 85mg/m2 IV Day 1: Leucovorin 400mg/m2* Days 1–3: Fluorouracil 1,600mg/m2/day × 2 days (total 3,200mg/m2 over 48 hours)† continuous infusion starting on day 1, ± Day 1: Bevacizumab 5mg/kg IV. Repeat cycle every 2 weeks.

Irinotecan21, 22

Days 1 and 8: Irinotecan 125mg/m2 IV over 30–90 minutes. Repeat cycle every 3 weeks. OR Day 1: Irinotecan 300–350mg/m2 IV over 30–90 minutes. Repeat cycle every 3 weeks.

Cetuximab (KRAS/NRAS WT gene only) ± irinotecan11,23

Cetuximab 400mg/m2 first infusion, then 250mg/m2 IV weekly OR cetuximab 500mg/m2 IV every 2 weeks, ± Irinotecan 300–350mg/m2 IV every 3 weeks OR irinotecan 180mg/m2 IV every 2 weeks OR irinotecan 125mg/m2 on days 1 and 8 and repeat every 3 weeks.

Cetuximab (KRAS/NRAS WT gene only)11

Day 1: Cetuximab 400mg/m2 first infusion, then 250mg/m2 IV weekly23 OR 500mg/m2 IV over 2 hours. Repeat cycle every 2 weeks.

Panitumumab24 (KRAS/NRAS WT gene only)

Panitumumab 6mg/kg IV over 60 minutes every 2 weeks.

Regorafenib25

Days 1–21: Regorafenib 160mg PO daily. Repeat cycle every 28 days. continued

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GASTROINTESTINAL CANCER Colon Cancer Treatment Regimens Adjuvant Chemotherapy Regimens1 Principals of Adjuvant Therapy1 Capecitabine appears to be equivalent to bolus 5-FU/leucovorin in patients with stage III colon cancer.26 FOLFOX is superior to fluoropyrimidine therapy alone for patients with stage III colon cancer.27,28 FOLFOX isreasonable for high-risk or intermediate-risk stage II patients and is not indicated for good- or average-risk patients with stage II colon cancer. FLOX is an alternative to FOLFOX.29 A survival benefit has not been demonstrated for the addition of oxaliplatin to 5-FU/leucovorin in stage II colon cancer.30 A benefit for the addition of oxaliplatin to 5-FU/leucovorin in patients age 70 and older has not been proven.30 Bolus 5-FU/leucovorin/irinotecan should not be used in adjuvant therapy,31 and infusional 5-FU/leucovorin/irinotecan (FOLFIRI) has not been shown to be superior to 5-FU/LV.32,33 Capecitabine/oxaliplatin is superior to bolus 5-FU/leucovorin.34 Bevacizumab, cetuximab, panitumumab, or irinotecan should not be used in the adjuvant setting for patients with stage II or III colon cancer outside the setting of a clinical trial. REGIMEN

DOSING

mFOLFOX6

FLOX38

5-FU 500mg/m2 IV bolus weekly × 6 + leucovorin 500mg/m2 IV weekly × 6, each 8-week cycle × 3 with oxaliplatin 85mg/m2 IV administered on weeks 1, 3, and 5 of each 8-week cycle × 3.

Capecitabine39

Days 1–14: 1,250mg/m2 twice daily PO. Repeat cycle every 3 weeks for 24 weeks.

CapeOx40

Day 1: Oxaliplatin 130mg/m2 over 2 hours, day 1 Days 1–14: Capecitabine 1,000mg/m2 twice daily PO. Repeat cycle every 3 weeks for 24 weeks.

5-FU/leucovorin41, 42

Leucovorin 500mg/m2 given as a 2-hour infusion and repeated weekly × 6 weeks, plus 5-FU 500mg/m2 given IV bolus 1 hour after the start of leucovorin and repeated weekly × 6 weeks. Repeat cycle every 8 weeks for 4 cycles. OR Simplified biweekly infusional 5-FU/LV (sLV5FU2) Leucovorin 400mg/m2* IV over 2 hours on day 1, followed by 5-FU bolus 400mg/m2 and then 1,200mg/m2/day × 2 days (total 2,400mg/m2 over 46-48 hours)† continuous infusion. Repeat cycle every 2 weeks.

35-37

* Leucovorin 400mg/m2 is the equivalent of levoleucovorin 200mg/m2. † NCCN recommends limiting chemotherapy orders to 24-hour units (i.e., 1,200mg/m2/day NOT 2,400mg/m2 over 48 hours) to minimize medication errors. ‡ The majority of safety and efficacy data for this regimen have been developed in Europe, where a capecitabine starting dose of 1,000mg/m2 twice daily for 14 days, repeated every 21 days, is standard. Evidence suggests that North American patients may experience greater toxicity with capecitabine (as well as with other fluoropyrimidines) than European patients, and may require a lower dose of capecitabine. The relative efficacy of CapeOx with lower starting doses of capecitabine has not been addressed in large-scale randomized trials.

References 1. 2. 3. 4.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Colon Cancer V.2.2015. Available at: http://www. nccn.org. Accessed October 6, 2014. deGramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced rectal cancer. J Clin Oncol. 2000;18:2938–2947. Cheeseman SL, Joel SP, Chester JD, et al. A “modified deGramont” regimen of fluorouracil, alone and with oxaliplatin, for advanced colorectal cancer. Br J Cancer. 2002;87:393–399. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12177775. Maindrault-Goebel F, deGramont A, Louvet C, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Ann Oncol. 2000; 11:1477–1483.

Emmanouilides C, Sfakiotaki G, Androulakis N, et al. Front-line bevacizumab in combination with oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) in patients with metastatic colorectal cancer: a multicenter phase II study. BMC Cancer. 2007;7:91. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase Ill trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study. J Clin Oncol. 2010;28: 4697–4705. Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase Ill study. J Clin Oncol. 2008;26:2013–2019. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18421054.

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GASTROINTESTINAL CANCER 8.

Andre T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. Eur J Cancer. 1999;35(9): 1343–1347. 9. Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treatment of metastatic colorectal cancer: results from the BICC-C Study. J Clin Oncol. 2007;25: 4779–4786. Available at: http://www.ncbi.nlm.nih.gov/pubmed/ 17947725. 10. Cunningham D, Humblet Y, Siena 5, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N EngI J Med. 2004;351: 337–345. 11. Martin-Martorell P, Rosellô S, Rodriguez-Braun E, et al. Biweekly cetuximab and irinotecan in advanced colorectal cancer patients progressing after at least one previous line of chemotherapy: results of a phase II single institution trial. Br J Cancer. 2008;99:455–458. 12. Peeters M, Price TJ, Cervantes A, et al. Randomized phase Ill study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Gun Oncol. 2010;28:4706–4713. Available at: http://www.ncbi.nlm.nih. gov/pubmed/20921462. 13. Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase Ill Randomized Trial in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen. J Clin Oncol. 2012;30:3499–3506. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22949147. 14. Van Cutsem E, Twelves C, Cassidy J, et al. Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase Ill study. J Clin Oncol. 2001;19:4097–4106. 15. Wolmark N. Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Protocol C-03. J Clin Oncol. 1993;11: 1879–1887. 16. Jäger E, Heike M, Bernhard H, et al. Weekly high-dose leucovorin versus low-dose leucovorin combined with fluorouracil in advanced colorectal cancer: results of a randomized multicenter trial. J Clin Oncol. 1996;14:2274–2279. 17. Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomized trial. Lancet. 2000;355:1041–1047. 18. Haller DG, Rothenberg ML, Wong AO, et al. Oxaliplatin plus irinotecan compared with irinotecan alone as second-line treatment after single agent fluoropyrimidine therapy for metastatic colorectal carcinoma. J Clin Oncol. 2008;26: 4544–4550. 19. Falcone A, Ricci S, Brunetti I, et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: The Gruppo Oncologico Nord Ovest. J Clin Oncol. 2007; 25(13):1670–1676. 20. Loupakis F, Cremolini C, Masi G, et al. FOLFOXIRI plus bevacizumab (bev) versus FOLFIRI plus bev as first-line treatment of metastatic colorectal cancer (MCRC): results of the phase III randomized TRIBE trial. J Clin Oncol. 2013;31(Suppl 4) Abstract 336. 21. Cunningham D, Pyrhonen S, James R, et al. Randomized trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet. 1998;352:1413–1418. 22. Fuchs CS, Moore MR, Harker G, et al. Phase Ill comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer. J Clin Oncol. 2003;21:807–814. 23. Van Cutsem E, Tejpar S, Vanbeckevoort D, et al. Intrapatient Cetuximab Dose Escalation in Metastatic Colorectal Cancer According to the Grade of Early Skin Reactions: The Randomized EVEREST Study. J Clin Oncol. 2012;30:2861–2868. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/22753904.

24. Van Custem E, Peeters M, Siena S, et al. Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol. 2007;25:1658–1664. 25. Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303–312. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23177514. 26. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engi J Med. 2005; 352(26):2696–2704 27. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Eng J Med. 2004:350:2343–2351. 28. Andre T, Boni C, Navarro M, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trail. J Clin Oncol. 2009;27:3109–3116 [Epub 2009 May 18]. 29. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007;25:2198–2204. 30. Toumigand C, André T, Bonnetain F, et al. Adjuvant therapy with fluorouracil and oxaliplatin in stage II and elderly (between ages 70 and 75 years) with colon cancer: a subgroup analyses of the Multicenter International Study of oxaliplatin, fluorouracil, and leucovorin in the adjuvant treatment of colon cancer trial. J Clin Oncol. August 20, 2012 [Epub ahead of print]. 31. Saltz LB, Niedzwieecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB C89803. J Clin Oncol. 2007:25:3546–3561. 32. Van Cutsem E, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol. 2009;27: 3117–3125. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19451425. 33. Ychou M, Raoul JL, Douillard JY, et al. A phase III randomized trial of LV5FU2 + irinotecan versus LV5FU2 alone in adjuvant high-risk colon cancer (FNCLCC Accord02/FFCD9802). Ann Oncol. 2009;20:674–80 [Epub 2009 Jan 29]. 34. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011; 29:1465–1471. 35. Andre T, Boni C, Mounedji-Boudiaf L, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N EngI J Med. 2004;350:2343–2351. 36. Cheeseman SL, Joel SP, Chester JD, et al. A “modified deGramont” regimen of fluorouracil, alone and with oxaliplatin, for advanced colorecta l cancer. Br J Cancer. 2002;87:393–399. Available at: http://www.ncbi.nlm.nih. gov/pubmed/12177775. 37. Maindrault-Goebel F, deGramont A, Louvet C, et al. Evaluation of oxaliplatin dose intensity in bimonthly leucovorin and 48-hour 5-fluorouracil continuous infusion regimens (FOLFOX) in pretreated metastatic colorectal cancer. Annals of Oncology. 2000;11:1477–1483. 38. Kuebler JP, Wieand HS, O’Connell MJ, et al. Oxaliplatin combined with weekly bolus fluorouracil and leucovorin as surgical adjuvant chemotherapy for stage II and III colon cancer: results from NSABP C-07. J Clin Oncol. 2007:25:2198–2204. 39. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Eng J Med. 2005; 352:2696–2704. 40. Schmoll HJ, Cartwright T, Tabernero J, et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol. 2007;25:102–109. Hailer DG, Tabernero J, Maroun J, et al. Capecitabine Plus Oxaliplatin Compared With Fluorouracil and Folinic Acid As Adjuvant Therapy for Stage Ill Colon Cancer. J Clin Oncol 2011;29:1465–1471. Available at: http://www.ncbi.nlm.nih.gov/ pubmed/21383294. 41. Haller DG, Catalano PJ, Macdonald JS Mayer RJ. Phase III study of fluorouracil, leucovorin and levamisole in high risk stage II and III colon cancer: final report of Intergroup 0089. J Clin Oncol. 2005:23:8671–8678. 42. Andre T, Louvet C, Maindrault-Goebel F, et al. CPT-11 (irinotecan) addition to bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFIRI) for pretreated metastatic colorectal cancer. Eur J Cancer. 1999;35(9):1343–1347.

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free. Indications: Metastatic colorectal carcinoma, in combination with 5-FU-based chemotherapy for first- or second-line treatment; or in combination with fluoropyrimidine-irinotecanor fluoropyrimidine-oxaliplatin-based therapy for second-line treatment in patients who have progressed on a first-line Avastin-containing regimen. Limitation of use: not for adjuvant treatment of colon cancer. Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins. 5mg/kg (when used with bolus-IFL) or 10mg/kg (when used with FOLFOX-4) once every 2 weeks until disease progression detected; 5mg/kg every 2 weeks or 7.5mg/kg every 3 weeks (when used with fluoropyrimidine-irinotecan- or fluoropyrimidine-oxaliplatin-based therapy). Children: Not established. Warnings/Precautions: Risk of GI perforations, surgery and wound healing complications, and hemorrhage. Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). Do not administer if recent history of hemoptysis of ≥ ½-teaspoon of red blood. Permanently discontinue if GI perforation, tracheoesophageal fistula, any grade 4 fistula, or grade 4 venous thromboembolic event. Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior reversible encephalopathy syndrome, or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction. History of arterial thromboembolism. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection. Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis; GI perforation and fistulae, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure, neutropenia, and infection. How supplied: Single-use vial–1

CYRAMZA Lilly

℞

Human IgG1 monoclonal antibody. Ramucirumab 10mg/mL; per vial; soln for IV infusion after dilution; preservative-free. Indications: As a single agent, or in combination with paclitaxel, for treatment of advanced or metastatic, gastric or gastro-esophageal junction adenocarcinoma with disease progression on or after prior fluoropyrimidine- or platinumcontaining chemotherapy. Adults: Give by IV infusion over 60 mins. Premedicate with IV histamine H1-antagonist (eg, diphenhydramine) prior to each infusion; or with dexamethasone and acetaminophen in those who have experienced Grade 1 or 2 infusion reaction. 8mg/kg every 2 weeks; continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Increased risk of hemorrhage; permanently discontinue if severe bleeding occurs. Control hypertension prior to initiating. Monitor blood pressure every 2 weeks or more frequently as indicated; if severe hypertension develops, temporarily suspend until medically controlled. Monitor for infusionrelated reactions during therapy. Have emergency resuscitative equipment available. Permanently discontinue if severe arterial thromboembolic events, severe uncontrolled hypertension (despite antihypertensives), hypertensive crisis or encephalopathy, Grade 3 or 4 infusion-related reactions, urine protein >3g/24hrs, nephrotic syndrome, or GI perforation occurs. Impaired wound healing: withhold Cyramza prior to surgery. Clinical deterioration in patients with Child-Pugh B or C cirrhosis (eg, new or worsening encephalopathy, ascites, hepatorenal syndrome). Discontinue if reversible posterior leukoencephalopathy syndrome develops. Pregnancy (Cat.C); avoid; use effective contraception during therapy and for ≥3 months after completion. Nursing mothers: not recommended. Adverse reactions: Hypertension, diarrhea, headache, fatigue, hyponatremia, anemia, intestinal obstruction, neutropenia, epistaxis, stomatitis/mucosal inflammation, rash, arterial thromboembolic events, proteinuria, GI perforation, infusion-related reactions. How supplied: Single-dose vial (10mL, 50mL)–1

ELOXATIN Sanofi Aventis

℞

Alkylating agent (organoplatinum complex). Oxaliplatin 5mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Adjuvant treatment for Stage III colon cancer in patients who have undergone complete resection of the primary tumor (in combination with infusional 5-FU/LV). Treatment of advanced colorectal cancer (in combination with infusional 5-FU/LV). Adults: See literature. Premedicate with antiemetics. Give by IV infusion every two

weeks for a total of 6 months (eg, 12 cycles). Day 1: 85mg/m2 + leucovorin, followed by 5-FU. Day 2: Leucovorin followed by 5-FU. Severe renal impairment: initially 65mg/m2. Neuropathy, other toxicities: see literature for dose adjustments. Children: Not recommended. Warnings/Precautions: Have epinephrine, corticosteroids, antihistamines available during infusion. Discontinue if interstitial lung disease or pulmonary fibrosis suspected. Monitor for neuropathy; reduce dose or discontinue if needed. Renal impairment. Monitor WBCs with differential, hemogloblin, platelets, blood chemistries (including ALT, AST, bilirubin, creatinine) before each treatment. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Caution with concomitant nephrotoxic agents. Monitor oral anticoagulants. Adverse reactions: Peripheral sensory neuropathy, neutropenia, thrombocytopenia, anemia, GI upset, increased liver enzymes, emesis, fatigue, stomatitis; hypersensitivity reactions (monitor), pulmonary fibrosis (may be fatal), hepatotoxicity. Testing considerations: ERCC1 overexpression How supplied: Single-use vials (50mg, 100mg, 200mg)–1

ERBITUX Bristol-Myers Squibb

℞

Epidermal growth factor receptor blocker. Cetuximab 100mg/vial, 200mg/vial; soln for IV infusion; preservative-free. Indications: K-Ras mutation-negative (wildtype), EGFR-expressing metastatic colorectal carcinoma: for use in combination with FOLFIRI (irinotecan, 5-fluorouracil, leucovorin) for first-line treatment, or in combination with irinotecan (if refractory to irinotecan-based chemotherapy), or as a single agent (after failure of both irinotecanand oxaliplatin-based regimens or if irinotecanintolerant). Not recommended for use with K-Ras mutation-positive or K-Ras somatic mutations in codon 12 or 13. Adults: Pretreat with H1 blocker. Give by IV infusion (use filter); max rate: 10mg/min. Initial dose: 400mg/m2 once over 2 hours; then 250mg/m2 once weekly over 1 hour until disease progression or unacceptable toxicity. Complete administration 1 hour prior to FOLFIRI. Permanently reduce infusion rate by 50% if Grade 1 or 2 and nonserious Grade 3 infusion reaction occurs; permanently discontinue if Grade 3 or 4 serious reaction occurs. Monitor patient during and for 1 hr post-infusion. Skin toxicity: see full labeling. Children: Not recommended. Warnings/Precautions: Confirm K-Ras mutation status and EGFR expression for colorectal cancer. Discontinue if severe infusion reactions or interstitial lung disease occur. Monitor for infusion reactions, cardiopulmonary arrest, pulmonary toxicity, skin inflammation/ infection; avoid sun, UV light. Additive cutaneous reactions with irradiation. Cardiovascular

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER diseases (w. irradiation or platinum-based therapy with 5-FU). Monitor electrolytes (eg, magnesium, potassium, calcium) during and after cetuximab therapy. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Increased mucositis (Grade 3–4), radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances with radiation and cisplatin. Adverse reactions: Cutaneous reactions (pruritus, nail changes), acneform rash, headache, diarrhea, infection, asthenia, mucositis, weight loss, xerostomia, dehydration, electrolyte abnormalities; infusion reactions (may be severe: eg, bronchospasm, dyspnea), interstitial lung disease, cardiopulmonary arrest, hypomagnesemia, fever, sepsis, kidney failure, pulmonary embolus; others (see full labeling). Testing considerations: EGFR amplification analysis, K-RAS mutation analysis, B-RAF mutation analysis. How supplied: Single-use vials–1

Fluorouracil (various)

℞

Antimetabolite. Fluorouracil 50mg/mL; soln for IV inj. Indications: Palliative management of carcinoma of the colon, rectum, and stomach. Adults: Give by IV inj. 12mg/kg once daily for 4 successive days; max 800mg/day. If no toxicity is observed, 6mg/kg are given on the 6th, 8th, 10th, and 12th days unless toxicity occurs. Maintenance therapy: repeat dosage of 1st course every 30 days after the last day of the previous course of treatment; or give a maintenance dose of 10–15mg/kg per week as a single dose; max: 1g/ week. Poor risk patients: see literature for dose adjustments. Children: Not recommended. Contraindications: Poor nutritional state. Depressed bone marrow function. Potentially serious infections. Warnings/Precautions: Narrow margin of safety; monitor for toxicity. Consider hospitalization for 1st course. History of highdose pelvic irradiation. Previous use of alkylating agents. Widespread involvement of bone marrow by metastatic tumors. Renal or hepatic impairment. Discontinue if signs of toxicity appear (eg, stomatitis, esophagopharyngitis, leukopenia, intractable vomiting, diarrhea, GI ulceration or bleeding, thrombocytopenia, hemorrhage). Monitor WBCs with differential before each dose. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Potentiated by leucovorin.

Adverse reactions: Stomatitis, esophagopharyngitis, GI upset, anorexia, leukopenia, alopecia, dermatitis, hand-foot syndrome; others. Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase). How supplied: Contact supplier.

FUSILEV Spectrum

℞

Folate analogue. Levoleucovorin (as calcium pentahydrate) 50mg/vial; pwd for IV inj after reconstitution; contains mannitol 50mg/vial; 175mg/17.5mL; soln for IV inj; preservative-free. Indications: Palliative treatment of advanced metastatic colorectal cancer in combination with 5-fluorouracil (5-FU). Adults: Administer levoleucovorin and 5-FU separately to avoid precipitate formation. Regimen 1: give levoleucovorin at 100mg/m2 by slow IV inj over a minimum of 3 minutes, followed by 5-FU at 370mg/m2 by IV inj. Regimen 2: give levoleucovorin at 10mg/m2 by IV inj, followed by 5-FU at 425mg/m2 by IV inj. Both: Treat daily for 5 days. Five-day treatment course may be repeated at 4 week (28 days) intervals for 2 courses, and then repeated at 4–5 week (28–35 days) intervals provided that patient recovered completely from toxic effects from prior treatment course. Dose adjustments for subsequent treatment course: see literature. Children: Not recommended. Warnings/Precautions: Not for treating pernicious anemia and megaloblastic anemia. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers. Interactions: Potentiates 5-fluorouracil toxicity. Antagonizes TMP/SMZ. Antagonizes anticonvulsants (eg, phenobarbital, primidone, phenytoin). May be affected by drugs that affect MTX elimination. Adverse reactions: Stomatitis, nausea, diarrhea. How supplied: Single-use vial (pwd, soln)–1

GLEEVEC Novartis

℞

Kinase inhibitor. Imatinib (as mesylate) 100mg, 400mg; scored tabs. Indications: Kit (CD117) (+) unresectable and/or metastatic malignant GI stromal tumors (GIST). Adjuvant treatment of adults following complete gross resection of Kit (CD117) (+) GIST. Adults: Take with food and water. May disperse tab in water or apple juice and take promptly. ≥18yrs: GIST: 400mg once daily; up to 800mg daily (given as 400mg twice daily) may be considered if clinically indicated. Adjuvant GIST treatment: 400mg once daily; 36 months of

treatment recommended (see full labeling). If severe non-hematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction. Severe hepatic impairment: reduce dose by 25%. Renal or hematologic reactions: see full labeling. Avoid concomitant strong CYP3A4 inducers (eg, rifampin): if needed, increase imatinib dose by at least 50%. Children: Not recommended. Warnings/Precautions: Hepatic or renal impairment. Monitor weight and for fluid retention regularly; CBCs weekly for 1st month, bi-weekly for 2nd month, then periodically (eg, every 2–3 months); liver function at baseline then monthly or as needed; GI symptoms at baseline. Cardiovascular disease or risk factors; monitor. Immunosuppression and potential toxicities (liver, kidney, cardiac) from long-term use. Monitor for tumor lysis syndrome; correct clinically significant dehydration and treat high uric acid levels before initiating therapy. Monitor growth in children. Possible cardiogenic shock/LV dysfunction in conditions with high eosinophil levels (eg, HES/CEL, MDS/MPD, ASM); consider concomitant systemic steroid prophylaxis (1–2mg/kg) for 1 or 2 wks if abnormal ECG or serum troponin. Monitor TSH levels in thyroidectomy patients undergoing levothyroxine replacement. Pregnancy (Cat.D); avoid. Use highly effective contraception during treatment. Nursing mothers: not recommended. Interactions: Avoid grapefruit juice. Potentiated by CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, nefazodone, clarithromycin, telithromycin). Antagonized by strong CYP3A4 inducers (eg, dexamethasone, fosphenytoin, phenytoin, phenobarbital, carbamazepine, oxcarbamazepine, primidone, St. John’s wort, rifampin, rifabutin, rifampicin); consider alternatives. May potentiate drugs metabolized by CYP3A4 (eg, benzodiazepines, dihydropyridine calcium channel blockers, cyclosporine, ergots, alfentanil, fentanyl, pimozide, quinidine, certain statins, sirolimus, tacrolimus), CYP2D6, or CYP2C9 (use heparin instead of warfarin). Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, Stevens-Johnson syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction. How supplied: 100mg–90; 400mg–30

Take advantage of our free online medical calculators at CancerTherapyAdvisor.com/MedicalCalculators.

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER HERCEPTIN Genentech

℞

Human epidermal growth factor receptor (HER2) inhibitor. Trastuzumab 440mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free. Indications: HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma, in combination with cisplatin and capecitabine or 5-fluorouracil, in patients who have not received prior treatment. Adults: Give as IV infusion. Initially 8mg/kg over 90 mins, followed by 6mg/kg over 30–90 mins every 3 weeks until disease progression. Infusion reactions or cardiomyopathy: see full labeling. Children: Not established. Warnings/Precautions: Increased risk of cardiomyopathy. Conduct cardiac assessment (eg, history, physical exam, LVEF) at baseline, every 3 months during and after therapy or every 6 months for ≥2yrs after therapy (if adjuvant); repeat LVEF at 4 week intervals if dose is withheld due to significant left ventricular cardiac dysfunction. Interrupt therapy if dyspnea or significant hypotension occurs; consider discontinuing permanently if severe infusion reactions, CHF, pulmonary toxicity, or significant left ventricular myocardial dysfunction develops. Symptomatic intrinsic lung disease. Extensive tumor involvement of the lungs. Test for HER2 protein overexpression and HER2 gene amplification using FDA-approved tests for specific tumor type (breast or gastric/gastroesophageal adenocarcinoma). Elderly. Pregnancy (Cat.D); use adequate contraception during and at least 6 months after therapy. Nursing mothers: not recommended. Interactions: Increased cardiomyopathy with anthracycline-containing chemotherapy. Increased toxicity with other myelosuppressives. Potentiated by paclitaxel. Adverse reactions: Diarrhea, fatigue, anemia, stomatitis, weight loss, upper respiratory tract infections, fever, thrombocytopenia, mucosal inflammation, nasopharyngitis, dysgeusia, infections; severe infusion reactions, febrile neutropenia/exacerbation of chemotherapyinduced neutropenia, pulmonary toxicity (eg, interstitial pneumonitis), cardiomyopathy (eg, left ventricular myocardial dysfunction); pregnant women (2nd & 3rd trimesters): possible oligohydramnios (monitor). Testing considerations: HER2 protein overexpression How supplied: Vial–1 (w. diluent)

Leucovorin Teva

℞

Folic acid derivative. Leucovorin calcium 100mg/vial, 350mg/vial; lyophilized pwd for IV or IM inj after reconstitution; preservative-free. Indications: Palliative treatment of advanced colorectal cancer in combination with 5-fluorouracil.

Adults: Max IV infusion rate: 160mg/min. 200mg/m2 by slow IV inj over a minimum of 3 minutes, followed by 5-fluorouracil (370mg/m2); or 20mg/m2 IV followed by 5-fluorouracil (425mg/m2); both regimens: daily for 5 days, may be repeated at 4-week intervals for 2 courses and then repeated at 4–5 week intervals (if completely recovered from toxic effects of previous course). Children: See literature. Contraindications: Pernicious anemia and other megaloblastic anemias due to Vit. B12 deficiency. Warnings/Precautions: Do not administer intrathecally. CNS metastases. Monitor CBCs with differential, platelets, electrolytes, liver function tests prior to each treatment, then periodically. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers. Interactions: Potentiates toxicity of 5-fluorouracil; use lower 5-fluorouracil dose. May antagonize phenobarbital, phenytoin, and primidone. Caution with trimethoprimsulfamethoxazole. Adverse reactions: Leukopenia, thrombocytopenia, infection, GI upset, stomatitis, constipation, lethargy, malaise, fatigue, alopecia, dermatitis, anorexia; seizures, syncope. How supplied: Single-use vials–1

NEXAVAR Bayer and Onyx

℞

Multikinase inhibitor. Sorafenib 200mg; tabs. Indications: Unresectable hepatocellular carcinoma. Adults: Take on an empty stomach. 400mg twice daily. If toxicity occurs, may reduce dose to 400mg once daily; if further dose reduction required, may reduce dose to 400mg every other day (see full labeling). Concomitant strong CYP3A4 inducers: consider increasing dose, monitor for toxicity. Children: Not established. Contraindications: Concomitant carboplatin/ paclitaxel in patients with squamous cell lung cancer. Warnings/Precautions: Avoid in congenital long QT syndrome. Monitor patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, electrolyte abnormalities. Discontinue if severe dermatologic toxicity, hypertension, GI perforation, hemorrhage, cardiac ischemia, MI occurs. Suspend therapy before major surgery. Monitor BP weekly during the first 6 weeks and thereafter. Monitor hepatic function regularly; discontinue if transaminases significantly elevated. Severe hepatic impairment (Child-Pugh C) or on dialysis. Use effective contraception during and for 2 weeks after stopping treatment. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: See Contraindications. Avoid strong CYP3A4 inducers (eg, St. John’s Wort, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampin, phenobarbital) and neomycin;

may decrease sorafenib levels. May potentiate warfarin (monitor PT & INR), other drugs metabolized by UGT1A1 or UGT1A9 pathway, or substrates of CYP2B6, CYP2C8, CYP2C9, P-gp. Concomitant Class Ia and III antiarrhythmics; may prolong QT interval. Adverse reactions: Dermatologic toxicity (eg, rash, hand-foot skin reaction, alopecia, pruritus, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis), fatigue, weight loss, diarrhea, anorexia, abdominal pain, hypertension, hemorrhage, electrolyte abnormalities; druginduced hepatitis, QT prolongation. How supplied: Tabs–120

PHOTOFRIN Pinnacle Biologics

℞

Photosensitizing agent. Porfimer (as sodium) 75mg/vial; pwd for IV inj after reconstitution; preservative-free. Indications: Palliation of patients with completely obstructing esophageal cancer or partially obstructing esophageal cancer who cannot be satisfactorily treated with Nd:YAG laser therapy. Ablation of high-grade dysplasia in Barrett’s esophagus patients who do not undergo esophagectomy. Adults: See literature. Give by slow IV inj over 3–5 minutes. 2mg/kg then illumination with laser light 40–50 hours following injection. Esophageal cancer: 2nd course may be given at a minimum of 30 days after initial therapy; max 3 courses (separated by ≥30 days). Ablation of high-grade dysplasia in Barrett’s esophagus: 2nd course may be given at a minimum of 90 days after initial therapy; max 3 courses (separated by ≥90 days). Children: Not recommended. Contraindications: Porphyria. Existing tracheoesophageal or bronchoesophageal fistula. Tumors eroding into a major blood vessel. Emergency treatment of patients with severe acute respiratory distress caused by an obstructing endobronchial lesion. Esophageal or gastric varices. Esophageal ulcers >1cm in diameter. Warnings/Precautions: Avoid direct sunlight or bright indoor light; wear dark sunglasses when outdoors. Increased risk of fatal massive hemoptysis with large, centrally located tumors, cavitating tumors, extensive tumor extrinsic to the bronchus. Caution with endobronchial tumors in locations where treatment-induced inflammation could obstruct airway. Avoid extravasation. Pregnancy (Cat.C; use adequate contraception), nursing mothers: not recommended. Interactions: Increased risk of photosensitivity reactions with other photosensitizing agents (eg, tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics, griseofulvin, fluoroquinolones). May be antagonized by dimethyl sulfoxide, β-carotene, ethanol, formate, mannitol, allopurinol, calcium channel blockers, prostaglandin synthesis

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER inhibitors, drugs that decreased clotting, vasoconstriction or platelet aggregation (eg, thromboxane A2 inhibitors), glucocorticoid hormones. Separate radiotherapy by 2–4 weeks. Adverse reactions: Photosensitivity reactions (eg, erythema, swelling, itching, burning sensation, feeling hot, blisters), fluid imbalance, chest pain, fever, pain, abdominal pain, GI upset, constipation, mucositis, ocular sensitivity, dyspnea, pleural effusion, anemia, fistula formation, fatal massive hemoptysis, others. How supplied: Vial–1

STIVARGA Bayer

℞

Kinase inhibitor. Regorafenib 40mg; tablets. Indications: Treatment of patients with metastatic colorectal cancer who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. Treatment of patients with locally advanced, unresectable or metastatic gastrointestinal stromal tumor (GIST) who have been previously treated with imatinib mesylate or sunitinib malate. Adults: Swallow whole with a low-fat breakfast (contains <30% fat). 160mg once daily for the first 21 days of each 28-day cycle; until disease progression or unacceptable toxicity. Dose modifications: see full prescribing information. Children: <18yrs: not established. Warnings/Precautions: Risk of severe hepatotoxicity (may be fatal). Monitor hepatic function before starting and at least every 2 weeks during first 2 months of treatment; interrupt and reduce or discontinue if hepatotoxicity or hepatocellular necrosis occurs. Severe hepatic impairment: not recommended. Increased risk of hemorrhage; permanently discontinue if severe or life-threatening. Interrupt and reduce or permanently discontinue if dermatological toxicity occurs (eg, hand-foot skin reaction [a.k.a. palmar-plantar erythrodysesthesia], rash). Ensure BP is controlled before starting; monitor weekly for the first 6 weeks then every cycle or as clinically indicated; withhold if severe or uncontrolled. Myocardial ischemia/infarction: withhold if new or acute onset develops; resume when resolved. Discontinue if reversible posterior leukoencephalopathy syndrome (RPLS) or GI perforation/fistula develops. Wound healing complications: stop treatment at least 2 weeks before surgery; discontinue if wound dehiscence occurs. Fetal toxicity. Pregnancy (Cat.D); use effective contraception during treatment and up to 2 months after completion. Nursing mothers: not recommended.

Interactions: Avoid concomitant strong CYP3A4 inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St. John’s Wort). Avoid concomitant strong CYP3A4 inhibitors (eg, clarithromycin, grapefruit juice, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole). Monitor INR levels with concomitant warfarin. Adverse reactions: Asthenia/fatigue, decreased appetite and food intake, hand-foot skin reaction, diarrhea, mucositis, weight loss, infection, hypertension, dysphonia, GI and abdominal pain, rash, fever, nausea; hepatotoxicity, hemorrhage, GI perforation, cardiac ischemia/infarction, RPLS. How supplied: Tabs–84 (3 × 28)

SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 50mg; gelatin caps. Indications: Gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate. Adults: 50mg once daily for 4 weeks, then 2 weeks off (see full labeling). May adjust dose in increments or decrements of 12.5mg. Concomitant strong CYP3A4 inhibitors (see Interactions): may reduce dose to 37.5mg daily. Concomitant strong CYP3A4 inducers (see Interactions): may increase to max 87.5mg daily. Children: Not established. Warnings/Precautions: Hepatotoxicity; may be severe or fatal. Monitor liver function tests before starting, during each cycle of treatment and as clinically needed; interrupt if Grade 3 or 4 hepatic adverse events occur and discontinue if no resolution; if severe liver function changes or signs/symptoms of failure, do not restart. Cardiovascular disease: monitor LVEF at baseline and periodically thereafter; interrupt or reduce dose if LVEF <50% and >20% below baseline; discontinue if CHF occurs. History of QT prolongation or proarrythmic conditions (eg, bradycardia, electrolyte disturbances); perform periodic ECG, monitor electrolytes. Monitor BP. Suspend therapy if severe hypertension, seizures, or pancreatitis develops. Obtain CBCs, platelets, serum chemistries at start of each cycle. Concomitant exposure to risk factors (eg, IV bisphosphonates therapy or dental disease) may increase the risk of osteonecrosis of the jaw; avoid or consider preventive dentistry prior to treatment. Risk of tumor lysis syndrome: monitor closely in RCC and GIST patients with high tumor burden. Monitor for thyroid dysfunction; obtain baseline levels prior to treatment. Undergoing major surgery. Stress (monitor for adrenal

insufficiency). Renal or hepatic impairment. Pregnancy (Cat.D; avoid). Nursing mothers: not recommended. Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole); grapefruit. May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); St. John’s wort: not recommended. Adverse reactions: Fatigue, asthenia, fever, diarrhea, nausea, vomiting, mucositis/stomatitis, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, handfoot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, bleeding; hepatotoxicity, left ventricular dysfunction, QT prolongation, hemorrhage, hypertension, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing, others (see full labeling). How supplied: Caps–28

VECTIBIX Amgen

℞

Human epidermal growth factor receptor (EGFR) inhibitor. Panitumumab 20mg/mL; soln for IV infusion after dilution; preservative-free. Indications: First-line treatment of wild-type KRAS metastatic colorectal carcinoma (mCRC) in combination with FOLFOX, or as monotherapy following disease progression after prior fluoropyrimidine-, oxaliplatin-, and irinotecancontaining chemotherapy as determined by an FDA-approved test. Limitation of use: not for treating KRAS-mutant mCRC or for whom KRAS mutation status is unknown. Adults: 6mg/kg by IV infusion over 60 mins once every 14 days. If 1st infusion is tolerated, give subsequent infusions over 30–60 mins. Doses >1000mg: infuse over 90 mins. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Confirm absence of a KRAS mutation using an FDA-approved test prior to initiation. Withhold or discontinue therapy for dermatologic or soft tissue toxicity associated with severe inflammatory or infectious complications; monitor. Discontinue if severe infusion reactions develop. Interrupt therapy if acute onset or worsening of pulmonary symptoms; discontinue if interstitial lung disease (ILD) is confirmed. Limit sun exposure. Monitor electrolytes (eg, magnesium, calcium)

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DRUG MONOGRAPHS

GASTROINTESTINAL CANCER prior to initiation, during, and for 8 weeks after completing therapy. Monitor for ocular toxicities (eg, keratitis); interrupt or discontinue if occur. May impair fertility in women; use effective contraception during treatment and for 6 months following last dose. Pregnancy (Cat.C). Nursing mothers: not recommended; discontinue during therapy and for 2 months after last dose. Interactions: Concomitant bevacizumab and chemotherapy: increased mortality and toxicity may occur. Adverse reactions: Skin rash, paronychia, fatigue, nausea, diarrhea; hypomagnesemia, hypocalcemia, hypokalemia, dermatologic toxicities with possible infection (may be fatal), infusion reactions, immunogenicity, ILD, pulmonary fibrosis, keratitis, photosensitivity, possible acute renal failure w. chemotherapy. Testing considerations: EGFR amplification analysis, K-RAS mutation analysis. How supplied: Single-use vial (5mL, 10mL, 20mL)–1

XELODA Roche

impairment (CrCl 51–80mL/min): monitor carefully; (CrCl 30–50mL/min): reduce capecitabine dose to 75% of starting dose (ie, 950mg/m2 twice daily). Children: <18yrs: not recommended. Contraindications: Severe renal impairment (CrCl <30mL/min). Dihydropyrimidine dehydrogenase deficiency. Pregnancy (Cat.D), nursing mothers: not recommended. Warnings/Precautions: Hepatic or renal dysfunction. Coronary artery disease. Elderly (≥80years). Interactions: Potentiated by leucovorin. Monitor warfarin, other CYP2C9 substrates, phenytoin. Adverse reactions: Diarrhea, lymphopenia, necrotizing enterocolitis, hand-and-foot syndrome, GI upset, stomatitis, fatigue, dermatitis, anorexia, cardiotoxicity, bone marrow suppression, blood dyscrasias, hyperbilirubinemia, paresthesias, eye irritation, fever, headache, edema, dizziness, insomnia, myalgia, dehydration, nail disorder, limb pain, skin discoloration, alopecia. Testing considerations: TS (thymidylate synthase), MSI (microsatellite instability), DPD (dihydropyrimidine dehydrogenase) How supplied: Tabs 150mg–60; 500mg–120

℞

Fluoropyrimidine. Capecitabine (prodrug of 5-fluorouracil) 150mg, 500mg; tabs. Indications: First-line treatment of metastatic colorectal carcinoma when fluoropyrimidine therapy alone is preferred. Adjuvant treatment of Dukes’ C colon cancer after complete resection of the primary tumor when fluoropyrimidine therapy alone is preferred. Adults: See literature. Give cyclically (2 weeks on, 1 week off). Take with water within 30 minutes after AM & PM meals. ≥18yrs: 1250mg/m2 twice daily. Continue for a total of 8 cycles. Interrupt, adjust dose, and/or treat symptoms if toxicity occurs (eg, hyperbilirubinemia, diarrhea, nausea, vomiting, hand-and-foot syndrome, stomatitis) (see literature); do not increase dose afterwards. Renal

ZALTRAP

℞

Regeneron and Sanofi Aventis

Fusion protein. Ziv-aflibercept 25mg/mL; soln for IV infusion after dilution; preservative-free. Indications: In combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) for patients with metastatic colorectal cancer (mCRC) that is resistant to or has progressed following an oxaliplatin-containing regimen. Adults: Start ziv-aflibercept prior to any component of the FOLFIRI regimen on treatment day. Give 4mg/kg as an IV infusion over 1hr every 2 weeks; continue until disease progression or

unacceptable toxicity. For recurrent or severe hypertension, suspend until controlled. Upon resumption, permanently reduce to 2mg/kg. For recurrent proteinuria, suspend until proteinuria <2g per 24hrs, then permanently reduce to 2mg/kg. Children: Not established. Warnings/Precautions: Increased risk of hemorrhage; monitor for signs/symptoms. Do not start in patients with severe hemorrhage; discontinue if develops. Monitor for GI perforation, fistula formation, compromised wound healing; discontinue if occurs. Suspend therapy at least 4 weeks prior to elective surgery; do not resume for at least 4 weeks following major surgery and until wound is fully healed. Monitor BP every 2 weeks and treat appropriately if hypertension occurs; temporarily suspend until controlled; discontinue if hypertensive crisis/encephalopathy occurs. Discontinue if arterial thromboembolic events (eg, transient ischemic attack, cerebrovascular accident, angina pectoris) occur. Monitor for proteinuria; suspend if proteinuria ≥2g per 24hrs; discontinue if nephrotic syndrome or thrombotic microangiopathy occurs. Monitor CBC with differential at baseline and prior to start of each cycle; delay until neutrophils ≥1.5×109/L. Risk of severe diarrhea and dehydration esp. in elderly (monitor). Discontinue if reversible posterior leukoencephalopathy syndrome occurs. Pregnancy (Cat.C). Use effective contraception during and up to 3 months after the last dose. Nursing mothers: not recommended. Adverse reactions: Leukopenia, diarrhea, neutropenia, proteinuria, AST/ALT increased, stomatitis, fatigue, thrombocytopenia, hypertension, weight decreased, decreased appetite, epistaxis, abdominal pain, dysphonia, serum creatinine increased, headache. How supplied: Single-use vials (100mg/4mL)–1, 3; (200mg/8mL)–1

LIVER FUNCTION ASSESSMENT Child-Pugh Score is used to assess residual liver function and injury severity in cirrhosis patients.

CHILD-PUGH SCORES Criteria

1 point

2 points

3 points

Total serum bilirubin (mg/dL)

2–3

Serum albumin (g/dL)

>3.5

2.8–3.5

<2.8

INR

<1.70

1.71–2.20

>2.20

Ascites

No ascites

Ascites controlled

Ascites not controlled

Encephalopathy

No encephalopathy

Encephalopathy controlled

Encephalopathy not controlled

Class A

Class B

Class C

Points

5–6

7–9

10–15

Life expectancy

15–20 years

Candidate for liver transplant

1–3 years

Perioperative mortality

10%

30%

82%

INTERPRETATION OF CHILD-PUGH SCORES

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DRUG MONOGRAPHS

GENITOURINARY CANCER AFINITOR Novartis

℞

mTOR kinase inhibitor. Everolimus 2.5mg, 5mg, 7.5mg, 10mg; tabs. Indications: In adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. In adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. Adults: Swallow tabs whole with water. Take at the same time each day either consistently with or without food. 10mg once daily. Mild hepatic impairment (Child-Pugh class A): 7.5mg daily, may reduce to 5mg if not tolerated. Moderate hepatic impairment (Child-Pugh class B): 5mg daily, may be reduce to 2.5mg if not tolerated. Severe hepatic impairment (Child-Pugh class C): max 2.5mg daily if benefits outweigh risk. Concomitant moderate CYP3A4/PgP inhibitors: reduce to 2.5mg once daily; may consider increasing to 5mg if tolerated. If moderate inhibitor is discontinued, allow 2–3 days washout period before increasing everolimus dose; return to dose used prior to initiating the moderate inhibitor. Concomitant strong CYP3A4/PgP inducers: consider doubling the daily dose by increments of 5mg or less. If strong inducer is discontinued, consider washout period of 3–5 days before returning to the dose used prior to initiating the strong inducer. Continue therapy until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions, or others: see full labeling. Children: Not recommended. Contraindications: Allergy to other rapamycin derivatives. Warnings/Precautions: Monitor for new or worsening respiratory symptoms. Increased risk of infections; some may be severe or fatal; monitor and treat promptly if occur. Pre-existing invasive fungal infections: treat before starting. Monitor for signs of wound-related complications. Peri-surgical period. Hepatic impairment (see Adult dose). Monitor CBCs, renal function, lipids, and blood glucose prior to starting and periodically thereafter. Avoid close contact with those who have received live vaccines. Pediatrics: complete childhood vaccination series according to ACIP guidelines prior to initiation. Elderly. Women of childbearing potential should use effective method of contraception during and up to 8 weeks after treatment. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Avoid live vaccines. Potentiated by strong CYP3A4/PgP inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin,

ritonavir, indinavir, nelfinavir, voriconazole), grapefruit or grapefruit juice; avoid. Caution with moderate CYP3A4/PgP inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem); reduce everolimus dose if used. Antagonized by strong CYP3A4/PgP inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s Wort; avoid. Adverse reactions: Pneumonitis (interrupt, reduce dose and/or manage with corticosteroids; if severe, discontinue; may reintroduce daily dose at approx. 50% lower than previously administered), infections (discontinue if invasive systemic fungal infection develops), stomatitis (treat with nonalcoholic, non-peroxide mouthwash), diarrhea, nausea, abdominal pain, rash, fatigue, edema, fever, asthenia, cough, headache, decreased appetite; increased serum creatinine, blood glucose, lipids; decreased hemoglobin, platelets, neutrophils, serum phosphate; proteinuria, renal failure, others (see full labeling). How supplied: Tabs–28 (4 blister cards × 7 tabs)

AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free. Indications: Metastatic renal cell carcinoma (mRCC) in combination with interferon alfa. Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins. 10mg/kg every 2 weeks with interferon alfa. Children: Not established. Warnings/Precautions: Risk of GI perforations, surgery and wound healing complications, and hemorrhage. Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). Do not administer if recent history of hemoptysis of ≥ ½-teaspoon of red blood. Permanently discontinue if GI perforation, tracheoesophageal fistula, any grade 4 fistula, or grade 4 venous thromboembolic event. Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior reversible encephalopathy syndrome, or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction. History of

arterial thromboembolism. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection. Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis; GI perforation and fistulae, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure, neutropenia, and infection. How supplied: Single-use vial–1

CASODEX AstraZeneca

℞

Antiandrogen. Bicalutamide 50mg; tabs. Indications: In combination with luteinizing hormone-releasing hormone (LHRH) analogue in stage D2 metastatic prostate carcinoma. Adults: Take at the same time each day. 50mg daily. Start treatment at same time as starting LHRH analogue. Children: Not applicable. Contraindications: Women of childbearing potential. Pregnancy (Cat.X). Warnings/Precautions: Moderate to severe hepatic impairment. Monitor prostate specific antigen and hepatic function (discontinue if ALT >2×ULN or if jaundice occurs). Nursing mothers. Interactions: Monitor oral anticoagulants. Adverse reactions: Hot flashes, gynecomastia, breast pain, diarrhea, pain, asthenia, infection, dyspnea, impotence, loss of libido, others (see literature); rare: hepatitis. How supplied: Tabs–30, 100

DELESTROGEN JHP

℞

Estrogen. Estradiol valerate 10mg/mL (in a vehicle containing chlorobutanol 5mg and sesame oil), 20mg/mL (in a vehicle containing benzyl benzoate 224mg, benzyl alcohol 20mg, and castor oil), 40mg/mL (in a vehicle containing benzyl benzoate 447mg, benzyl alcohol 20mg, and castor oil); soln for IM inj. Indications: Advanced androgen-dependent carcinoma of the prostate (for palliation only). Adults: Give by deep IM inj into upper, outer quadrant of gluteal muscle. 30mg or more every 1 or 2 weeks. Children: Not applicable.

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DRUG MONOGRAPHS

GENITOURINARY CANCER Contraindications: Thrombophlebitis. Thromboembolic disorders. Cerebrovascular disorders. Abnormal undiagnosed genital bleeding. Estrogen-depended neoplasias. Liver dysfunction or disease. Pregnancy (Cat.X). Warnings/Precautions: Hepatic dysfunction. Conditions aggravated by fluid retention. Cardiovascular disorders, arterial vascular disease, and risks factors (eg, hypertension, diabetes, obesity, SLE). Familial hyperlipoprotenemia. Monitor BP. Discontinue if jaundice occurs and before prolonged immobilization (eg, surgery). Adverse reactions: See literature. GI upset, headache, hypertension, edema, hypercalcemia, gallbladder or thromboembolic disease, gynecomastia, impotence, impaired glucose tolerance. How supplied: Multi-dose vials (5mL)–1

ELIGARD 7.5mg 1-MONTH

℞

Sanofi Aventis

GnRH analogue. Leuprolide acetate 7.5mg per inj; ext-rel susp; for SC inj. ℞ Also: ELIGARD 22.5mg 3-MONTH Leuprolide acetate 22.5mg per inj; ext-rel susp; for SC inj. ℞ Also: ELIGARD 30mg 4-MONTH Leuprolide acetate 30mg per inj; ext-rel susp; for SC inj. ℞ Also: ELIGARD 45mg 6-MONTH Leuprolide acetate 45mg per inj; ext-rel susp; for SC inj. Indications: Palliative treatment of advanced prostate cancer. Adults: Allow product to reach room temperature before using; inject within 30 minutes of mixing. Use correct formulation. 7.5mg SC once per month; or 22.5mg SC once every 3 months; or 30mg SC once every 4 months; or 45mg SC once every 6 months. Rotate inj site. Children: Not established. Contraindications: Women. Pregnancy (Cat.X). Warnings/Precautions: May worsen metastatic vertebral lesions and/or urinary tract obstruction; monitor closely during first few weeks. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose, HbA1c, and for signs/ symptoms of CVD during therapy. Monitor serum testosterone, PSA periodically. Adverse reactions: Malaise, fatigue, hot flashes/sweats, testicular atrophy, gynecomastia, local reactions, asthenia, pain, spinal cord compression, decreased bone density; transient worsening of signs/symptoms (eg, bone pain, neuropathy, hematuria, bladder outlet obstruction); rare: pituitary apoplexy. How supplied: Single-use kit–1

EMCYT Pfizer

℞

Estramustine phosphate sodium (prodrug of estradiol) 140mg; caps. Indications: Palliative of metastatic, progressive prostate cancer.

Adults: Take 1 hour before or 2 hours after meals. 14mg/kg in 3 or 4 divided doses; reevaluate after 30 to 90 days. Continue as long as favorable response maintained. Children: Not applicable. Contraindications: Active thrombophlebitis or thromboembolic disorders (except when tumor mass caused by thromboembolic phenomenon). Allergy to estradiol, nitrogen mustard. Warnings/Precautions: History of thrombophlebitis, thrombosis, thromboembolic disorders. Cerebro- or cardiovascular disease. Diabetes. Hypertension. Conditions aggravated by fluid retention. Renal or hepatic dysfunction. Monitor bilirubin and hepatic enzymes during and for 2 months after treatment is discontinued. Metabolic bone diseases associated with hypercalcemia. Use effective contraception. Interactions: Absorption impaired by calcium. Adverse reactions: Edema, dyspnea, leg cramps; nausea, diarrhea, GI upset; pruritus, dry skin, easy bruising; breast tenderness and enlargement; lethargy, emotional lability, insomnia; leucopenia; abnormal bilirubin, LDH, SGOT. Thrombosis, MI. How supplied: Caps–100

ESTRACE Warner Chilcott

℞

Estrogen. Estradiol 0.5mg, 1mg, 2mg+; scored tabs; +contains tartrazine. Indications: Palliative treatment of androgendependent advanced prostate cancer. Adults: 1–2mg 3 times daily. Children: Not applicable. Contraindications: Thrombophlebitis. Thromboembolic disorders. Cerebrovascular disorders. Abnormal undiagnosed genital bleeding. Estrogen-depended neoplasias. Liver dysfunction or disease. Pregnancy (Cat.X). Warnings/Precautions: Asthma (2mg tabs). Hepatic dysfunction. Conditions aggravated by fluid retention. Cardiovascular disorders, arterial vascular disease, and risks factors (eg, hypertension, diabetes, obesity, SLE). Familial hyperlipoprotenemia. Monitor BP. Discontinue if jaundice occurs and before prolonged immobilization (eg, surgery). Nursing mothers. Adverse reactions: See literature. GI upset, headache, hypertension, edema, hypercalcemia, gallbladder or thromboembolic disease, gynecomastia, impotence, impaired glucose tolerance. How supplied: Tabs–100

FIRMAGON Ferring

℞

GnRH receptor antagonist. Degarelix 80mg/vial, 120mg/vial; pwd for SC inj after reconstitution. Indications: Advanced prostate cancer. Adults: Give by SC inj in abdomen once every 28 days; avoid waist and rib areas. Two 120mg injections once, then one 80mg inj once every 28 days. Children: Not established.

Contraindications: Pregnancy (Cat.X). Warnings/Precautions: Severe renal or hepatic impairment. Congenital long QT syndrome. Electrolyte imbalances. CHF. Monitor serum PSA. Discontinue if serious hypersensitivity reaction occurs; do not rechallenge. Nursing mothers: not recommended. Interactions: Caution with Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, sotalol) antiarrhythmics. Adverse reactions: Inj site reactions (eg, pain, erythema, swelling, induration), hot flashes, increased weight, fatigue, increased transaminases, increased gammaglutamyltransferase; QT prolongation. How supplied: Treatment Initiation pack (120mg/vial)–2 (w. supplies) Treatment Maintenance pack (80mg/vial)–1 (w. supplies)

Flutamide (various)

℞

Antiandrogen. Flutamide 125mg; caps. Indications: In combination with LHRH agonists (GnRH analogues) in locally confined stage B2–C and stage D2 metastatic prostate carcinoma. Adults: 250mg every 8 hrs. Children: Not applicable. Contraindications: Severe hepatic impairment. ALT ≥2×ULN: not recommended. Warnings/Precautions: Monitor liver function at baseline, monthly for first 4 months, then periodically, and if liver dysfunction occurs; if ALT >2×ULN or jaundice occurs, discontinue and monitor closely until resolution. Monitor prostate specific antigen (PSA). Consider monitoring methemoglobin levels in patients susceptible to aniline toxicity (eg, G6PD deficiency, smokers, hemoglobin M disease). Pregnancy (Cat.D); not for use in women. Interactions: Monitor warfarin. Adverse reactions: Diarrhea, hot flashes, loss of libido, impotence, GI disturbances, gynecomastia, rash, edema, hypertension, CNS effects, blood dyscrasias, urine discoloration, liver failure. How supplied: Contact supplier.

IFEX Baxter

℞

Alkylating agent. Ifosfamide 1g, 3g; per vial; pwd for IV infusion after reconstitution. Indications: Third-line adjunctive treatment of germ cell testicular cancer. Adults: Give by slow IV infusion over at least 30 mins. 1.2g/m2 per day for 5 consecutive days; repeat every 3 weeks or after hematological recovery (platelets ≥100000/µL, WBC ≥4000/µL). Children: Not recommended. Contraindications: Severe bone marrow depression. Warnings/Precautions: Discontinue if neurologic effects (eg, somnolence, confusion, hallucinations) occur. Do urinalysis before each dose, postpone dose if hematuria occurs. Give mesna and at least 2L fluids daily. Do hematologic

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DRUG MONOGRAPHS

GENITOURINARY CANCER profile before each dose; discontinue if WBCs <2000/µL or platelets <50000/µL. May interfere with wound healing. Impaired hepatic, renal, or hematopoetic function. Prior radiation therapy or other cytotoxic agents. Ensure adequate hydration. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Increased risk of myelosuppression with other chemotherapy agents. Adverse reactions: Alopecia, GI upset, hematuria, CNS toxicity, infection, renal or liver dysfunction, phlebitis, fever, urotoxicity (eg, hemorrhagic cystitis), leukopenia, thrombocytopenia. How supplied: Single-dose vials–1

INLYTA Pfizer

℞

Kinase inhibitor. Axitinib 1mg, 5mg; tabs. Indications: Treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy. Adults: Take 12hrs apart. Swallow whole with a glass of water. Initially 5mg twice daily. If tolerated for at least two consecutive weeks with no adverse reactions >Grade 2, normotensive, and not receiving antihypertensives, may increase dose to 7mg twice daily, then 10mg twice daily. May reduce dose from 5mg twice daily to 3mg twice daily, then 2mg twice daily if additional dose reduction required. Concomitant strong CYP3A4/5 inhibitors: avoid; if warranted, decrease Inlyta dose by approximately ½. If strong CYP3A4/5 inhibitor discontinued, return Inlyta dose (after 3–5 half-lives of the inhibitor) to that used prior to CYP3A4/5 inhibitor initiation. Moderate hepatic impairment: decrease dose by approximately ½. Children: Not studied. Warnings/Precautions: Control and monitor BP prior to and during therapy; discontinue if severe and persistent hypertension (despite antihypertensive therapy and dose reduction). Risk of thromboembolic events. Untreated brain metastasis, recent active GI bleed: not recommended. Interrupt therapy if bleeding requires medical intervention. GI perforation and fistula formation; monitor. Monitor thyroid, liver function (ALT, AST, bilirubin), and for proteinuria before starting therapy, then periodically. Reduce dose or temporarily interrupt for moderate to severe proteinuria. Risk of reversible posterior leukoencephalopathy syndrome (permanently discontinue if occurs). Stop treatment at least 24hrs prior to scheduled surgery. Severe hepatic impairment. End-stage renal disease.

Pregnancy (Cat.D); avoid. Use adequate contraception during therapy. Nursing mothers: not recommended. Interactions: See Adult dose. Avoid strong CYP3A4/5 inhibitors (eg, grapefruit juice, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), CYP3A4/5 inducers (eg, rifampin, dexamethasone, phenytoin, carbamazepine, rifabutin, rifapentin, phenobarbital, St. John’s wort), moderate CYP3A4/5 inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin). Adverse reactions: Diarrhea, nausea, vomiting, hypertension, fatigue, decreased appetite, dysphonia, palmar-plantar erythrodysesthesia (hand-foot) syndrome, weight decreased, asthenia, constipation, proteinuria. How supplied: Tabs 1mg–180; 5mg–60

JEVTANA Sanofi Aventis

℞

Antimicrotubule agent. Cabazitaxel 60mg/1.5mL; soln for IV infusion after dilution; contains polysorbate 80, diluent contains ethanol. Indications: In combination with prednisone, hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen. Adults: Pretreat with IV antihistamine, corticosteroid, and H2 blocker 30 mins before each dose (see full labeling) and with antiemetic (IV or oral as needed). 25mg/m2 by IV infusion over 1hr every 3 weeks, with oral prednisone 10mg/day during treatment. Do not treat if neutrophil count ≤1,500 cells/mm3. Prolonged grade ≥3 neutropenia (>1 week), febrile neutropenia, grade ≥3 diarrhea: delay treatment and/or reduce dose to 20mg/m2 (see full labeling). Discontinue if reactions persist after dosing at 20mg/m2. Children: Not established. Contraindications: Baseline neutrophil count ≤1,500cells/mm3. Allergy to polysorbate 80. Warnings/Precautions: Do CBC weekly in 1st cycle and before each subsequent cycle. Increased risk of neutropenia complications; consider G-CSF prophylaxis. Discontinue if hypersensitivity reactions occur. Increased risk of GI disorders in patients with neutropenia, age, or history of pelvic radiotherapy, adhesions, ulceration, and GI bleeding. Evaluate and treat if serious GI toxicity occurs; treatment delay or discontinuation may be needed. Hepatic impairment: not recommended. Severe renal impairment (CrCl <30mL/min) or ESRD. Elderly (increased susceptibility to adverse reactions);

monitor closely. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) (may potentiate cabazitaxel); caution with moderate CYP3A4 inhibitors. Avoid concomitant strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital) (may antagonize cabazitaxel). Avoid St. John’s Wort. Increased GI toxicity with concomitant steroids, NSAIDs, antiplatelets, anticoagulants. Adverse reactions: Bone marrow suppression (esp. neutropenia, anemia, leukopenia, thrombocytopenia), febrile neutropenia, diarrhea (may be fatal), nausea, vomiting, constipation, fatigue, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy, pyrexia, dyspnea, dysgeusia, cough, arthralgia, alopecia; renal failure, hypersensitivity reactions (eg, rash, hypotension, bronchospasm). How supplied: Kit (single-use vial + diluent)–1

Leuprolide acetate (various)

℞

GnRH analogue. Leuprolide acetate 5mg/mL; soln for SC inj; contains benzyl alcohol. Indications: Palliative treatment of advanced prostatic carcinoma. Adults: 1mg SC daily. Rotate inj site. Children: Not applicable. Contraindications: Women. Pregnancy (Cat.X). Warnings/Precautions: Metastatic vertebral lesions. Urinary obstruction. Monitor serum testosterone, PSA, acid phosphatase. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose, HbA1c, and for signs/ symptoms of CVD during therapy. Risk of QT prolongation: long-term androgen deprivation therapy, congenital long QT syndrome, electrolyte abnormalities, or CHF, and concomitant Class IA or III antiarrhythmics. Instruct patient on correct self administration. Interactions: Concomitant Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, sotalol) antiarrhythmics may prolong the QT interval. Adverse reactions: Hot flashes/sweats, inj site reaction, initial worsening of signs/symptoms (eg, bone pain, urinary tract obstruction, hematuria), edema, GI upset, pain, cardiovascular events, CNS and antiandrogenic effects, asthenia, spinal cord compression; hyperglycemia, anaphylactoid, photosensitivity. How supplied: Contact supplier.

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DRUG MONOGRAPHS

GENITOURINARY CANCER LUPRON DEPOT 7.5mg AbbVie ℞ GnRH analogue. Leuprolide acetate 7.5mg; depot susp for IM inj. Indications: Palliative treatment of advanced prostatic carcinoma. Adults: 7.5mg IM once a month. Rotate inj site. Children: Not applicable. Also: LUPRON DEPOT-3 MONTH 22.5mg ℞ Leuprolide acetate 22.5mg; depot susp for IM inj. Adults: 22.5mg IM inj every 3 months (84 days). Do not split doses. Children: Not applicable. Also: LUPRON DEPOT-4 MONTH 30mg ℞ Leuprolide acetate 30mg; depot susp for IM inj; preservative-free. Adults: 30mg as single IM inj every 4 months (16 weeks). Do not split doses. Children: Not applicable. Also: LUPRON DEPOT-6 MONTH 45mg ℞ Leuprolide acetate 45mg; depot susp for IM inj. Adults: 45mg as single IM inj every 6 months (24 weeks). Do not split doses. Children: Not applicable. Contraindications: Women. Pregnancy (Cat.X). Warnings/Precautions: Metastatic vertebral lesions. Urinary obstruction. Monitor serum testosterone, PSA, acid phosphatase. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose, HbA1c, and for signs/ symptoms of CVD during therapy. Risk of QT prolongation: long-term androgen deprivation therapy, congenital long QT syndrome, electrolyte abnormalities, or CHF, and concomitant Class IA or III antiarrhythmics. Instruct patient on correct self administration. Interactions: Concomitant Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, sotalol) antiarrhythmics may prolong the QT interval. Adverse reactions: Hot flashes/sweats, inj site reaction, initial worsening of signs/symptoms (eg, bone pain, urinary tract obstruction, hematuria), edema, GI upset, pain, cardiovascular events, CNS and antiandrogenic effects, asthenia, spinal cord compression; hyperglycemia, anaphylactoid, photosensitivity. How supplied: Depot kit–1 (prefilled dualchamber syringe w. supplies)

MENEST Pfizer

℞

Estrogen. Esterified estrogens 0.3mg, 0.625mg, 1.25mg, 2.5mg; tabs. Indications: Palliative treatment of androgendependent advanced prostate cancer. Adults: 1.25–2.5mg 3 times daily. Children: Not applicable. Contraindications: Thrombophlebitis. Thromboembolic disorders. Cerebrovascular or coronary artery disease. Pregnancy (Cat.X). Warnings/Precautions: Hepatic dysfunction. Gallbladder disease. Conditions aggravated by fluid retention. Familial hyperlipoproteinemia. Discontinue if jaundice occurs. Nursing mothers.

Adverse reactions: See literature. Migraine, depression, edema, weight changes, hypertension, GI upset, gynecomastia, impotence. How supplied: Tabs 2.5mg–50 0.3mg, 0.625mg, 1.25mg–100

Mitoxantrone HCl (various)

℞

Topoisomerase II inhibitor. Mitoxantrone (as HCl) 2mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Treatment of pain in advanced hormone-refractory prostrate cancer in combination with corticosteroids. Adults: Give as a short IV infusion. 12–14mg/m2 every 21 days. Children: Not established. Warnings/Precautions: Risk of myelosuppression esp. in high doses (>14mg/m2 daily for 3 days); do not administer if baseline neutrophil count <1500 cell/mm3, except in ANLL. Increased risk of cardiotoxicity with pre-existing cardiovascular disease, prior radiotherapy to mediastinal/pericardial area, or previous anthracycline therapy. Assess cardiac history, physical exam, ECG, and LVEF prior to therapy. Increased risk of secondary acute myeloid leukemia. Hepatic impairment. Monitor CBCs, platelets, liver function tests prior to each course. Monitor for signs of infection. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Caution with concomitant cardiotoxic drugs. Adverse reactions: Myelosuppression, nausea, vomiting, infection, fever, fatigue, alopecia, dyspnea, hypersensitivity reactions, bluishgreen urine, sclera discoloration, hyperuricemia (monitor), menstrual disorders, amenorrhea, interstitial pneumonitis; cardiotoxicity (eg, CHF). How supplied: Contact supplier.

NEXAVAR Bayer and Onyx

℞

Multikinase inhibitor. Sorafenib 200mg; tabs. Indications: Advanced renal cell carcinoma. Adults: Take on an empty stomach. 400mg twice daily. If toxicity occurs, may reduce dose to 400mg once daily; if further dose reduction required, may reduce dose to 400mg every other day (see full labeling). Concomitant strong CYP3A4 inducers: consider increasing dose, monitor for toxicity. Children: Not established. Contraindications: Concomitant carboplatin/ paclitaxel in patients with squamous cell lung cancer. Warnings/Precautions: Avoid in congenital long QT syndrome. Monitor patients with CHF, bradyarrhythmias, drugs known to prolong the QT interval, electrolyte abnormalities. Discontinue if severe dermatologic toxicity, hypertension, GI perforation, hemorrhage, cardiac ischemia, MI occurs. Suspend therapy before major surgery. Monitor BP weekly during the first 6 weeks and

thereafter. Monitor hepatic function regularly; discontinue if transaminases significantly elevated. Severe hepatic impairment (Child-Pugh C) or on dialysis. Use effective contraception during and for 2 weeks after stopping treatment. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: See Contraindications. Avoid strong CYP3A4 inducers (eg, St. John’s Wort, dexamethasone, phenytoin, carbamazepine, rifabutin, rifampin, phenobarbital) and neomycin; may decrease sorafenib levels. May potentiate warfarin (monitor PT & INR), other drugs metabolized by UGT1A1 or UGT1A9 pathway, or substrates of CYP2B6, CYP2C8, CYP2C9, P-gp. Concomitant Class Ia and III antiarrhythmics; may prolong QT interval. Adverse reactions: Dermatologic toxicity (eg, rash, hand-foot skin reaction, alopecia, pruritus, dry skin, Stevens-Johnson syndrome, toxic epidermal necrolysis), fatigue, weight loss, diarrhea, anorexia, abdominal pain, hypertension, hemorrhage, electrolyte abnormalities; druginduced hepatitis, QT prolongation. How supplied: Tabs–120

NILANDRON Covis

℞

Antiandrogen. Nilutamide 150mg; tabs. Indications: Metastatic prostate cancer (Stage D2), as an adjunct to surgical castration. Adults: 300mg once daily for 30 days then 150mg once daily, starting day of or day after surgical castration. Children: Not applicable. Contraindications: Severe hepatic impairment or respiratory insufficiency. Warnings/Precautions: Obtain baseline liver and pulmonary function tests and chest X-ray. Monitor for interstitial pneumonitis; discontinue if occurs. Monitor liver function for first 4 months then periodically; discontinue if ALT > 2×ULN or jaundice occurs. May discolor urine or sclera. Pregnancy (Cat.C): not for use in women. Nursing mothers. Interactions: Monitor drugs metabolized by CYP450 (eg, Vit. K antagonists, theophylline, phenytoin); may need to adjust dose. May cause alcohol intolerance. Adverse reactions: Hot flushes, impaired night vision, GI upset, increased liver enzymes, constipation, dizziness, abnormal vision, hypertension, hepatitis, interstitial pneumonitis. How supplied: Tabs–30

PREMARIN Pfizer

℞

Estrogen. Conjugated estrogens 0.3mg, 0.45mg, 0.625mg, 0.9mg, 1.25mg; tabs. Indications: Treatment of advanced androgendependent carcinoma of the prostate (for palliation only). Adults: 1.25mg–2.5mg 3 times daily. Children: Not applicable. Contraindications: Known, suspected, or history of breast cancer, except in appropriately

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DRUG MONOGRAPHS

GENITOURINARY CANCER selected patients being treated for metastatic disease. Known or suspected estrogen-dependent neoplasia. Undiagnosed abnormal genital bleeding. Pulmonary embolism/DVT (active or history of). Arterial thromboembolism (eg, stroke, MI; active or history of). Liver dysfunction or disease. Protein C, protein S, or antithrombin deficiency, or other known thrombophilic disorders. Known or suspected pregnancy (Cat.X). Warnings/Precautions: Not for prevention of cardiovascular disease. Use for shortest duration consistent with treatment goals and risks. Reevaluate periodically. Patients with an intact uterus should almost always receive a progestin with systemic estrogens to avoid endometrial hyperplasia. Discontinue if cardiovascular events occur or are suspected; if jaundice occurs; and during immobilization or at least 4–6 weeks before surgery associated with thromboembolism. Hepatic dysfunction. Conditions aggravated by fluid retention. Gallbladder disease. Bone disease associated with hypercalcemia. Hereditary angioedema. Do initial complete physical and repeat annually (include BP, mammogram, PAP smear). Adolescents. Nursing mothers: not recommended. Adverse reactions: See literature. Increased risk of cardiovascular events, estrogen-dependent carcinoma, gallbladder disease, thromboembolic disorders, hepatic tumors. GI upset, breakthrough bleeding, edema, weight changes, mastodynia, hypertension, depression, anaphylactic reactions, angioedema, intolerance to contact lenses. How supplied: Tabs 0.3mg, 0.625mg, 1.25mg–100, 1000; 0.45mg, 0.9mg–100

PROLEUKIN Prometheus

℞

ischemia or perforation, GI bleeding requiring surgery). Warnings/Precautions: See literature. History of cardiac or pulmonary disease. Renal, hepatic, or CNS impairment. Seizure disorder. Bacterial infections (treat prior to starting therapy; esp. patients with indwelling central lines). Withhold dose if organ perfusion is not maintained, urine output is reduced, systolic BP <90mmHg, CHF, cardiac ischemia or arrhythmias occur; or if moderate-to-severe lethargy or somnolence (continuing may result in coma) develops. Evaluate and treat CNS metastases; obtain negative scan before starting treatment. Do thallium stress test; monitor vital signs, weight, fluid intake and output daily. Correct hypovolemia or fluid accumulations if occur. Obtain CBCs, differential and platelets, blood chemistries (electrolytes, renal and hepatic function tests), chest X-rays, serum creatinine (should be ≤1.5mg/dL before starting therapy), pulmonary function tests, arterial blood gases. Monitor for capillary leak syndrome, mental status changes, thyroid changes, diabetes onset. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Psychotropics may increase CNS toxicity. Increased toxicity with other nephrotoxic, hepatotoxic, myelotoxic, or cardiotoxic drugs. Hypersensitivity reactions with other antineoplastics. Myocardial injury and rhabdomyolysis risk increased with interferonalfa. Antagonized by glucocorticoids (avoid). β-blockers and other antihypertensives may potentiate hypotension. Delayed reactions to iodinated contrast media. May increase risk of allograft rejection. Adverse reactions: Hypotension, GI upset, oliguria, flu-like syndrome, respiratory disorders (eg, dyspnea), CNS effects (eg, confusion, somnolence), rash, metabolic and nutritional disorders (eg, bilirubinemia, increased creatinine), hyperglycemia, thyroid disorder, thrombocytopenia, anemia, impaired neutrophil function, capillary leak syndrome, cardiotoxicity, exacerbation of autoimmune and inflammatory disease, eosinophilia, possible antibody formation; others. How supplied: Single-use vials–1

PROVENGE Dendreon

℞

Autologous cellular immunotherapy. Sipuleucel-T (autologous CD54+ cells activated with PAP-GMCSF); minimum 50 million cells/dose; suspension for IV infusion. Indications: Asymptomatic or minimally symptomatic metastatic castrate-resistant (hormone-refractory) prostate cancer.

Adults: Autologous use only. Obtain product release from manufacturer, match patient identity on product and Cell Product Disposition form, check expiration date and time on product before infusing. Premedicate 30 minutes before infusion with acetaminophen and antihistamine. Give three doses at 2-week intervals. For each dose: give entire contents of bag by IV infusion over 60 minutes; do not use filter; do not use if clumps do not disperse with gentle mixing. Observe patient for at least 30 minutes after infusion. May interrupt or slow infusion if acute transfusion reaction occurs; do not restart if product at room temp for >3 hours. Children: Not applicable. Warnings/Precautions: Cardiac or pulmonary conditions. Each dose requires a standard leukapheresis procedure about 3 days before infusion. If scheduled infusion is missed, do an additional leukapheresis procedure if treatment course is to be continued. Risk of disease transmission. Pregnancy, lactation: not applicable. Interactions: May be antagonized by concomitant chemotherapy or immunosuppressive therapy. Adverse reactions: Infusion reactions (eg, chills, fever, respiratory events, GI upset, hypertension, tachycardia), fatigue, back pain, joint ache, headache. Note: If product sterility tests indicate microbial contamination, manufacturer will contact physician (tests are incomplete at time of infusion). How supplied: Patient-specific bag (250mL)–1

SUTENT Pfizer

℞

Multikinase inhibitor. Sunitinib (as malate) 12.5mg, 25mg, 50mg; gelatin caps. Indications: Advanced renal cell carcinoma (RCC). Adults: 50mg once daily for 4 weeks, then 2 weeks off (see full labeling). May adjust dose in increments or decrements of 12.5mg. Concomitant strong CYP3A4 inhibitors (see Interactions): may reduce dose to 37.5mg daily. Concomitant strong CYP3A4 inducers (see Interactions): may increase to max 87.5mg daily. Children: Not established. Warnings/Precautions: Hepatotoxicity; may be severe or fatal. Monitor liver function tests before starting, during each cycle of treatment and as clinically needed; interrupt if Grade 3 or 4 hepatic adverse events occur and discontinue if no resolution; if severe liver function changes or signs/symptoms of failure, do not restart. Cardiovascular disease: monitor LVEF at

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DRUG MONOGRAPHS

GENITOURINARY CANCER baseline and periodically thereafter; interrupt or reduce dose if LVEF <50% and >20% below baseline; discontinue if CHF occurs. History of QT prolongation or proarrythmic conditions (eg, bradycardia, electrolyte disturbances); perform periodic ECG, monitor electrolytes. Monitor BP. Suspend therapy if severe hypertension, seizures, or pancreatitis develops. Obtain CBCs, platelets, serum chemistries at start of each cycle. Concomitant exposure to risk factors (eg, IV bisphosphonates therapy or dental disease) may increase the risk of osteonecrosis of the jaw; avoid or consider preventive dentistry prior to treatment. Risk of tumor lysis syndrome: monitor closely in RCC and GIST patients with high tumor burden. Monitor for thyroid dysfunction; obtain baseline levels prior to treatment. Undergoing major surgery. Stress (monitor for adrenal insufficiency). Renal or hepatic impairment. Pregnancy (Cat.D; avoid). Nursing mothers: not recommended. Interactions: May be potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole); grapefruit. May be antagonized by CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital); St. John’s wort: not recommended. Adverse reactions: Fatigue, asthenia, fever, diarrhea, nausea, vomiting, mucositis/stomatitis, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, handfoot syndrome, skin discoloration, dry skin, hair color changes, altered taste, headache, back pain, arthralgia, extremity pain, cough, dyspnea, anorexia, bleeding; hepatotoxicity, left ventricular dysfunction, QT prolongation, hemorrhage, hypertension, osteonecrosis of the jaw, tumor lysis syndrome, thyroid dysfunction, impaired wound healing, others (see full labeling). How supplied: Caps–28

THERACYS Sanofi Pasteur

℞

BCG Live. Live Bacillus Calmette and Guerin (BCG) strain of attenuated Mycobacterium bovis; 81mg per vial; pwd for intravesical administration after reconstitution and dilution; preservativefree. Indications: Treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder. Prophylaxis of stage Ta and/or T1 papillary tumors following transurethral resection (TUR). Adults: Drain bladder via urethral catheter prior to instillation. Induction: Instill 1 dose intravesically once per week for 6 weeks. Maintenance: one dose at 3, 6, 12, 18, and 24 months after initial dose. Retain in bladder for up to 2 hours, then void seated. Increase fluid intake to flush bladder. Children: Not recommended. Contraindications: Immunosuppressed. Active TB. Febrile illness. UTI (withhold until complete

resolution). Gross hematuria. Do not give within 7–14 days after biopsy, TUR, or traumatic catheterization. Warnings/Precautions: Not for the prevention of cancer or TB. Determine PPD status prior to therapy; rule out active TB if (+). Not for stage TaG1 papillary tumors unless high tumor recurrence risk. Not for IV, IM, or SC injection. Monitor for systemic BCG reaction; may occur as a hypersensitivity reaction (eg, malaise, fever, chills) or active infection (eg, fever ≥101.3°F, or acute localized inflammation such as epididymitis, prostatitis, or orchitis persisting ≥2 days); if persistent fever or acute febrile illness consistent with BCG infection occurs, discontinue BCG permanently and treat with ≥2 antimycobacterial drugs (except pyrazinamide). Local irritative effects: do not use antimycobacterial drugs prophylactically. Pre-existing arterial aneurysm or prosthetic devices: risk of ectopic BCG infection. Highrisk for HIV. Latex allergy. Small bladder. PPD seroconversion may occur with treatment. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: See contraindications. Immunosuppressants, myelosuppressants, radiation, antimicrobial therapy may reduce efficacy. Adverse reactions: Bladder irritation, inflammation (begins after 4 hrs and last up to 72 hrs), dysuria, urinary frequency, malaise, hematuria, fever, chills, cystitis, anemia, UTI, GI upset, renal toxicity, genital pain, arthralgia, incontinence, cramps, flu-like syndrome, systemic BCG infection. How supplied: Vial–1 (w. diluent)

TICE BCG Merck

℞

BCG Live. Bacillus of Calmette and Guerin (BCG) strain of Mycobacterium bovis live, attenuated culture preparation; 50mg per vial; pwd for intravesical administration after reconstitution and dilution; preservative-free. Indications: Treatment and prophylaxis of carcinoma in situ (CIS) of the urinary bladder. Prophylaxis of stage Ta and/or T1 papillary tumor of the urinary bladder. Adults: 1 vial in 50mL preservative-free saline intravesically once per week for 6 weeks (may repeat this regimen once if remission not achieved); then monthly for 6–12 months if needed. Avoid fluid at least 4 hrs before treatment and void immediately before administration. Retain in bladder for 2 hours. Children: Not recommended. Contraindications: Immunosuppressed. Active TB. Febrile illness. UTI. Gross hematuria. Do not give within 7 days after bladder biopsy, transurethral resection (TUR), or traumatic catheterization. Warnings/Precautions: Not a vaccine for prevention of cancer or TB. Not for IV or SC use. Determine PPD status prior to therapy; rule out

active TB if (+). Monitor for signs of systemic BCG infection: flu-like symptoms >72 hrs, fever ≥103°F, persistent LFT abnormalities; prostatitis, epididymitis, orchitis >2 days; treat with at least 2 antimycobacterial drugs (except pyrazinamide). Local irritative toxicities: do not treat with antimycobacterials. Bleeding bladder mucosa, small bladder. Disinfect fluid voided after therapy with bleach. PPD seroconversion may occur with treatment. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Immunosuppressants, myelosuppressants, radiation, antimicrobial therapy may reduce efficacy. Adverse reactions: Urine discoloration, bladder irritation, inflammation (begins after 4 hrs and last up to 72 hrs), malaise, fever, chills, flu-like syndrome, systemic BCG infection, dysuria, urinary frequency, hematuria, cystitis, urgency, nocturia, cramps, pain, incontinence, rigors, arthralgia. How supplied: Vial–1

TORISEL Pfizer

℞

mTOR kinase inhibitor. Temsirolimus 25mg/mL; ethanolic soln for IV infusion after two dilutions (first w. supplied diluent); contains alcohol, polysorbate 80. Indications: Advanced renal cell carcinoma. Adults: 25mg once weekly. Infuse IV over 30–60min, using an infusion pump. Continue until disease progression or unacceptable toxicity occurs. Premedicate with IV antihistamine (eg, diphenydramine). Hold dose if ANC <1000/mm3, platelets <75000/mm3, or NCI CTCAE ≥Grade 3 adverse reaction occurs; may restart at a dose reduced by 5mg/week (no lower than 15mg/week) if adverse reactions resolve to ≤Grade 2. Hepatic impairment: bilirubin >1–1.5×ULN or AST > ULN but bilirubin ≤ ULN: reduce to 15mg/week; >1.5×ULN: contraindicated. See Interactions. Children: Not recommended. Contraindications: Bilirubin >1.5×ULN. Warnings/Precautions: Sirolimus or related allergy. Hemodialysis. Perioperative period (may interfere with wound healing). CNS tumors. Monitor for opportunistic infections; consider prophylaxis for pneumocystis jiroveci pneumonia (PJP) when concomitant corticosteroids, other immunosuppresives required. Monitor for interstitial lung disease (ILD); discontinue if suspected. Monitor CBCs weekly and chemistry panels every 2 weeks, blood glucose, lipids, renal function, and for worsening respiratory or GI symptoms (eg, acute abdomen, blood in stool). Elderly. Pregnancy (Cat.D) (avoid pregnancy during and for 3 months after therapy, male patients should use appropriate contraception), nursing mothers: not recommended. Interactions: Avoid strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole,

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DRUG MONOGRAPHS

GENITOURINARY CANCER grapefruit juice); if used, consider reducing temsirolimus dose to 12.5mg/week (allow 1 week after discontinuing CYP3A4 inhibitor before readjusting temsirolimus dose). Avoid strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifampicin, phenobarbital, St. John’s Wort); if used, consider increasing temsirolimus dose to 50mg/week. Avoid live vaccines, close contact with vaccinees. Additive toxicity with sunitinib (rash, gout/ cellulitis), anticoagulants (intracerebral bleeding). Adverse reactions: Rash, asthenia, mucositis, nausea, edema, anorexia, infection, pain, anemia, hyperglycemia, hyperlipemia, hypertriglyceridemia, elevated alkaline phosphatase, elevated serum creatinine, lymphopenia, hypophosphatemia, thrombocytopenia, elevated AST, leukopenia; hypersensitivity/infusion reactions (anaphylaxis, dyspnea, flushing, chest pain), immunosuppression, PJP, ILD, bowel perforation, acute renal failure, abnormal wound healing; others (see full labeling). How supplied: Kit (vial + diluent)–1

TRELSTAR Actavis

℞

GnRH analogue. Triptorelin pamoate 3.75mg, 11.25mg, 22.5mg; pwd for IM inj after reconstitution; contains mannitol. Indications: Palliative treatment of advanced prostate cancer. Adults: Give by IM inj in buttock. 3.75mg every 4 weeks, or 11.25mg every 12 weeks, or 22.5mg every 24 weeks. Children: Not established. Contraindications: Women. Pregnancy (Cat.X). Warnings/Precautions: Must administer under physician supervision. Discontinue if hypersensitivity occurs. Initial transient increase in serum testosterone may result in worsening of symptoms. Spinal cord compression. Renal or hepatic impairment. Metastatic vertebral lesions. Upper or lower urinary tract obstruction. Increased risk of diabetes, MI, sudden cardiac death, stroke; monitor blood glucose and for signs/symptoms of CVD during therapy. Interactions: Avoid hyperprolactinemic drugs. Adverse reactions: Inj site reactions, hot flushes, skeletal pain, fatigue, hypertension, headache, dizziness, diarrhea, vomiting, leg edema, insomnia, impotence, emotional lability, anemia, pruritus, urinary retention, UTI, erectile dysfunction, testicular atrophy; hyperglycemia. How supplied: Single-dose vial–1 MixJect system–1 (vial + vial adapter + prefilled syringe)

VALSTAR Endo

℞

Anthracycline. Valrubicin 40mg/mL; soln for intravesical instillation after dilution; contains 50% polyoxyl castor oil/50% dehydrated alcohol; preservative-free. Indications: Intravesical therapy of BCGrefractory carcinoma in situ (CIS) of the urinary bladder in patients for whom immediate cystectomy would be associated with unacceptable morbidity or mortality. Adults: Drain bladder before instilliation. 800mg given intravesically via urethral catheter once weekly for 6 weeks. Retain drug for 2 hours before voiding, then void. Children: Not recommended. Contraindications: Concurrent UTI. Small bladder capacity (eg, unable to tolerate a 75mL instillation). Warnings/Precautions: Monitor for disease recurrence or progression with cystoscopy, biopsy, and urine cytology every 3 months; if there is not a complete response of CIS to treatment after 3 months or if CIS recurs, cystectomy must be reconsidered. Severe irritable bladder symptoms. Perforated bladder. Bladder mucosa compromised. Delay administration for at least 2 weeks after transurethral resection and/or fulguration. Maintain adequate hydration. Pregnancy (Cat.C); avoid, both males and females should use effective birth control. Nursing mothers: not recommended. Adverse reactions: Bladder symptoms (eg, urinary frequency, dysuria, urinary urgency, spasm, hematuria, pain, incontinence, cystitis, nocturia, local burning, urethral pain, pelvic pain, UTI). How supplied: Single-use vials–4, 24

VANTAS Endo

℞

GnRH analogue. Histrelin acetate 50mg; SC implant. Indications: Palliative treatment of advanced prostate cancer. Adults: Insert 1 implant SC in the inner aspect of the upper arm. Remove after 12 months; may replace. Children: Not applicable. Contraindications: Pregnancy (Cat.X). Nursing mothers. Not for use in women or children. Warnings/Precautions: Metastatic vertebral lesions, urinary tract obstruction (monitor closely in 1st few weeks). Avoid wetting inserted arm for 24hrs and heavy lifting or strenuous exertion for 1st week. Increased risk of developing diabetes; monitor blood glucose and HbA1c periodically;

treat if occurs. Increased risk of developing MI, sudden cardiac death, stroke; monitor for signs/ symptoms of cardiovascular disease. Measure serum testosterone, PSA levels periodically. Implant not visible on X-ray. Interactions: May interfere with pituitary gonadotropic and gonadal function tests. Adverse reactions: Hot flashes, initial worsening of signs/symptoms (eg, bone pain, urinary tract obstruction, hematuria), fatigue, local reactions, CNS or antiandrogenic effects, renal impairment, constipation; hyperglycemia, diabetes, cardiovascular disease. How supplied: Kit–1 (w. implant and supplies)

VOTRIENT GlaxoSmithKline

℞

Kinase inhibitor. Pazopanib 200mg; tabs. Indications: Advanced renal cell carcinoma. Limitation of use: not for treating adipocytic soft tissue sarcoma or gastrointestinal stromal tumors. Adults: Take on an empty stomach. Swallow whole. 800mg once daily. Dose adjustments: see full labeling. Hepatic impairment: moderate: 200mg once daily; severe: not recommended. Concomitant strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir, clarithromycin): avoid and consider alternate drug; if warranted, reduce dose of pazopanib to 400mg; may reduce further if toxicity occurs. Concomitant strong CYP3A4 inducers (eg, rifampin): avoid and consider alternate drug. Children: Not established (increased toxicity in developing organs). Warnings/Precautions: Not indicated for use in combination with other cancer agents. Risk of severe and fatal hepatotoxicity. Monitor liver tests before starting and at Weeks 3, 5, 7, and 9, thereafter at Months 3 and 4, then periodically. If ALT between 3×ULN and 8×ULN continue therapy with weekly monitoring until ALT returns to Grade 1 or baseline. If ALT >8×ULN interrupt therapy until ALT returns to Grade 1 or baseline; may consider reintroducing at a reduced dose, measure liver tests weekly for 8 weeks; if ALT>3×ULN recurs, permanently discontinue. Permanently discontinue if ALT>3×ULN and bilirubin >2×ULN. Gilbert’s syndrome (see full labeling). History of QT prolongation. Cardiac dysfunction risk: evaluate LVEF at baseline and periodically; monitor for CHF. Monitor ECG, electrolytes (eg, calcium, magnesium, potassium), thyroid. History of hemoptysis, cerebral, or clinically significant GI hemorrhage in the past 6 months: not recommended. Risk of arterial thrombotic events (within previous 6 months: not recommended). Monitor for VTE,

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DRUG MONOGRAPHS

GENITOURINARY CANCER PE, infection, proteinuria (reduce dose if 24-hour urine protein ≥3g), thrombotic microangiopathy, GI perforation or fistula. Monitor BP and manage hypertension promptly. Discontinue if severe and persistent hypertension (despite antihypertensives and dose reduction), if repeat episodes of proteinuria (despite dose reductions), thrombotic microangiopathy, or serious infection occurs. Stop therapy at least 7 days before surgery; discontinue in patients with wound dehiscence. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: See Adult dosing: Potentiated by strong CYP3A4 inhibitors, grapefruit juice. Avoid concomitant strong Pgp or BCRP inhibitors. Antagonized by strong CYP3A4 inducers. Concomitant drugs with narrow therapeutic windows metabolized by CYP3A4, CYP2D6, or CYP2C8: not recommended. Increased risk of ALT elevations with concomitant simvastatin; caution and monitor closely; follow dosing guidelines or consider alternatives to pazopanib, or discontinuing simvastatin if develops. Separate antacids by several hours. Caution with concomitant drugs that prolong QT interval (eg, antiarrhythmics). Adverse reactions: Diarrhea, hypertension, hair color changes, nausea, anorexia, vomiting, fatigue, decreased weight, decreased appetite, tumor pain, musculoskeletal pain, headache, dysgeusia, dyspnea, skin hypopigmentation; hepatoxicity, QT prolongation, hemorrhagic events, arterial thrombotic events (eg, MI, angina, ischemic stroke, TIA), venous thrombotic events (eg, VTE, PE), GI perforation or fistula, impaired wound healing, hypothyroidism, proteinuria, infection, reversible posterior leukoencephalopathy syndrome (discontinue if occurs). How supplied: Tabs–120

XOFIGO Bayer

℞

Alpha particle-emitting radioactive therapeutic agent. Radium Ra 223 dichloride 1000 kBq/mL (27 microcurie/mL) with a total radioactivity of 6000 kBq/vial (162 microcurie/vial) at the reference date; IV injection. Indications: Treatment of patients with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastatic disease. Adults: See full labeling. Administer by slow IV over 1 min. 50kBq (1.35 microcurie) per kg given at 4 week intervals for 6 injections. Children: <18yrs: not established. Contraindications: Women who are or may become pregnant. Pregnancy (Cat.X). Warnings/Precautions: Not for use in women. Bone marrow suppression. Perform hematologic evaluation at baseline and prior to every dose. Before 1st dose, the ANC should be ≥1.5 ×109/L, platelets ≥100 ×109/L and hemoglobin ≥10g/dL. Before subsequent doses, the ANC should be ≥1 ×109/L and platelets ≥50 ×109/L; discontinue

if no recovery within 6–8 weeks after last dose despite receiving supportive care. Monitor closely if evidence of compromised bone marrow reserve. Discontinue if life-threatening complications occur despite supportive care for bone marrow failure. Monitor oral intake and fluid status carefully. Males (use condoms) and female partners of reproductive potential should use highly effective contraceptive method during and 6 months after completion. Nursing mothers: not recommended. Interactions: Concomitant chemotherapy: not established. Discontinue if concomitant with chemotherapy, other systemic radioisotopes or hemibody external radiotherapy. Adverse reactions: Nausea, diarrhea, vomiting, peripheral edema, anemia, lymphocytopenia, leukopenia, thrombocytopenia, neutropenia. How supplied: Single-use vials (6mL)–1

XTANDI Astellas

℞

Androgen receptor inhibitor. Enzalutamide 40mg; soft gelatin caps. Indications: Treatment of metastatic castrationresistant prostate cancer. Adults: Swallow whole. 160mg once daily. Dose modifications: ≥Grade 3 toxicity or intolerable side effect: withhold dosing for 1 week or until symptoms improve to ≤Grade 2, then resume at same or reduced dose (120mg or 80mg), if warranted. Concomitant strong CYP2C8 inhibitors: avoid if possible. If co-administration necessary, reduce enzalutamide dose to 80mg once daily; if inhibitor is discontinued, return enzalutamide dose to the dose used prior to initiation of inhibitor. Children: Not established. Contraindications: Pregnancy (Cat.X). Warnings/Precautions: Risk of seizure; permanently discontinue if develops during treatment. Severe renal or hepatic impairment. Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP2C8 inhibitors (eg, gemfibrozil) if possible; reduce enzalutamide dose if cannot be avoided. Avoid concomitant CYP2C8 inducers (eg, rifampin), CYP3A4 inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, bosentan, efavirenz, etravirine, modafinil, nafcillin), and St. John’s Wort if possible. Potentiated by CYP3A4 inhibitors (itraconazole). Antagonizes midazolam (CYP3A4 substrate), warfarin (CYP2C9 substrate), and omeprazole (CYP2C19 substrate). Avoid concomitant drugs with narrow therapeutic indexes metabolized by CYP3A4 (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus), CYP2C9 (eg, phenytoin, warfarin), CYP2C19 (eg, S-mephenytoin); enzalutamide may decrease their exposure. Caution with concomitant drugs that may lower the seizure threshold. Conduct more INR monitoring if concomitant warfarin cannot be avoided.

Adverse reactions: Asthenia/fatigue, back pain, decreased appetite, constipation, arthralgia, diarrhea, hot flush, upper respiratory tract infection, peripheral edema, dyspnea, musculoskeletal pain, weight decreased, headache, hypertension, dizziness/vertigo. How supplied: Caps–120

ZYTIGA Janssen Biotech

℞

CYP17 inhibitor. Abiraterone acetate 250mg; tablets. Indications: In combination with prednisone for the treatment of metastatic castration-resistant prostate cancer. Adults: Take on empty stomach (no food 2 hours before or 1 hour after administration). Swallow whole with water. 1g once daily (in combination with prednisone 5mg twice daily). Moderate hepatic impairment (Child-Pugh Class B): 250mg once daily. If hepatotoxicity occurs: interrupt, then restart at reduced dose; discontinue if severe (see full labeling). If concomitant strong CYP3A4 inducer necessary, increase abiraterone dose frequency to twice daily during co-administration period (eg, from 1g once daily to 1g twice daily); reduce back to previous dose/frequency when CYP3A4 inducer is discontinued. Children: Not established. Contraindications: Pregnancy (Cat.X). Women who are or may become pregnant. Warnings/Precautions: Risk of mineralocorticoid excess: patients with history of cardiovascular disease, LVEF <50%, Class III or IV heart failure, recent MI, ventricular arrhythmias. Monitor BP, serum potassium, and for fluid retention monthly. Control hypertension and correct hypokalemia before and during treatment. Monitor for adrenocortical insufficiency. Stress (may need higher corticosteroid dose). Baseline severe hepatic impairment (Child-Pugh Class C); avoid. Monitor liver function (ALT/AST, bilirubin) prior to starting treatment, every 2 weeks for the first 3 months, and monthly thereafter; interrupt, reduce dose, or discontinue if hepatic dysfunction occurs. Nursing mothers: not recommended. Interactions: Avoid concomitant CYP2D6 substrates with narrow therapeutic index (eg, thioridazine); if no alternatives, use caution and consider dose reduction of substrate. Potentiates dextromethorphan. May affect, or be affected by, strong inhibitors or inducers of CYP3A4; avoid or use caution. Concomitant CYP2C8 substrates: monitor closely for signs of toxicity. Adverse reactions: Joint swelling or discomfort, fatigue, hypokalemia, edema, myalgia, hot flush, diarrhea, vomiting, UTI, cough, hypertension, dyspnea, arrhythmias, urinary frequency, nocturia, URI, adrenocortical insufficiency, hepatotoxicity. Note: Pregnant women and those of childbearing potential should not handle Zytiga tablets without protection (eg, gloves). Partners must use appropriate barrier contraception. How supplied: Tabs–120

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CANCER TREATMENT REGIMEN

GYNECOLOGIC CANCER Uterine Sarcoma Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Systemic Therapy for Uterine Sarcoma1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Combination Regimens Docetaxel + gemcitabine2*

Days 1 and 8: Gemcitabine 900mg/m2 IV over 90 minutes followed by docetaxel 100mg/m2 IV over 60 minutes on day 8† followed by Days 9–15: Granulocyte colony-stimulating factor (G-CSF) 150μ/m2 SQ Or Pegfilgrastim 6mg SQ on day 9 or 10. Repeat cycle every 3 weeks until disease progression or toxicity occurs.

Doxorubicin + ifosfamide3

Day 1: Doxorubicin 50mg/m2 over 15 minutes followed by ifosfamide 5g/m2 via 24-hour continuous IV admixed with mesna 6g/m2 36-hour continuous IV. Repeat cycle every 3 weeks.

Doxorubicin + dacarbazine4

Day 1: Doxorubicin 60mg/m2 IV. Days 1–4: Dacarbazine 750mg/m2 IV via continuous infusion for 96 hours. Repeat cycle every 3 weeks.

Gemcitabine + dacarbazine5

Day 1: Gemcitabine 10mg/m2/min IV over 180 minutes followed by dacarbazine 500mg/m2 IV over 20 minutes every 2 weeks for a total of 12 cycles.

Gemcitabine + vinorelbine6

Days 1 and 8: Vinorelbine 25mg/m2 IV over 10 minutes followed by gemcitabine 800mg/m2 IV over 90 minutes. Repeat cycle every 21 days.

Single-Agent Regimens Dacarbazine5

Day 1: Dacarbazine 1200mg/m2 IV over 20 minutes. Repeat cycle every 3 weeks for total of 8 cycles

Doxorubicin7

Day 1: Doxorubicin 75mg/m2 IV bolus. Repeat every 31 days.

Epirubicin8

Day 1: Epirubicin 75mg/m2 IV bolus. Repeat every 3 weeks.

Gemcitabine9

Days 1, 8, and 15: Gemcitabine 1,000mg/m2 IV. Repeat every 4 weeks.

Ifosfamide10

Days 1–5: Ifosfamide 1.5gm/m2 IV daily with mesna.

Liposomal doxorubicin11

Day 1: Liposomal doxorubicin 50mg/m2. Repeat every 4 weeks.

Pazopanib12

Pazopanib 800mg PO once daily until disease progression.

Temozolomide

Temozolomide 50–75mg/m2 daily for 6 of 8 weeks.

Vinorelbine (category 2B)13

Days 1 and 8: Vinorelbine 30mg/m2. Repeat every 21 days.

Docetaxel (category 3)14

Days 1, 8, and 15: Docetaxel 36mg/m2 IV over 1 hour. Repeat every 28 days.

Hormone Therapy (Endometroid histologies only)1 Medroxyprogesterone acetate, megestrol acetate, aromatase inhibitors, gonadotropin-releasing hormone analogs (category 2B) * Preferred for leiomyosarcoma. † Patients with prior pelvic irradiation received gemcitabine 675mg/m2 IV and docetaxel 75mg/m2 IV.

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CANCER TREATMENT REGIMEN

GYNECOLOGIC CANCER References 1. 2. 3. 4. 5.

6. 7.

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Uterine Neoplasms V.1.2014. Available at: http://www. nccn.org. Accessed April 4, 2014. Hensley ML, Blessing JA, Mannel R, Rose PG. Fixed-dose rate gemcitabine plus docetaxel as first-line therapy for metastatic uterine leiomyosarcoma: a Gynecologic Oncology Group phase II trial. Gynecol Oncol. 2008;109:329–334. Sutton G, Blessing JA, Malfetano JH. Ifosfamide and doxorubicin in the treatment of advanced leiomyosarcomas of the uterus: a Gynecologic Oncology Group study. Gynecol Oncol. 1996;62:226–229. Zalupski M, Metch B, Balcerzak S, et al. Phase III comparison of doxorubicin and dacarbazine given by bolus versus infusion in patients with soft-tissue sarcomas: a Southwest Oncology Group study. J Natl Cancer Inst. 1991 Jul 3;83(13):926–932. Garcia-Del-Muro X, Lopez-Pousa A, Maurel J, et al. Randomized phase II study comparing gemcitabine plus dacarbazine versus dacarbazine alone in patients with previously treated soft tissue sarcoma: a Spanish Group for Research on Sarcomas study. J Clin Oncol. 2011;29:2528–2533. Dileo P, Morgan J, Zahrieh D, et al. Gemcitabine and vinorelbine combination chemotherapy for patients with advanced soft tissue sarcomas. Cancer. 2007;109(9):1863–1869. Judson I, Radford JA, Harris M, et al. Randomized phase II trial of pegylated liposomal doxorubicin (DOXIL/CAELYX) versus doxorubicin in the treatment of advanced or metastatic soft tissue sarcoma: a study by the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer. 2001;37:870–877.

9. 10. 11. 12. 13. 14.

Mouridsen HT, Bastholt L, Somers R, et al. Adriamycin versus epirubicin in advanced soft tissue sarcomas. A randomized phase II/phase III study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer Clin Oncol. 1987;23(10):1477. Look KY, Sandler A, Blessing JA, et al. Phase II trial of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group (GOG) Study. Gynecol Oncol. 2004;92:644–647 Sutton GP, Blessing JA, Barrett RJ, et al. Phase II trial of ifosfamide and mesna in leiomyosarcoma of the uterus: a Gynecologic Oncology Group study. Am J Obstet Gynecol. 1992; 166(2):556–559. Amant F, Coosemans A, Debiec-Rychter M, et al. Clinical management of uterine sarcomas. Lancet Oncol. 2009;10: 1188–1198. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2012;379:1879–1886. Muggia F, Blessing JA, Method M. Evaluation of vinorelbine in persistent or recurrent squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 2004;92(2):639–643. Garcia AA, Blessing JA, Nolte S, Mannel RS. A phase II evaluation of weekly docetaxel in the treatment of recurrent or persistent endometrial carcinoma: a study by the Gynecologic Oncology Group. Gynecol Oncol. 2008;111:22–26.

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DRUG MONOGRAPHS

GYNECOLOGIC CANCER ALKERAN GlaxoSmithKline

℞

Nitrogen mustard derivative. Melphalan 2mg; scored tabs. Indications: For the palliation of non-resectable epithelial ovarian cancer. Adults: 0.2mg/kg per day for 5 days; repeat course every 4–5 weeks. Continue treatment as hematological recovery permits (esp. WBCs and platelets); for other regimens: see literature. Children: Not recommended. Contraindications: Prior resistance to melphalan. Warnings/Precautions: Prior irradiation or chemotherapy. Bone marrow suppression. Azotemia. Monitor platelets, hemoglobin, WBC and differential at start of therapy and prior to each course; discontinue if WBC <3,000cells/µL or platelets <100,000cells/µL. Moderate to severe renal impairment. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Radiotherapy potentiates antineoplastic effect. For IV: caution with cyclosporine, cisplatin, BCNU, nalidixic acid. Adverse reactions: Bone marrow suppression, GI upset, hepatic dysfunction, anemia, blood dyscrasias, secondary malignancies (eg, nonlymphocytic leukemia), rash, alopecia, pulmonary fibrosis, interstitial pneumonitis, gonadal toxicity (amenorrhea, infertility); hypersensitivity reactions, cardiac arrest (rare). How supplied: Tabs–50; single-use vial–1 (w. diluent)

AVASTIN Genentech

℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free. Indications: Persistent, recurrent, or metastatic cervical cancer in combination with paclitaxel and cisplatin, or paclitaxel and topotecan. Platinumresistant recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer in patients who received no more than 2 prior chemotherapy regimens, in combination with paclitaxel, pegylated liposomal doxorubicin or topotecan. Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins. Cervical cancer: 15mg/kg every 3 weeks with either paclitaxel/cisplatin, or paclitaxel/topotecan. Epithelial ovarian, fallopian tube or primary peritoneal cancer: 10mg/kg every 2 weeks with either paclitaxel, pegylated liposomal doxorubicin, or topotecan (weekly); 15mg/kg every 3 weeks with topotecan (every 3 weeks). Children: Not established.

Warnings/Precautions: Risk of GI perforations, surgery and wound healing complications, and hemorrhage. Do not start therapy before or for at least 28 days after surgery; allow surgical incisions to completely heal (see full labeling). Do not administer if recent history of hemoptysis of ≥ ½-teaspoon of red blood. Permanently discontinue if GI perforation, tracheoesophageal fistula, any grade 4 fistula, or grade 4 venous thromboembolic event. Discontinue if fistula involving internal organ, wound healing complications, hemorrhage, severe arterial thromboembolic event (ATE), hypertensive crisis or encephalopathy, posterior reversible encephalopathy syndrome, or nephrotic syndrome occurs; suspend therapy if severe hypertension, moderate-to-severe proteinuria (resume when <2g/24hrs), or severe infusion reaction occurs. Avoid in ovarian cancer if evidence of recto-sigmoid involvement by pelvic exam, bowel involvement on CT scan, or symptoms of bowel obstruction. History of arterial thromboembolism. Diabetes. Monitor BP every 2–3 weeks. Monitor proteinuria by dipstick urine analysis; if ≥2+, do further assessment with a 24-hour urine collection. Elderly. Increased risk of ovarian failure; inform females of reproductive potential prior to starting therapy. Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, exfoliative dermatitis; GI perforation and fistulae, wound dehiscence/impaired healing, necrotizing fasciitis (discontinue if occurs), hemorrhage, non-GI fistula formation, arterial or venous thromboembolic events, posterior reversible encephalopathy syndrome, infusion reactions, ovarian failure, neutropenia, and infection. How supplied: Single-use vial–1

DOXIL Janssen Biotech

℞

Anthracycline. Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free. Indications: Ovarian cancer refractory to platinum-based chemotherapy. Adults: Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 50mg/m2 once every 4 weeks; continue for at least 4 cycles as tolerated. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and

anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling. Children: Not established. Warnings/Precautions: Not substitutable on a mg/mg basis with other doxorubicin products. Cardiotoxicity, acute infusion-related reactions, myelosuppression may occur. Have resuscitative/ antiallergic equipment and expertise available. Hepatic impairment. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (esp. myocardial biopsy). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity. Adverse reactions: Asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea, constipation, hand and foot syndrome, rash, neutropenia, thrombocytopenia, anemia; infusion reactions, cardiovascular events (eg, cardiomyopathy, CHF, acute LV failure), recall of skin reaction from prior radiation therapy, toxoplasmosis, urine discoloration (red/orange). How supplied: Single-use vials (10mL, 25mL)–1

HEXALEN Eisai

℞

S-triazine derivative. Altretamine 50mg; caps. Indications: Palliative treatment of persistent or recurrent ovarian cancer following first-line therapy with a cisplatin and/or alkylating agentbased combination. Adults: 260mg/m2 daily in four divided doses (after meals and at bedtime), for either 14 or 21 consecutive days in a 28-day cycle. Discontinue for >14 days if GI intolerance is unresponsive to treatment, WBC count <2000/mm3 or granulocyte count <1000/mm3, platelet count <75000/mm3, or progressive neurotoxicity occurs. Restart at 200mg/m2 daily. Discontinue indefinitely if neurologic symptoms fail to stabilize. Children: Not recommended. Contraindications: Severe myelosuppression or neurologic toxicity, except cisplatin-related neuropathy. Warnings/Precautions: Monitor for myelosuppression (do monthly CBCs) and neurotoxicity. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Avoid pyridoxine. Severe orthostatic hypotension with MAOIs.

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DRUG MONOGRAPHS

GYNECOLOGIC CANCER Adverse reactions: Nausea, vomiting, peripheral neuropathy, CNS symptoms (eg, mood disorders, ataxia, dizziness), myelosuppression, renal dysfunction, increased alkaline phosphatase. How supplied: Caps–100

HYCAMTIN GlaxoSmithKline

℞

Topoisomerase inhibitor. Topotecan (as HCl) 4mg/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free. Indications: Metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy. Stage IV-B, recurrent or persistent carcinoma of the cervix in combination with cisplatin. Adults: Confirm baseline neutrophils >1,500cells/mm3 and platelets >100,000cells/mm3 prior to 1st course of therapy. Give by IV infusion over 30 minutes. Ovarian cancer: 1.5mg/m2 daily for 5 consecutive days starting on Day 1 of a 21-day cycle. Cervical cancer: 0.75mg/m2 on Days 1, 2, and 3; followed by cisplatin. Dose adjustments, renal impairment: see literature. Children: Not recommended. Contraindications: Severe bone marrow depression. Pregnancy (Cat.D). Nursing mothers. Warnings/Precautions: Monitor peripheral blood cell counts during therapy; hold subsequent doses until neutrophils >1,000cells/mm3, platelets >100,000cells/mm3, and hemoglobin ≥9g/dL. History of interstitial lung disease, pulmonary fibrosis, lung cancer, thoracic exposure to radiation, use of pneumotoxic drugs and/or colony stimulating factors: increased risk of interstitial lung disease; monitor, discontinue if occurs. Moderate to severe renal impairment. Avoid extravasation. Elderly. Interactions: Myelosuppression potentiated with platinum agents. Neutropenia potentiated by G-CSF. Adverse reactions: See literature. Neutropenia, leukopenia, thrombocytopenia, anemia, GI upset, anorexia, abdominal pain, stomatitis, headache, dyspnea, cough, pyrexia, alopecia, fatigue; infection, sepsis, interstitial lung disease, neutropenic colitis (may be fatal). How supplied: Single-use vials–1, 5

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps. Indications: Recurrent metastatic or inoperable ovarian carcinoma. Adults: See literature. Intermittant therapy for solid tumors: 80mg/kg as single dose every 3rd day. Continuous therapy for solid tumors: 20–30mg/kg/day as single dose. Renal impairment: reduce dose. Children: Not recommended. Contraindications: Marked bone marrow depression. Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders;

discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated urease, uricase, lactate dehydrogenase. Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer. Note: Wear disposable gloves when handling caps or bottle. How supplied: Caps–100

LYNPARZA AstraZeneca

℞

Poly (ADP-ribose) polymerase (PARP) inhibitor. Olaparib 50mg; caps. Indications: Monotherapy in patients with deleterious or suspected deleterious germline BRCA-mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with ≥3 prior lines of chemotherapy. Adults: Swallow whole. 400mg twice daily; max 800mg daily. Continue until disease progression or unacceptable toxicity. Dose adjustments for adverse reactions: reduce to 200mg twice daily; may further reduce to 100mg twice daily. If concomitant strong CYP3A inhibitor unavoidable: reduce to 150mg twice daily; or if concomitant moderate CYP3A inhibitor unavoidable: reduce to 200mg twice daily. Children: Not established. Warnings/Precautions: Monitor CBC at baseline and monthly thereafter; do not start therapy until recovery from hematological toxicity due to previous chemotherapy (CTCAE Grade ≤1). Discontinue if myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) is confirmed. Interrupt therapy and evaluate if new or worsening respiratory symptoms occur; discontinue if pneumonitis is confirmed. Hepatic and moderateto-severe renal impairment: not studied. Pregnancy (Cat.D); avoid. Use effective contraception during therapy and for at least 1 month after last dose. Nursing mothers: not recommended. Interactions: Increased myelosuppressive toxicity with concomitant other myelosuppressive anticancer agents, including DNA damaging agents. Avoid concomitant strong CYP3A inhibitors (eg, itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritonavir, lopinavir/ritonavir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) and moderate CYP3A inhibitors (eg, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil);

if unavoidable, reduce dose (see Adults). Avoid grapefruit and Seville oranges. Avoid concomitant strong CYP3A inducers (eg, phenytoin, rifampicin, carbamazepine, St. John’s Wort) and moderate CYP3A inducers (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin); if unavoidable, be aware of potential for decreased efficacy. Adverse reactions: Anemia, nausea, fatigue, asthenia, vomiting, diarrhea, dysgeusia, dyspepsia, headache, decreased appetite, nasopharyngitis/ pharyngitis/URI, cough, arthralgia/musculoskeletal pain, myalgia, back pain, dermatitis/rash, abdominal pain/discomfort; lab abnormalities (see full labeling), MDS/AML, pneumonitis. How supplied: Caps–112

Megestrol acetate (various)

℞

Progestin. Megestrol acetate 20mg, 40mg; scored tabs. Indications: Palliative treatment of advanced endometrial carcinoma. Adults: 40–320mg daily in divided doses. Children: Not applicable. Warnings/Precautions: History of thromboembolic disease. Diabetes. Monitor for adrenal insufficiency. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: May increase insulin requirements. Decreases indinavir levels. Adverse reactions: Weight gain, thromboembolic events, heart failure, GI upset, edema, breakthrough menstrual bleeding, dyspnea, tumor flare, hyperglycemia, alopecia, hypertension, carpal tunnel syndrome, mood changes, hot flashes, malaise, asthenia, lethargy, sweating, rash. How supplied: Contact supplier.

TREXALL Teva

℞

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DRUG MONOGRAPHS

GYNECOLOGIC CANCER counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration). Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer. Ulcerative colitis. Infection.

Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin). Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome). How supplied: Tabs–30; soln (2mL, 4mL, 8mL, 10mL)–10 (single-use vials); pwd (1 gram)–1 (single-use vial)

FDA-APPROVED OVARIAN CANCER TREATMENTS Generic Brand AlkylATINg AgENT

Strength

Form

Usual Dose

altretamine

Hexalen

50mg

caps

260mg/m2 daily in four divided doses for either 14 or 21 consecutive days in a 28-day cycle

carboplatin

—

10mg/mL

soln for IV infusion

Advanced ovarian cancer (previously untreated): 300mg/m2 on Day 1 every 4wks for 6 cycles Recurrent ovarian cancer: 360mg/m2 on Day 1 every 4wks

cisplatin

—

1mg/mL

soln for IV infusion after dilution 100mg/m2 once every 4wks

cyclophosphamide —

25mg, 50mg tabs

1–5mg/kg/day

Cytoxan injection

500mg, 1g, 2g

pwd for inj after reconstitution

40–50mg/kg in divided doses over 2–5 days or 10–15mg/kg every 7–10 days or 3–5mg/kg twice weekly

melphalan

Alkeran

2mg

scored tabs

0.2mg/kg/day for 5 days; repeat every 4–5wks

thiotepa

—

15mg

pwd for IV, intravesical, or intracavitary administration after reconstitution

0.3–0.4mg/kg IV once every 1–4wks

ANTIbIOTICS (CyTOTOxIC) doxorubicin

—

doxorubicin (liposomal)

Doxil

10mg, pwd for IV inj after 20mg, 50mg reconstitution

Monotherapy: 60–75mg/m2 every 21 days Combination therapy: 40–60mg/m2 every 21 to 28 days

2mg/mL

soln for IV inj

2mg/mL

dispersion for IV infusion after dilution

50mg/m2 once every 4wks

ANTIMETAbOlITE gemcitabine

gemzar

200mg, 1g

pwd for IV infusion after reconstitution

1000mg/m2 on Days 1 and 8 of each 21-day cycle

hydroxyurea

Hydrea

500mg

caps

Intermittant therapy: 80mg/kg as single dose every 3rd day Continuous therapy: 20–30mg/kg/day as single dose

soln for IV administration after dilution

Previously untreated ovarian cancer: 175mg/m2 over 3hrs or 135mg/m2 over 24hrs; repeat every 3wks Previously treated ovarian cancer: 135mg/m2 or 175mg/m2 over 3hrs every 3wks

pwd for IV infusion after reconstitution and dilution

1.5mg/m2 daily for 5 consecutive days starting on Day 1 of a 21-day cycle

ANTIMICROTubulE AgENTS paclitaxel

Taxol

6mg/mL

TOPOISOMERASE INHIbITOR topotecan

Hycamtin 4mg

Notes

Not an inclusive list of medications and/or doses. Please see drug monograph at www.eMPR.com and/or contact company for full drug labeling.

(Rev. 7/2013)

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DRUG MONOGRAPHS

HEAD AND NECK CANCER ERBITUX Bristol-Myers Squibb

℞

Epidermal growth factor receptor blocker. Cetuximab 100mg/vial, 200mg/vial; soln for IV infusion; preservative-free. Indications: In combination with radiation therapy for treating locally or regionally advanced squamous cell carcinoma of the head and neck (SCCHN). In combination with platinum-based therapy with 5-fluorouracil (5-FU) for first-line treatment of recurrent locoregional disease or metastatic SCCHN. As a single agent for recurrent or metastatic SCCHN after failure of prior platinum-based therapy. Adults: Pretreat with H1 blocker. Give by IV infusion (use filter); max rate: 10mg/min. Initial dose: 400mg/m2 once over 2 hours; then 250mg/m2 once weekly over 1 hour. Combination therapy: Give initial dose 1 week prior to initiation of radiation therapy. Complete administration 1 hour prior to platinum-based therapy with 5-FU. Give subsequent weekly dose for duration of radiation therapy (6–7 weeks) or until disease progression or unacceptable toxicity. Permanently reduce infusion rate by 50% if Grade 1 or 2 and non-serious Grade 3 infusion reaction occurs; permanently discontinue if Grade 3 or 4 serious reaction occurs. Monitor patient during and for 1 hr post-infusion. Skin toxicity: see full labeling. Children: Not recommended. Warnings/Precautions: Discontinue if severe infusion reactions or interstitial lung disease occur. Monitor for infusion reactions, cardiopulmonary arrest, pulmonary toxicity, skin inflammation/infection; avoid sun, UV light. Additive cutaneous reactions with irradiation. Cardiovascular diseases (w. irradiation or platinum-based therapy with 5-FU). Monitor electrolytes (eg, magnesium, potassium, calcium) during and after cetuximab therapy. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Increased mucositis (Grade 3–4), radiation recall syndrome, acneiform rash, cardiac events, and electrolyte disturbances with radiation and cisplatin. Adverse reactions: Cutaneous reactions (pruritus, nail changes), acneform rash, headache, diarrhea, infection, asthenia, mucositis, weight loss, xerostomia, dehydration, electrolyte abnormalities; infusion reactions (may be severe: eg, bronchospasm, dyspnea), interstitial lung disease, cardiopulmonary arrest, hypomagnesemia, fever, sepsis, kidney failure, pulmonary embolus; others (see full labeling). How supplied: Single-use vials–1

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps. Indications: Adjunct with irradiation therapy in primary squamous cell (epidermoid) carcinomas of the head and neck, excluding the lip. Adults: See literature. 80mg/kg as single dose every 3rd day. Renal impairment: reduce dose. Children: Not recommended.

Contraindications: Marked bone marrow depression. Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated urease, uricase, lactate dehydrogenase. Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer. Note: Wear disposable gloves when handling caps or bottle. How supplied: Caps–100

TREXALL Teva

℞

Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated. Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin). Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome). How supplied: Tabs–30; soln (2mL, 4mL, 8mL, 10mL)–10 (single-use vials); pwd (1 gram)–1 (single-use vial)

GENERIC NAME The active ingredients and strengths are listed under the name of each dosage form. If the product contains tartrazine, alcohol, flavors, or is alcohol-, sugar-, or dye-free, it is noted. Abbreviations are used to describe the dosage form and its formulation, e.g.: tabs = tablets caps = capsules e-c = enteric coated sust rel = sustained-release ext rel = extended-release

BRAND NAME The main name under which the product and all other dosage forms in the monograph are marketed.

LEGAL CATEGORY Federal schedule. The laws governing the prescribing/ dispensing of products vary from state to state.

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DRUG MONOGRAPHS

HEAD AND NECK CANCER ANTICOAGULANT DOSING CONVERSIONS Conversion of DABIGATRAN ETEXILATE Switching from DABIGATRAN to WARFARIN • Adjust starting time of warfarin based on CrCl as follows: ° CrCl >50mL/min: Start warfarin 3 days before discontinuing dabigatran ° CrCl 30–50mL/min: Start warfarin 2 days before discontinuing dabigatran ° CrCl 15–30mL/min: Start warfarin 1 day before discontinuing dabigatran ° CrCl <15mL/min: No recommendations can be made • Since dabigatran can increase INR, the INR will better reflect warfarin’s effect only after dabigatran has been stopped for at least 2 days Switching from DABIGATRAN to PARENTERAL ANTICOAGULANT • Currently receiving dabigatran: ° Wait 12hrs (CrCl ≥30mL/min) or 24hrs (CrCl <30mL/min) after the last dose of dabigatran before initiating treatment with a parenteral anticoagulant

Conversion of APIXABAN Switching from APIXABAN to WARFARIN • Apixiban affects INR levels, so the INR measurement during co-administration with warfarin may not be useful for determing the appropriate dose of warfarin ° Discontinue apixaban and start both a parenteral anticoagulant and warfarin at the time the next dose of apixaban would have been taken, then discontinue the parenteral anticoagulant when INR reaches an acceptable range Switching between APIXABAN and ANTICOAGULANTS other than WARFARIN • Discontinue one being taken and begin the other at the next scheduled dose

Conversion of RIVAROXABAN Switching from RIVAROXABAN to WARFARIN • Rivaroxaban affects INR levels, so INR measurements during co-administration with warfarin may not be useful for determining the appropriate dose of warfarin ° Discontinue rivaroxaban and start both a parenteral anticoagulant and warfarin at the time the next dose of rivaroxaban would have been taken Switching from RIVAROXABAN to ANTICOAGULANTS other than WARFARIN • Currently taking rivaroxaban and transitioning to an anticoagulant with rapid onset: ° Discontinue rivaroxaban and give 1st dose of the other anticoagulant (oral or parenteral) at the time the next dose of rivaroxaban would have been taken Switching from ANTICOAGULANTS other than WARFARIN to RIVAROXABAN • Currently receiving an anticoagulant other than warfarin: ° Start rivaroxaban 0–2hrs prior to the next scheduled evening dose of the drug (eg, low molecular weight heparin or non-warfarin oral anticoagulant and omit administration of the other anticoagulant ° Start rivaroxaban at the same time a continuous infusion of unfractionated heparin is discontinued

Conversion of HEPARIN Switching from HEPARIN to WARFARIN • Dose warfarin with the usual initial amount (eg, 2–5mg PO or IV daily) and determine PT/INR at the usual intervals • Overlap warfarin with full dose heparin therapy for 4–5 days until warfarin has produced the desired therapeutic response as determined by PT/INR. Heparin may be discontinued at that time without tapering. • The interference with heparin anticoagulation is of minimal clinical significance during initial therapy with warfarin • Patients receiving both heparin and warfarin should have blood for PT/INR determination drawn at least: ° 5hrs after the last IV bolus dose of heparin, or ° 4hrs after cessation of a continuous IV infusion of heparin, or ° 24hrs after the last subcutaneous heparin injection Switching from HEPARIN/PARENTERAL ANTICOAGULANT to DABIGATRAN • Currently receiving a parenteral anticoagulant: ° Start dabigatran 0–2hrs before the next scheduled dose of the parenteral drug would have been given, or ° Start dabigatran at the time of discontinuation of a continuously administered parenteral drug (eg, IV unfractionated heparin)

Conversion of WARFARIN Switching from WARFARIN to DABIGATRAN • Discontinue warfarin and start dabigatran when INR is <2.0 Switching from WARFARIN to APIXABAN • Discontinue warfarin and start apixaban when INR is <2.0 Switching from WARFARIN to RIVAROXABAN • Discontinue warfarin and start rivaroxaban as soon as INR is <3.0 to avoid periods of inadequate anticoagulation

Notes

Please see drug monograph at www.eMPR.com and/or contact company for full drug labeling.

(Rev. 11/2013)

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CANCER TREATMENT REGIMEN

HEMATOLOGIC CANCER Hodgkin Lymphoma Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Classical Hodgkin Lymphoma—First-Line Treatment1 Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

Stage IA, IIA Favorable Doxorubicin + bleomycin + vinblastine + dacarbazine (ABVD)2-5

Doxorubicin + vinblastine + Days 1 and 15: Doxorubicin 25mg/m2 IV push + vinblastine 6mg/m2 IV over 5–10 minutes mechlorethamine + etoposide + Day 1: Mechlorethamine 6mg/m2 IV push vincristine + bleomycin + prednisone Days 8 and 22: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes + bleomycin 5units/m2 IV push (Stanford V)6-8 Days 15 and 16: Etoposide 60mg/m2 IV over 60 minutes Days 1–28: Prednisone 40mg/m2 orally every other day. Taper prednisone dose by 10mg every other day beginning Day 15 of Cycle 2. Repeat cycle every 4 week for 2 cycles followed by radiation therapy. Stage I–II Unfavorable (Bulky and Non-Bulky Disease) Doxorubicin + bleomycin + vinblastine + dacarbazine (ABVD)2-5,9

Days 1 and 15: Doxorubicin 25mg/m2 IV push + bleomycin 10units/m2 IV push + vinblastine 6mg/m2 IV over 5–10 minutes + dacarbazine 375mg/m2 IV over 60 minutes. Repeat cycle every 4 weeks for 4–6 cycles with or without subsequent radiation therapy (bulky disease) (Category 1), for 2 cycles when given after escalated BEACOPP and followed by radiation therapy, or for 2–6 cycles with or without subsequent radiation (nonbulky disease).

Doxorubicin + vinblastine + Days 1 and 15: Doxorubicin 25mg/m2 IV push + vinblastine 6mg/m2 IV over 5–10 minutes mechlorethamine + etoposide + Day 1: Mechlorethamine 6mg/m2 IV push vincristine + bleomycin + prednisone Days 8 and 22: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes + bleomycin 5units/m2 IV push (Stanford V)6-8 Days 15 and 16: Etoposide 60mg/m2 IV over 60 minutes Days 1–28: Prednisone 40mg/m2 orally every other day. Taper prednisone dose by 10mg every other day beginning Day 15 of Cycle 3. Repeat cycle every 4 week for 3 cycles with or without subsequent radiation therapy. Bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone (Escalated BEACOPP)9,10

Day 1: Cyclophosphamide 1,250mg/m2 IV over 60 minutes + doxorubicin 35mg/m2 IV push Days 1–3: Etoposide 200mg/m2 IV over 2 hours Days 1–7: Procarbazine 100mg/m2 orally. Day 8: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes + bleomycin 10units/m2 IV push. Days 1–14: Prednisone 40mg/m2 orally daily. Repeat cycle every 3 weeks for 2 cycles followed by ABVD and then by radiation therapy.

Stage III–IV Doxorubicin + bleomycin + vinblastine + dacarbazine (ABVD)2-5

Doxorubicin + vinblastine + Days 1 and 15: Doxorubicin 25mg/m2 IV push + vinblastine 6mg/m2 IV over 5–10 minutes mechlorethamine + etoposide + Day 1: Mechlorethamine 6mg/m2 IV push vincristine + bleomycin + prednisone Days 8 and 22: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes + bleomycin 5units/m2 IV push (Stanford V)6-8 Days 15 and 16: Etoposide 60mg/m2 IV over 60 minutes Days 1–28: Prednisone 40mg/m2 orally every other day. Taper prednisone dose by 10mg every other day beginning Day 15 of Cycle 3. Repeat cycle every 4 week for 3 cycles with or without subsequent radiation therapy.

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CANCER TREATMENT REGIMEN

HEMATOLOGIC CANCER Classical Hodgkin Lymphoma—First-Line Treatment1 (continued) Stage III–IV (continued) REGIMEN

DOSING

Bleomycin + etoposide + doxorubicin + cyclophosphamide + vincristine + procarbazine + prednisone (Escalated BEACOPP)10

Day 1: Cyclophosphamide 1,250mg/m2 IV over 60 minutes + doxorubicin 35mg/m2 IV push Days 1–3: Etoposide 200mg/m2 IV over 2 hours Days 1–7: Procarbazine 100mg/m2 orally daily. Day 8: Vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes + bleomycin 10units/m2 IV push. Days 1–14: Prednisone 40mg/m2 orally daily. Repeat cycle every 3 weeks for 4–6 cycles with or without subsequentradiation therapy.

Second Line Therapy Brentuximab11

Day 1: Brentuximab 1.8mg/kg (maximum 180mg) IV over 30 minutes. Repeat cycle every 3 weeks until maximal response or unacceptable toxicity.

Cyclophosphamide + Vincristine + Procarbazine + Prednisone (C-MOPP) (Category 2B)12,13

Day 1: Cyclophosphamide 650mg/m2 IV over 30 minutes + vincristine 1.4mg/m2 (maximum 2mg) IV Days 1–7: Procarbazine 100mg/m2 orally daily Days 1–14: Prednisone 40mg/m2 orally daily. Repeat cycle every 4 weeks for 4–8 cycles. OR Days 1 and 8: Cyclophosphamide 500mg/m2 IV over 30 minutes + vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes Days 1–14: Procarbazine 100mg/m2 orally daily. Days 1–3 and 8–10: Prednisone 40mg/m2 orally daily. Repeat cycle every 4 weeks for 4–8 cycles.

Dexamethasone + Cytarabine + Cisplatin (DHAP)14,15

Days 1–4: Dexamethasone 40mg orally or IV daily Day 1: Cisplatin 100mg/m2 IV continuous infusion over 24 hours Day 2: Cytarabine 2,000mg/m2 IV over 3 hours every 12 hours. Repeat cycle every 3 to 4 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates).

Etoposide + Methylprednisolone + Cytarabine + Cisplatin (ESHAP)16,17

Days 1–4: Etoposide 40mg/m2 IV over 60 minutes + methylprednisolone 500mg IV over 15 minutes + cisplatin 25mg/m2 continuous IV infusion over 24 hours Day 5: Cytarabine 2,000mg/m2 IV over 3 hours. Repeat cycle every 3–4 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates).

Everlolimus18

Everolimus 10mg PO daily until disease progression or unacceptable toxicity.

Gemcitabine + Carboplatin + Dexamethasone (GCD)19

Days 1 and 8: Gemcitabine 1000mg/m2 IV over 30 minutes Day 1: Carboplatin AUC 5mg • min/mL (maximum 800mg) IV over 60 minutes Days 1–4: Dexamethasone 40mg orally daily. Repeat cycle every 3 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates).

Gemcitabine + Vinorelbine + Pegylated liposomal doxorubicin (GVD)20

For transplant-naive patients: Days 1 and 8: Gemcitabine 1,000mg/m2 IV over 30 minutes + vinorelbine 20mg/m2 IV over 5–10 minutes + pegylated liposomal doxorubicin 15mg/m2 IV over 60 minutes. Repeat cycle every 3 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates). For post-transplant patients: Days 1 and 8: Gemcitabine 800mg/m2 IV over 30 minutes + vinorelbine 15mg/m2 IV over 5–10 minutes + pegylated liposomal doxorubicin 10mg/m2 IV over 60 minutes. Repeat cycle every 3 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates).

Ifosfamide + Carboplatin + Etoposide Days 1–3: Etoposide 100mg/m2 IV over 60 minutes (ICE)15,21 Day 2: Carboplatin AUC 5mg • min/mL (max 800mg) IV + ifosfamide 5,000mg/m2 IV continuous infusion over 24 hours and mesna 5,000mg/m2 IV continuous infusion over 24 hours concurrently with ifosfamide. Repeat cycle every 2–3 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates). Ifosfamide + Gemcitabine + Etoposide + Vinorelbine (IGEV)22

Days 1–4: Mesna 400mg/m2 IV over 15 minutes prior to ifosfamide dose and at 4 and 8 hours from the start of each ifosfamide dose + ifosfamide 2,000mg/m2 over 3 hours Days 1 and 4: Gemcitabine 800mg/m2 IV over 30 minutes Day 1: Vinorelbine 20mg/m2 IV over 5–10 minutes Days 1–4: Prednisone 100mg PO daily. Repeat cycle every 3 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates). continued

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CANCER TREATMENT REGIMEN

HEMATOLOGIC CANCER Hodgkin Lymphoma Treatment Regimens Classical Hodgkin Lymphoma—First-Line Treatment1 (continued) Second Line Therapy (continued) REGIMEN

DOSING

Carmustine + Cytarabine + Etoposide + Melphalan (Mini-BEAM)23,24

Days 1: Carmustine 60mg/m2 IV over 2 hours Days 2–5: Etoposide 75mg/m2 IV over 60 minutes daily + cytarabine 100mg/m2 IV over 3 hours every 12 hours Day 6: Melphalan 30mg/m2 IV over 15 minutes. Repeat cycle every 4–6 weeks for 2–4 cycles.

Mitoxantrone + Ifosfamide + Etoposide (MINE)25

Days 1–3: Mesna 300mg/m2 IV over 15 minutes prior to ifosfamide dose and at 4 and 8 hours after each ifosfamide dose + ifosfamide 1,330mg/m2 over 3 hours + etoposide 65mg/m2/day IV over 1 hour. Day 1: Mitoxantrone 8mg/m2 IV over 30 minutes. Repeat cycle every 3 weeks for 2–4 cycles (transplant candidates) or 4–8 cycles (nontransplant candidates).

Third Line Therapy Bendamustine26

Days 1 and 2: Bendamustine 90–120mg/m2 IV over 30 minutes. Repeat cycle every 4 weeks until maximal response or unacceptable toxicity for a maximum of 6 cycles.

Lenalidomide27

Days 1–21: Lenalidomide 25mg orally daily. Repeat cycle every 4 weeks until disease progression or unacceptable toxicity.

Nodular Lymphocyte-Predominant Hodgkin Lymphoma—First-Line Treatment1 Doxorubicin + Bleomycin + Days 1 and 15: Doxorubicin 25mg/m2 IV push + bleomycin 10units/m2 IV push + vinblastine 6mg/m2 IV over 5–10 Vinblastine + Dacarbazine (ABVD) ± minutes + dacarbazine 375mg/m2 IV over 60 minutes, ± Rituximab28,29,31-34 Day 1: Rituximab 375mg/m2 IV for all cycles. OR Days 1, 8, 15, and 22: Rituximab 375mg/m2 IV for cycle 1 only. Repeat cycle every 4 weeks for 6–8 cycles with or without subsequent radiation therapy. Cyclophosphamide + Doxorubicin + Vincristine + Prednisone (CHOP) ± Rituximab30-34

Day 1: Cyclophosphamide 750mg/m2 over 60 minutes + doxorubicin 50mg/m2 IV push + vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes Days 1–5: Prednisone 100mg orally daily, ± Day 1: Rituximab 375mg/m2 IV. Repeat cycle every 3 weeks for 6 cycles with or without subsequent radiation therapy.

Cyclophosphamide + Vincristine + Prednisone (CVP) ± Rituximab31-34

Day 1: Cyclophosphamide 750mg/m2 OR 1,000mg/m2 over 60 minutes + vincristine 1.4mg/m2 (maximum 2mg) IV over 5–10 minutes Days 1–5: Prednisone 100mg orally daily, ± Day 1: Rituximab 375mg/m2 IV. Repeat cycle every 3 weeks for 6–8 cycles with or without subsequent radiation therapy.

References 1. 2.

3. 4. 5. 6.

NCCN Clinical Practice Guidelines in Oncology™. Hodgkin Lymphoma.V.2.2014. Available at: http://www.nccn.org/professionals/ physician_gls/pdf/hodgkins.pdf. Accessed November 3, 2014. Eich HT, Diehl V, Görgen H, et al. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28: 4199–4206. Engert A, Plutschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin’s lymphoma. N Engl J Med. 2010;363:640–652. Meyer R, Gospodarowicz M, Connors J, et al. ABVD alone versus radiation based therapy in limited stage Hodgkin’s lymphoma. N Engl J Med. 2012;366:399–408. Bonadonna G, Bonfante V, Viviani S, et al. ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin’s disease: long-term results. J Clin Oncol. 2004;22: 2835–2841. Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapyin locally extensive and advancedstage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013;31:684–691.

8. 9. 10.

11. 12.

Advani RH, Hoppe RT, Baer DM, et al. Efficacy of abbreviated Stanford V chemotherapy and involved field radiotherapy in early stage Hodgkin’s disease: mature results of the G4 trial. Ann Oncol. 2013;24:1044–1048. Edwards-Bennett SM, Jacks LM, Moskowitz CH, et al. Stanford V program for locally extensive and advanced Hodgkin lymphoma: the Memorial Sloan-Kettering Cancer Center experience. Ann Oncol. 2010;21:574–581. von Tresckow B, Plutschow A, Fuchs M, et al. Dose-intensification in early unfavorable Hodgkin’s lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012; 30:907–913. Engert A, Haverkamp H, Cobe C, et al. Reduced-intensity chemotherapy and PETguided radiotherapy in patients with advanced stage Hodgkin’s lymphoma (HD15 trial): a randomized, open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828): 1791–1799. Younes A, Bartlett NL, Leonard JP et al. Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med. 2010;4;363:1812–1821. Montoto S, Camós M, López-Guillermo A, et al. Hybrid chemotherapy consisting of C-MOPP/ABV as first-line treatment for patients with advanced Hodgkin disease. Cancer. 2000;88(9): 2142–2148.

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HEMATOLOGIC CANCER 13.

Takenaka T, Mikuni C, Miura A, et al. Alternating combination chemotherapy C-MOPP and ABVD in clinical stage II–IV Hodgkin’s disease: a multicenter phase II study (JCOG 8905). The Lymphoma Study Group of the Japan Clinical Oncology Group. Jpn J Clin Oncol. 2000;30(3):146–152. 14. Josting A, Rudolph C, Reiser M, et al. Time-intensified dexamethasone/cisplatin/ cytarabine: an effective salvage therapy with low toxicity in patients with relapsed and refractory Hodgkin’s disease. Ann Oncol. 2002;13(10):1628–1635. 15. Abali H, Urün Y, Oksüzoğlu B, Budakoğlu B, et al. Comparison of ICE versus DHAP as salvage chemotherapy in patients with relapsed or refractory lymphoma. Cancer Invest. 2008;26(4): 401–406. 16. Aparicio J, Segura A, Garcera S, et al. ESHAP is an active regimen for relapsing Hodgkin’s disease. Ann Oncol. 1999;10(5):593–595. 17. Fernández de Larrea C, Martinez C, et al. Salvage chemotherapy with alternating MINE-ESHAP regimen in relapsed or refractory Hodgkin’s lymphoma followed by autologous stem cell transplantation. Ann Oncol. 2010;21(6):1211–1216. 18. Johnston PB, Inwards DJ, Colgan JP, et al. A phase II trial of the oral mTOR inhibitor everolimus in relapsed Hodgkin lymphoma. Am J Hematol. 2010;85:320–324. 19. Gopal AK, Press OW, Shustov AR, et al. Efficacy and safety of gemcitabine, carboplatin, dexamethasone, and rituximab in patients with relapsed/refractory lymphoma: a prospective multi-center phase II study by the Puget Sound Oncology Consortium. Leuk Lymphoma. 2010;51:1523–1529. 20. Bartlett NL, Niedzwiecki D, JL Johnson JL et al. Gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD), a salvage regimen in relapsed Hodgkin’s lymphoma: CALGB 59804. Ann Oncol. 2007;18:1071–1079. 21. Moskowitz CH, Nimer SD, Zelenetz AD, et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hogdkin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001; 97(3):616–623. 22. Santoro A, Magagnoli M, Spina M, et al. Ifosfamide, gemcitabine, and vinorelbine: a new induction regimen for refractory and relapsed Hodgkin’s lymphoma. Haematologica. 2007; 92(1):35–41. 23. Colwill R, Crump M, Couture F, et al. Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin’s disease before intensive therapy and autologous bone marrow transplantation. J Clin Oncol. 1995;13:396–402.

24. Martin A, Fernández-Jiménez MC, Caballero MD, et al. Long-term follow-up in patients treated with Mini-BEAM as salvage therapy for relapsed or refractory Hodgkin’s disease. Br J Haematol. 2001;113(1):161–171. 25. Rodriguez MA et al. A phase II trial of mesna/ifosfamide, mitoxantrone and etoposide for refractory lymphoma. Ann Oncol 1995;6:609. 26. Moskowitz AJ, Hamlin PA, Perales M-A, et al. Phase II study of bendamustine in relapsed and refractory classical Hodgkin lymphoma. Blood. 2011;118(19):5119–5125. 27. Fehniger TA, Larson S, Trinkaus K, et al. A phase 2 multi-center study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood. 2011;118:5119–5125. 28. Savage KJ, Skinnider B, Al-Mansour M, et al. Treating limited stage nodular lymphocyte predominant Hodgkin lymphoma similarly to classical Hodgkin lymphoma with ABVD may improve outcome. Blood. 2011;118:4585–4590. 29. Canellos GP, Mauch P. What is the appropriate systemic chemotherapy for lymphocyte-predominant Hodgkin’s Lymphoma? J Clin Oncol. 2010;28:e8. 30. Fanale MA, Lai C-M, McLaughlin P, et al. Outcomes of nodular lymphocyte predominant Hodgkin’s Lymphoma (NLPHL) patients treated with R-CHOP. ASH Annual Meeting Abstracts. 2010;116:2812. 31. Ekstrand BC, Lucas JB, Horwitz SM, et al. Rituximab in lymphocyte-predominant Hodgkin disease: results of a phase 2 trial. Blood. 2003;101:4285–4289. 32. Schulz H, Rehwald U, Morschhauser F, et al. Rituximab in relapsed lymphocyte-predominant Hodgkin lymphoma: long-term results of a phase 2 trial by the German Hodgkin Lymphoma Study Group (GHSG). Blood. 2008;111: 109–111. 33. Horning SJ, Bartlett NL, Breslin S, et al. Results of a prospective phase II trial of limited and extended rituximab treatment in nodular lymphocyte predominant Hodgkin’s disease (NLPHD). ASH Annual Meeting Abstracts. 2007; 110:644. 34. Eichenauer DA, Fuchs M, Pluetschow A, et al. Phase 2 study of rituximab in newly diagnosed stage 1A nodular lymphocyte- predominant Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood. 2011;118:4363–4365. (Revised 11/2014) © 2015 by Haymarket Media, Inc.

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HEMATOLOGIC CANCER Non-Hodgkin Lymphoma Treatment Regimens: Burkitt Lymphoma Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Induction Therapy—Low Risk1* Note: All recommendations are Category 2A unless otherwise indicated.

REGIMEN

DOSING

CALGB 10002

Cycle 1: Day 1: Triple intrathecal therapy for CNS prophylaxis Days 1–5: Cyclophosphamide 200mg/m2 IV Days 1–7: Prednisone 60mg/m2 orally. Cycles 2 (beginning Day 8), 4, and 6: Day 1: Triple intrathecal therapy for CNS prophylaxis Days 1–5: Ifosfamide 800mg/m2 IV + dexamethasone 10mg/m2 IV Day 1: Methotrexate 1.5g/m2 IV (with leucovorin rescue) + vincristine 2mg IV Days 4 and 5: Cytarabine 1g/m2 IV + etoposide 80mg/m2 IV Day 8: Rituximab 50mg/m2 IV for cycle 2, then 375mg/m2 IV for cycles 4 and 6 Days 10 and 12 (Cycle 2 only): Rituximab 375mg/m2 IV. Cycles 3, 5, and 7: Day 1: Triple intrathecal therapy for CNS prophylaxis Days 1–5: Cyclophosphamide 200mg/m2 IV + dexamethasone 10mg/m2 IV Day 1: Methotrexate 1.5g/m2 IV + vincristine 2mg IV Days 4 and 5: Doxorubicin 25mg/m2 IV Day 8: Rituximab 375mg/m2 IV. Deliver cycles every 21 days.

CODOX-M (original or modified) (cyclophosphamide + doxorubicin + vincristine with intrathecal MTX + cytarabine, followed by systemic MTX and cytarabine) ± rituximab3

Dose-adjusted EPOCH (etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin) + intrathecal MTX + rituximab4–6†

Day 1: Rituximab 375mg/m2 IV Days 1–4: Etoposide 50mg/m2 continuous IV infusion + doxorubicin 10mg/m2 continuous IV infusion + vincristine 0.4mg/m2 continuous IV infusion Days 1–5: Prednisone 60mg/m2 orally twice daily. Day 5: Cyclophosphamide 750mg/m2 IV Day 6: G-CSF 300µg administered until ANC >5,000cells/µL Days 1 and 5 (Cycles 3–6): Methotrexate 12mg intrathecally. Repeat cycle every 3 weeks for 6 cycles.

HyperCVAD (cyclophosphamide + vincristine + doxorubicin + dexamethasone alternating with high-dose methotrexate and cytarabine)7,8

Cycles 1, 3, 5, and 7—HyperCVAD Days 1–3: Cyclophosphamide 300mg/m2 IV every 12 hours for 6 doses + mesna 600mg/m2 continuous IV infusion Days 4 and 11: Vincristine 2mg IV Day 4: Doxorubicin 50mg/m2 IV Days 1–4 and Days 11–14: Dexamethasone 40mg IV daily Days 1 and 11 (Cycles 1 and 3 only): Rituximab 375mg/m2 IV. Cycles 2, 4, 6, 8—High-dose MTX and Cytarabine Day 1: MTX 1g/m2 IV over 24 hours Days 2 and 3: Cytarabine 3g/m2 IV every 12 hours for 4 doses Days 2 and 8 (Cycles 2 and 4): Rituximab 375mg/m2 IV. Repeat every 3 weeks for 8 cycles.

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HEMATOLOGIC CANCER Combination Regimens—High-Risk1* REGIMEN

DOSING

CALGB 100022

CODOX-M (original or modified) (cyclophosphamide + doxorubicin + vincristine, plus intrathecal MTX + cytarabine, followed by systemic MTX) alternating with IVAC (ifosfamide + cytarabine + etoposide) and intrathecal MTX ± rituximab3,9,10

Day 1: Cyclophosphamide 800mg/m2 IV + doxorubicin 40mg/m2 IV Days 2–5: Cyclophosphamide 200mg/m2/day IV Days 1 and 3: Cytarabine 70mg intrathecally Days 1 and 8: Vincristine 1.5mg/m2 IV Day 10: Methotrexate 1,200mg/m2 IV over 1 hour, then 240mg/m2/hour continuous IV infusion for the next 23 hours Day 11: Leucovorin 192mg/m2 IV 36 hours after initiation of MTX, followed by leucovorin 12mg/m2 IV every 6 hours until MTX level <5 × 10–8 M Day 13: G-CSF 5µg/kg SC daily beginning 24 hours after initiation of leucovorin until absolute granulocyte count ≥1 × 109/L Day 15: Methotrexate 12mg intrathecally Day 16: Leucovorin 15mg orally given 24 hours after intrathecal MTX, ± Day 1: Rituximab 375mg/m2 IV. Alternate Cycles With: Day 1: Cytarabine 2g/m2 IV every 12 hours for 4 doses. Days 1–5: Etoposide 60mg/m2 IV + ifosfamide 1,500mg/m2 IV, plus mesna 360mg/m2 Day 5: Methotrexate 12mg intrathecally Day 6: Leucovorin 15mg orally 24 hours after intrathecal MTX Day 7: G-CSF 5µg/kg SC daily until absolute granulocyte count ≥1 × 109/L, ± Day 1: Rituximab 375 mg/m2 IV. Repeat for 4 cycles alternating between CODOX-M and IVAC regimens.

Dose-adjusted EPOCH (etoposide + prednisone + vincristine + cyclophosphamide + doxorubicin) + intrathecal MTX + rituximab4–6†

Day 1: Rituximab 375mg/m2 IV Days 1–4: Etoposide 50mg/m2 continuous IV infusion + doxorubicin 10mg/m2 continuous IV infusion + vincristine 0.4mg/m2 continuous IV infusion Days 1–5: Prednisone 60mg/m2 orally twice daily Day 5: Cyclophosphamide 750mg/m2 IV Day 6: G-CSF 300µg administered until ANC >5,000cells/µL Days 1 and 5 (Cycles 3–6): Methotrexate 12mg intrathecally. Repeat cycle every 3 weeks for 6 cycles.

HyperCVAD (cyclophosphamide + vincristine + doxorubicin + dexamethasone alternating with high-dose methotrexate and cytarabine) + rituximab7,8

Cycles 1, 3, 5, and 7—HyperCVAD Days 1–3: Cyclophosphamide 300mg/m2 IV every 12 hours for 6 doses + mesna 600mg/m2 continuous IV infusion Days 4 and 11: Vincristine 2mg IV Day 4: Doxorubicin 50mg/m2 IV Days 1–4 and Days 11–14: Dexamethasone 40mg IV daily Days 1 and 11 (Cycles 1 and 3 only): Rituximab 375mg/m2 IV Cycles 2, 4, 6, 8—High-dose MTX and Cytarabine Day 1: MTX 1g/m2 IV over 24 hours Days 2 and 3: Cytarabine 3g/m2 IV every 12 hours for 4 doses Days 2 and 8 (Cycles 2 and 4): Rituximab 375mg/m2 IV. Repeat every 3 weeks for 8 cycles. continued

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HEMATOLOGIC CANCER Non-Hodgkin Lymphoma Treatment Regimens: Burkitt Lymphoma Second Line Therapy1* REGIMEN

DOSING

Dose-adjusted EPOCH (etoposide + prednisone + vincristine + cyclophosphamide+ doxorubicin) + intrathecal MTX + rituximab4–6†

Day 1: Rituximab 375mg/m2 IV Days 1–4: Etoposide 50mg/m2 continuous IV infusion + doxorubicin 10mg/m2 continuous IV infusion + vincristine 0.4mg/m2 continuous IV infusion Days 1–5: Prednisone 60mg/m2 orally twice daily Day 5: Cyclophosphamide 750mg/m2 IV Day 6: G-CSF 300µg administered until ANC >5,000cells/µL Days 1 and 5 (Cycles 3–6): Methotrexate 12mg intrathecally. Repeat cycle every 3 weeks for 6 cycles.

RICE (rituximab + ifosfamide + carboplatin + etoposide)11

Day 1: Rituximab 375mg/m2 IV Day 2: Ifosfamide 5,000mg/m2 and Mesna 5,000mg/m2 IV + carboplatin AUC 5 mg • min/mL (maximum 800mg) IV Day 1–3: Etoposide 100mg/m2 IV. Repeat cycle every 3 weeks.

RIVAC (rituximab + ifosfamide + cytarabine + etoposide)10

Day 1: Rituximab 375mg/m2 IV Day 1: Cytarabine 2g/m2 IV every 12 hours for 4 doses Days 1–5: Etoposide 60mg/m2 IV + ifosfamide 1,500mg/m2 IV, plus mesna 360mg/m2 Day 5: Methotrexate 12mg intrathecally Day 6: Leucovorin 15mg orally 24 hours after intrathecal MTX Day 7: G-CSF 5µg/kg SC daily until absolute granulocyte count ≥1 × 109/L. Repeat cycle every 3 weeks.

RGDP (rituximab + gemcitabine + dexamethasone + cisplatin)12

Day 1: Rituximab 375mg/m2 IV Day 1 and 8: Gemcitabine 1,000mg/m2 IV Day 1–3: Cisplatin 25mg/m2 IV Day 1–4: Dexamethasone 40mg IV. Repeat cycle every 3 weeks.

HDAC13

Days 1, 3, and 5: High-dose cytarabine 3g/m2 IV every 12 hours. Repeat for 4 cycles.

* All regimens for Burkitt lymphoma include CNS prophylaxis/therapy. † For patients without CNS disease

References 1.

NCCN Clinical Practice guidelines in Oncology™. Burkitt Lymphoma. v 5.2014. Available at: http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed November 17, 2014. Rizzieri DA, Johnson JL, Byrd JC, et al. Efficacy and toxicity of rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or Burkitt–like leukemia/lymphoma: Cancer and Leukemia Group B (Calgb) study 10002. Presented at American Society of Hematology Annual Meeting and Exposition; December 4–7, 2010; Orlando, FL. Blood. 2010;116:Abstract 858. Lacasce A, Howard O, Li S, et al. Modified Magrath regimens for adults with Burkitt and Burkitt-like lymphomas: preserved efficacy with decreased toxicity. Leuk Lymphoma. 2004;45:761–767. Dunleavy K, Wayne A, Little R, et al. The addition of rituximab to dose-adjusted EPOCH with HAART suspension is highly effective and tolerable in AIDS-related lymphoma (ARL) and allows the delivery of abbreviated chemotherapy. Poster presented at: American Society of Hematology Annual Meeting and Exposition; December 10–13, 2005; Atlanta, GA. Blood. 2005;106:Abstract 930. Dunleavy K, Little RF, Pittaluga S, et al. A prospective study of dose-adjusted EPOCH with rituximab in adult patients with newly diagnosed Burkitt lymphoma: a regimen with high efficacy and low toxicity. 10th International Conference on Malignant Lymphomas Abstracts. Ann Oncol. 2008;19(suppl 4):iv83–iv84. Wilson WH, Grossbard ML, Pittaluga S, et al. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood. 2002;99:2685–2693.

10.

11.

12.

13.

Thomas DA, Faderl S, O’Brien S, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-like lymphoma or acute lymphoblastic leukemia. Cancer. 2006;106:1569–1580. Thomas DA, Kantarjian HM, Cortes J, et al. Long-term outcome after hyper-CVAD and rituximab chemoimmunotherapy for Burkitt (BL) or Burkitt-like (BLL) leukemia/lymphoma and mature B-cell acute lymphocytic leukemia (ALL). Poster presented at: American Society of Hematology Annual Meeting and Exposition; December 6–9, 2008; San Francisco, CA. Blood. 2008;112:Abstract 1929. Mead GM, Sydes MR, Walewski J, et al. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adults Burkitt’s lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol. 2002;13:1264–1274. Barnes JA, Lacasce AS, Feng Y, et al. Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt’s lymphoma: a retrospective analysis. Ann Oncol. 2011;22:1859–1864. Griffin TC, Weitzman S, Weinstein H et al. A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Pediatr Blood Cancer. 2009;52:177–181. Fan Y, Huang ZY, Luo LH, Yu HF. Efficacy of GDP regimen on relapsed or refractory aggressive non-Hodgkin’s lymphoma: a report of 24 cases. Ai Zheng. 2008;27(11):1222–1225. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Engl J Med. 1994;331:896–903.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER ADCETRIS Seattle Genetics

℞

CD30-directed antibody-drug conjugate. Brentuximab vedotin 50mg/vial; pwd for IV infusion after reconstitution; preservative-free. Indications: Treatment of Hodgkin lymphoma (HL) after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates. Treatment of systemic anaplastic large cell lymphoma (sALCL) after failure of at least one prior multiagent chemotherapy regimen. Adults: Give by IV infusion over 30 minutes. 1.8mg/kg every 3 weeks (if >100kg, calculate dose based on wt. of 100kg); continue until a max of 16 cycles, disease progression or unacceptable toxicity. Peripheral neuropathy: if Grade 2/3: withhold until resolve to ≤Grade 1, then restart with 1.2mg/kg; if Grade 4: discontinue therapy. Neutropenia: Grade 3/4: withhold until resolve to ≤Grade 2; may consider growth factor support; recurrent Grade 4: discontinue or consider reducing dose to 1.2mg/kg. Children: Not established. Contraindications: Concomitant bleomycin. Warnings/Precautions: Risk of JC virus infection. Monitor for progressive multifocal leukoencephalopathy (PML); withhold dose if suspected and discontinue if confirmed. Monitor for neuropathy and delay, change, or discontinue dose accordingly. Monitor for infusion-related reactions; permanently discontinue and treat if anaphylaxis occurs. Monitor CBCs prior to each dose and frequently for Grade 3 or 4 neutropenia; if develops, delay, reduce or discontinue dose. Increased risk of tumor lysis syndrome in rapidly proliferating tumor/high tumor burden patients; monitor closely. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: See Contraindications. Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole); monitor. Antagonized by potent CYP3A4 inducers (eg, rifampin). Adverse reactions: Neutropenia, peripheral sensory neuropathy, fatigue, GI upset, anemia, upper respiratory tract infection, pyrexia, rash, thrombocytopenia, cough; infusion reactions, Stevens-Johnson syndrome (discontinue if occurs), PML (may be fatal). How supplied: Single-use vial–1

ALKERAN GlaxoSmithKline

℞

Nitrogen mustard derivative. Melphalan 2mg; scored tabs. Indications: Palliative treatment for multiple myeloma.

Adults: 6mg once daily for 2–3 weeks; stop for up to 4 weeks, maintenance 2mg per day. Continue treatment as hematological recovery permits (esp. WBCs and platelets); for other regimens: see literature. Children: Not recommended. Also: ALKERAN FOR INJECTION ℞ Melphalan HCl 50mg/vial; pwd for IV infusion after reconstitution and dilution. Indications: Palliative treatment of multiple myeloma when oral therapy is not appropriate. Adults: Give by IV infusion over 15–20 minutes. 16mg/m2 every 2 weeks for a total of 4 doses, then at 4-week intervals. Continue treatment as hematological recovery permits. Renal insufficiency (BUN≥30mg/dL): consider reducing dose by 50%. Children: Not recommended. Contraindications: Prior resistance to melphalan. Warnings/Precautions: Prior irradiation or chemotherapy. Bone marrow suppression. Azotemia. Monitor platelets, hemoglobin, WBC and differential at start of therapy and prior to each course; discontinue if WBC <3,000cells/ µL or platelets <100,000cells/µL. Moderate to severe renal impairment. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Radiotherapy potentiates antineoplastic effect. For IV: caution with cyclosporine, cisplatin, BCNU, nalidixic acid. Adverse reactions: Bone marrow suppression, GI upset, hepatic dysfunction, anemia, blood dyscrasias, secondary malignancies (eg, nonlymphocytic leukemia), rash, alopecia, pulmonary fibrosis, interstitial pneumonitis, gonadal toxicity (amenorrhea, infertility); hypersensitivity reactions, cardiac arrest (rare). How supplied: Tabs–50; single-use vial–1 (w. diluent)

ARRANON GlaxoSmithKline

℞

Nucleoside analogue. Nelarabine 250mg/vial; soln for IV infusion. Indications: T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) that is unresponsive or has relapsed after ≥2 chemotherapy regimens. Adults and Children: Contact manufacturer. From the pediatric trial: Patients ≤21 yrs: 650mg/m2 by IV infusion over 1 hour daily for 5 consecutive days; repeat every 21 days. From the adult trial: Patients 16–65yrs: 1500mg/m2 by IV infusion over 2 hours on days 1, 3, and 5; repeat every 21 days. The recommended duration of treatment has not been clearly established. Treatment was generally continued until there

was evidence of disease progression, the patient experienced unacceptable toxicity, the patient became a candidate for bone marrow transplant, or the patient no longer continued to benefit from treatment. See literature. Warnings/Precautions: Discontinue if ≥ Grade 2 neurotoxicity occurs; may delay dosing if other toxicities occur (eg, hematologic toxicity). Prior or concurrent intrathecal chemotherapy or craniospinal irradiation (increased risk of neurotoxicity). Renal or hepatic impairment. Obtain CBCs, platelet counts. Monitor for signs/ symptoms of infection, tumor lysis syndrome. Ensure adequate hydration. Elderly. Pregnancy (Cat.D); use effective contraception. Nursing mothers: not recommended. Interactions: Avoid live vaccines. Concomitant adenosine deaminase inhibitors (eg, pentostatin): not recommended. Adverse reactions: Hematologic disorders (eg, anemia, neutropenia, thrombocytopenia), headache, GI upset, constipation, fatigue, somnolence, dizziness, peripheral neuropathy, seizures, respiratory disorders, pyrexia; increased transaminase levels, bilirubin; decreased potassium, albumin. How supplied: Vials–6

ARZERRA GlaxoSmithKline

℞

CD20-directed cytolytic monoclonal antibody. Ofatumumab 20mg/mL; soln for IV infusion after dilution; preservative-free. Indications: In combination with chlorambucil in previously untreated patients with chronic lymphocytic leukemia (CLL), for whom fludarabine-based therapy is considered inappropriate. CLL refractory to fludarabine and alemtuzumab. Adults: See full labeling. Premedicate with acetaminophen (oral), antihistamine (oral or IV), corticosteroid (IV). Give by IV infusion (use in-line filter; rate varies with dose and during infusion). Previously untreated: initially 300mg on Day 1, then 1 week later by 1000mg on Day 8 (Cycle 1), follow by 1000mg on Day 1 of subsequent 28-day cycles for at least 3 cycles until best response or max 12 cycles. Refractory: initially 300mg once, then 1 week later by 2000mg weekly for 7 doses, followed 4 weeks later by 2000mg every 4 weeks for 4 doses. Children: Not established. Warnings/Precautions: Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Monitor CBCs at regular intervals during

Please see brief summary of Full Prescribing Information on pages 68–69. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. TRE-40083 October 2014.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER and after therapy, increase frequency if Grade 3/4 cytopenias develop. Monitor for new onset of or changes in neurological signs/symptoms. Increased risk of tumor lysis syndrome (TLS) in high tumor burden and/or high circulating lymphocytes; consider prophylaxis with anti-hyperuricemics and hydration beginning 12–24hrs prior to infusion. Pregnancy (Cat.C). Nursing mothers. Interactions: Avoid vaccination with live viral vaccines. Adverse reactions: Neutropenia, thrombocytopenia, anemia, pneumonia, pyrexia, cough, fatigue, dyspnea, rash, nausea, diarrhea, bronchitis, upper respiratory tract infections; infusion reactions (eg, bronchospasm; laryngeal, pulmonary, or angioedema; flushing, hyper- or hypotension, syncope, cardiac ischemia, back or abdominal pain, fever, urticaria) (interrupt, adjust infusion rate and monitor; permanently discontinue if anaphylaxis occurs), progressive multifocal leukoencephalopathy (discontinue if suspected and evaluate), infections (eg, sepsis), hepatotoxicity, TLS. How supplied: Single-use vial (5mL)–3; (50mL)–1

BELEODAQ Spectrum

℞

Histone deacetylase inhibitor. Belinostat 500mg; per vial; lyophilized pwd for IV inj after reconstitution and dilution. Indications: Relapsed or refractory peripheral T-cell lymphoma. Adults: Give 1000mg/m2 once daily by IV infusion over 30 mins on Days 1–5 of a 21-day cycle; can repeat cycles every 21 days until disease progression or unacceptable toxicity. Dose modifications: Hematologic toxicities: if ANC nadir <0.5×109/L or platelet count <25×109/L: decrease dose by 25% (750mg/m2); discontinue if recurrent ANC <0.5×109/L or platelet count <25×109/L nadirs after 2 dose reductions; Nonhematologic toxicities: if any CTCAE Grade 3/4 reaction: decrease dose by 25% (750mg/m2); discontinue if recurrent CTCAE Grade 3/4 reaction after 2 dose reductions. Patients with homozygous UGT1A1*28 allele: initially 750mg/m2. Children: Not established. Warnings/Precautions: Risk of hematologic toxicity; monitor blood counts with differential at baseline and weekly during therapy; adjust dose as necessary. Active infection: do not administer. History of extensive or intensive chemotherapy: may be at higher risk of life-threatening infections. Renal or hepatic impairment. Monitor serum chemistry, renal and hepatic function before treatment and the start of each cycle; interrupt, adjust, or discontinue dose based on severity of hepatotoxicity. Tumor lysis syndrome; monitor patients with advanced stage disease and/or high tumor syndrome. GI toxicity; may require use of antiemetics and antidiarrheals. Embryo-fetal toxicity. Pregnancy (Cat.D), nursing mothers: not recommended.

Interactions: Avoid concomitant use of strong UGT1A1 inhibitors. Adverse reactions: Nausea, fatigue, pyrexia, anemia, vomiting; hematologic toxicity, infection, hepatotoxicity, tumor lysis syndrome, GI toxicity. How supplied: Single-use vial (30mL)–1 ℞

Note: For technical questions call (877) 4239927. How supplied: Dosimetric pack (tositumomab 2 × 225mg/vial + 1 × 35mg/vial and Iodine I131 tositumomab 1 × 20mL single-use vial)–1; Therapeutic pack (tositumomab 2 × 225mg/vial + 1 × 35mg/vial and Iodine I131 tositumomab 1 or 2 × 20mL single-use vial)–1

Radionuclide (B-lymphocyte-restricted differentiation antigen [CD20] inhibitor). Tositumomab 35mg/vial, 225mg/vial; soln; Iodine I131 tositumomab 0.61mCi/mL, 5.6mCi/mL soln; both for IV infusion after dilution; preservative-free. Indications: Non-Hodgkin’s lymphoma (CD20 antigen-expressing relapsed or refractory, low grade, follicular, transformed, or rituximabrefractory). Adults: See literature. Pretreat with acetaminophen 650mg and oral diphenhydramine 50mg and thyroid blockers; continue thyroid blockers 2 weeks after therapeutic dose. Give by IV infusion. Dosimetric step: Tositumomab 450mg over 1hr, then Iodine I131 tositumomab (containing 5mCi I131 and 35mg tositumomab) over 20 minutes. Therapeutic step (7–14 days after dosimetric step if biodistribution acceptable): tositumomab 450mg over 1hr, then calculated therapeutic dose of Iodine I131 tositumomab over 20 minutes. Reduce infusion rate by 50% if infusional toxicity occurs; stop if severe; may continue at 50% rate if severe symptoms resolve. Children: Not recommended. Contraindications: Hypersensitivity to murine proteins. Pregnancy (Cat.X). Warnings/Precautions: Use only by physicians trained in radionuclide therapy. Handle and dispose of properly. See literature on patient contact restrictions. Not for initial treatment. >25% lymphoma marrow involvement and/or impaired bone marrow reserve, platelet count <100000cells/mm3, neutrophil count <1500cells/mm3, or intolerant to thyroid blockers: not recommended. High tumor burden. Splenomegaly. Renal impairment. Screen for human anti-mouse antibodies (increases anaphylaxis risk). Obtain CBCs and platelet counts before and for up to 12 weeks after therapy. Monitor TSH (before and annually), serum creatinine (before). Use adequate contraception during and for 12 months after therapy. Elderly. Nursing mothers: not recommended. Interactions: Concomitant other forms of irradiation or chemotherapy: not recommended. Caution with live viral vaccines, anticoagulants, platelet aggregation inhibitors. Adverse reactions: Thrombocytopenia, neutropenia, anemia, headache, asthenia, fever, chills, pain, GI upset, cough, pneumonia, pleural effusion, dehydration, rash, infection, hemorrhage, hypersensitivity reactions (may be fatal), myelodysplastic syndrome, secondary malignancies, antibody formation.

Bispecific CD19-directed CD3 T-cell engager. Blinatumomab 35mcg; per vial; lyophilized pwd for IV infusion after reconstitution; preservativefree. Indications: Philadelphia chromosome-negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Adults: Strictly follow preparation and administration instructions. Pre-medicate with IV dexamethasone 20mg 1 hour prior to 1st dose of each cycle, prior to a step dose, or when restarting infusion after interruption (≥4 hours). Hospitalization recommended for first 9 days of Cycle 1 and first 2 days of Cycle 2. One single cycle = 4 weeks of continuous IV infusion followed by a 2-week treatment-free interval. ≥18yrs (≥45kg): Give by continuous IV infusion at a rate of 10mL/hr for 24 hours or 5mL/hr for 48 hours. Cycle 1: 9mcg/day on Days 1–7 and 28mcg/day on Days 8–28. Subsequent cycles: 28mcg/day on Days 1–28. Treat up to a total of 5 cycles. Dose adjustments: see full labeling. Children: <18yrs: not established. Warnings/Precautions: Monitor for signs/ symptoms of cytokine release syndrome or neurological toxicities; interrupt or discontinue as recommended (see full labeling). Monitor for infections; give antibiotic prophylaxis as appropriate. Monitor for tumor lysis syndrome; interrupt or discontinue as needed. Obtain lab tests (including WBC, ANC) during infusion; interrupt if prolonged neutropenia occurs. Monitor ALT, AST, GGT, and total bilirubin prior to and during treatment; interrupt if transaminases rise >5×ULN or if bilirubin rises >3×ULN. Risk of leukoencephalopathy, esp. in those with prior treatment with cranial irradiation and antileukemic chemotherapy (including high-dose methotrexate or intrathecal cytarabine). Renal impairment (CrCl <30mL/min) or hemodialysis. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Caution with concomitant CYP450 substrates (esp. drugs with narrow therapeutic index); adjust dose as needed. Monitor for toxicity with warfarin. Monitor cyclosporine. Adverse reactions: Pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, tremor, rash, constipation; pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, confusion, overdose, possible immunogenicity. How supplied: Pack–1 (single-use vial + IV solution stabilizer)

BEXXAR GlaxoSmithKline

BLINCYTO Amgen

℞

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER BOSULIF Pfizer

℞

Tyrosine kinase inhibitor. Bosutinib 100mg, 500mg; tabs. Indications: Treatment of chronic, accelerated, or blast phase Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML) with resistance or intolerance to prior therapy. Adults: 500mg once daily with food. Continue until disease progression or patient intolerance. Consider dose escalation to 600mg once daily in patients who do not reach complete hematological response (CHR) by Week 8 or a complete cytogenetic response (CCyR) by Week 12, who did not have Grade 3 or higher adverse reactions. Adjust dose for hematologic and non-hematologic toxicity: see full labeling. Hepatic impairment: 200mg daily. Severe renal impairment (CrCl <30mL/min): 300mg daily. Children: <18yrs: not established. Warnings/Precautions: Monitor and manage GI toxicity, fluid retention; withhold, reduce dose, or discontinue as necessary. Perform CBC weekly for first month, then monthly; hepatic enzyme tests monthly for first three months (more frequently if transaminase elevations occur); withhold, reduce dose, or discontinue as necessary. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Potentiated by concomitant strong or moderate CYP3A and/or P-gp inhibitors (eg, ritonavir, indinavir, nelfinavir, saquinavir, ketoconazole, boceprevir, telaprevir, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, nefazodone, conivaptan, fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprenavir, crizotinib, imatinib, verapamil, grapefruit products, ciprofloxacin); avoid. Antagonized by concomitant strong or moderate CYP3A inducers (eg, rifampin, phenytoin, carbamazepine, St. John’s Wort, rifabutin, phenobarbital, bosentan, nafcillin, efavirenz, modafinil, etravirine); avoid. Antagonized by proton pump inhibitors (eg, lansoprazole); consider shortacting antacids or H2 blockers instead; separate dosing by more than 2hrs. May potentiate drugs that are P-gp substrates (eg, digoxin). Adverse reactions: Diarrhea, nausea, thrombocytopenia, vomiting, abdominal pain, rash, anemia, pyrexia, fatigue; fluid retention (monitor), hepatic toxicity. How supplied: Tabs 100mg–120; 500mg–30

BUSULFEX Otsuka

℞

Alkylating agent. Busulfan 6mg/mL; soln for IV administration after dilution. Indications: In combination with cyclophosphamide, as a conditioning regimen

prior to allogeneic hematopoietic progenitor cell transplantation for chronic myelogenous leukemia. Adults: See literature. Premedicate with phenytoin and antiemetics. Give by IV infusion over 2 hours. 0.8mg/kg of ideal body weight or actual body weight, whichever is lower, every 6 hours for 4 days (total of 16 doses). Obese: base dose on adjusted ideal body weight. Children: See literature. Warnings/Precautions: Myelosuppression. Seizure disorder. Head trauma. Renal or hepatic impairment. Obtain CBCs with differential, platelet count, liver enzymes, bilirubin during treatment and until recovery. Monitor for infection and bleeding. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Potentiated by itraconazole and acetaminophen. May be antagonized by phenytoin. Caution with potentially epileptogenic drugs. Adverse reactions: Myelosuppression (eg, granulocytopenia, thrombocytopenia, anemia), GI upset, stomatitis, anorexia, abdominal pain, dyspepsia, fever, headache, asthenia, chills, pain, tachycardia, hypertension, edema, dyspnea, dizziness, depression, elevated creatinine, hypomagnesemia, hyperglycemia, hypokalemia, hypocalcemia, hyperbilirubinemia, insomnia, anxiety, rhinitis, rash; seizures (with higher doses), hepatic veno-occlusive disease, cardiac tamponade (in pediatric patients with thalassemia); rare: bronchopulmonary dysplasia with pulmonary fibrosis. How supplied: Single-use vials (10mL)–8

CAMPATH Genzyme

℞

Monoclonal antibody, CD52 (recombinant, humanized). Alemtuzumab 30mg/mL; soln; for IV infusion after dilution; preservative-free. Indications: B-cell chronic lymphocytic leukemia (B-CLL). Adults: Premedicate with antihistamine and acetaminophen before 1st dose, and at dose escalations. Give by IV infusion over 2 hrs. Initially 3mg per day until infusion reactions are ≤ grade 2, then increase to 10mg per day until infusion reactions are ≤ grade 2, then to maintenance 30mg/day three times per week (on alternate days); duration of therapy (including escalation): 12 weeks. Do not exceed max single dose 30mg/dose or 90mg/week. Give prophylactic antibiotics and antivirals during treatment and for at least 2 months after completion or until CD4+ counts resolve (whichever occurs later). Dose adjustments for neutropenia and thrombocytopenia: see literature. Retitrate if therapy interrupted for ≥7 days. Children: Not recommended.

Warnings/Precautions: Discontinue dose for autoimmune or recurrent/persistent severe cytopenias (except lymphopenia). Withhold dose for severe cytopenias (except lymphopenia), grade 3 or 4 infusion reactions, serious infections, or during antiviral treatment for cytomegalovirus (CMV) infection or confirmed CMV viremia. Obtain CBCs, platelet counts weekly, assess CD4+ counts after treatment until recovery to ≥200cells/µL. Monitor for infusion reactions; CMV infection (continue for 2 months after therapy ends). Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Avoid live virus vaccines (after recent therapy). May interfere with tests using antibodies. Irradiate any blood products given (GVHD may occur). Adverse reactions: See literature; may be fatal. Infusion reactions, cytopenias (eg, neutropenia, lymphopenia, thrombocytopenia, anemia), infections (eg, CMV), GI upset, insomnia, anxiety; others. How supplied: Single-use vials–1, 3

CERUBIDINE Bedford

℞

Anthracycline. Daunorubicin HCl 20mg/vial; lyophilized pwd for IV infusion after reconstitution; contains mannitol. Indications: In combination with other chemotherapy for remission induction in acute nonlymphocytic leukemia (myelogenous, monocytic, erythroid) of adults and for remission induction in acute lymphocytic leukemia of children and adults. Adults: Give by IV infusion. Acute nonlymphocytic leukemia (in combination with cytosine arabinoside): <60yrs: 45mg/m2 daily on days 1, 2 and 3 of the first course and on days 1, 2 of subsequent courses; ≥60yrs: 30mg/m2 daily on days 1, 2 and 3 of the first course and on days 1, 2 of subsequent courses. Acute lymphocytic leukemia (in combination with vincristine, prednisone, L-asparaginase): 45mg/m2 daily on days 1, 2 and 3. Hepatic or renal impairment: reduce dose (see literature). Children: Give by IV infusion. <2yrs or BSA<0.5m2: use weight (mg/kg) to calculate dose. 25mg/m2 on Day 1 every week (in combination with vincristine and prednisone). Warnings/Precautions: Treat if any systemic infections 1st. Pre-existing drug-induced bone marrow suppression. Cardiovascular disease, thoracic irradiation, previous doxorubicin therapy (cumulative doses >550mg/m2): increased risk of cardiotoxicity. Monitor blood counts, cardiac, hepatic and renal function prior to each treatment. Renal or hepatic impairment.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER Hyperuricemia; monitor blood uric acid levels and give allopurinol prophylatically. Avoid extravasation. Children. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Do not use if previously received max cumulative doxorubicin dose; or if concomitant with cyclophosphamide: increased cardiotoxicity. Concomitant myelosuppressives: consider dose reduction. Increased risk of liver toxicity with hepatotoxic agents (eg, high-dose methotrexate). Adverse reactions: Myelosuppression, cardiotoxicity, alopecia, rash, inj site reactions, GI upset, mucositis, abdominal pain, hyperuricemia; rare: anaphylaxis. How supplied: Single-dose vials–10

Cladribine (various)

℞

Chlorinated purine nucleoside analog. Cladribine 1mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Active hairy cell leukemia. Adults: Give by continuous IV infusion for 7 consecutive days. 0.09mg/kg per day. Children: See full labeling. Warnings/Precautions: Delay or discontinue if neurotoxicity or renal toxicity occurs. Myelosuppression. Active infection. Renal or hepatic insufficiency. Monitor blood counts (esp. during first 4–8 weeks post-dose), renal and hepatic function. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Live attenuated vaccines: not recommended. Increased toxicity with myelosuppressive, immunosuppressive, or nephrotoxic agents. Adverse reactions: Severe myelosuppression (eg, neutropenia, anemia, thrombocytopenia), fever, infection, fatigue, nausea, rash, headache, inj site reactions, others; neurotoxicity, nephrotoxicity, tumor lysis syndrome (rare). How supplied: Contact supplier.

CLOLAR Genzyme

℞

Purine nucleoside antimetabolite. Clofarabine 1mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Acute lymphoblastic leukemia (ALL) in patients 1–21 years of age after relapses from, and/or refractoriness to, at least two prior regimens. Adults: Not established. Children: Monitor blood pressure, cardiac, renal, and hepatic function before and during therapy. Give by IV infusion over 2 hours. 1–21yrs: 52mg/m2 daily for 5 consecutive days; repeat approximately every 2–6 weeks following recovery or return to baseline organ function. Provide supportive care (eg, IV fluids, antihyperuricemics, alkalinize urine, steroids, antiemetics, diuretics, albumin) throughout treatment. Renal impairment (CrCl

30–60mL/min): reduce dose by 50%. Dose modifications: see full labeling. Warnings/Precautions: Obtain CBCs and platelets daily during the 5 days of therapy, then 1–2 times weekly or as needed. Monitor for signs/symptoms of infection, tumor lysis syndrome, cytokine release (eg, tachypnea, hypotension); if cytokine release progresses to systemic inflammatory response syndrome (SIRS)/capillary leak syndrome and/or if organ dysfunction (grade 3 or 4 hepatic or renal toxicity) occurs, discontinue and treat; may restart at lower dose if organ function recovers and patient is stable. Ensure adequate hydration. Monitor for venous occlusive disease of the liver in patients who previously received hematopoietic stem cell transplant; discontinue if suspected. Pregnancy (Cat.D); use effective contraception. Nursing mothers: not recommended. Interactions: Minimize exposure to drugs with known renal toxicity during treatment. Consider avoiding concomitant drugs known to induce hepatic toxicity. Caution with drugs that affect BP or cardiac function; monitor. Adverse reactions: Nausea, vomiting, diarrhea, headache, rash, pruritus, pyrexia, fatigue, palmarplantar erythrodysesthesia syndrome, anxiety, flushing, mucosal inflammation; bone marrow suppression (eg, febrile neutropenia, anemia, leukopenia, thrombocytopenia), infections, hyperuricemia, hypotension, cardiac events, SIRS/capillary leak syndrome. How supplied: Single-use vial (20mL)–1, 4

Cytarabine Bedford

℞

Antimetabolite. Cytarabine 100mg, 500mg, 1g, 2g; per vial; lyophilized pwd for IV, intrathecal, SC inj after reconstitution. Indications: Remission induction in acute nonlymphocytic leukemia of adults and children. Acute lymphocytic leukemia. Chronic myelocytic leukemia (blast phase). Prophylaxis and treatment of meningeal leukemia (intrathecal route). Adults and Children: Induction therapy of acute non-lymphocytic leukemia: 100mg/m2 per day by continuous IV infusion (days 1–7) or 100mg/m2 IV every 12 hours (days 1–7). Acute lymphocytic leukemia and chronic myelocytic leukemia: see literature. Meningeal leukemia: Usual range: 5–75mg/m2 intrathecally; may give once daily for 4 days to once every 4 days; most frequently used dose: 30mg/m2 every 4 days until cerebrospinal fluid findings are normal. Warnings/Precautions: Do not use diluent with benzyl alcohol for intrathecal administration. Pre-existing myelosuppression. Renal or hepatic impairment. Monitor blood counts, renal, hepatic function. Neonates. Pregnancy (Cat.D); avoid use. Nursing mothers. Interactions: May antagonize gentamicin, fluorocytosine. Adverse reactions: Myelosuppression (leukopenia, thrombocytopenia, anemia), GI upset, anorexia, abdominal pain, oral ulceration,

rash, fever, hepatic dysfunction, infection, bleeding; cytarabine syndrome, hyperuricemia, pancreatitis, paralysis (rare), others. How supplied: Vials (100mg, 200mg)–10 1g, 2g–1

DACOGEN Otsuka

℞

Nucleoside analogue. Decitabine 50mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution. Indications: Myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all FrenchAmerican-British subtypes and Intermediate-1, Intermediate-2, and High-risk International Prognostic Scoring System groups. Adults: May premedicate with antiemetics. Treat for a minimum of 4 cycles; may take longer for a complete or partial response. Regimen 1: Give by continuous IV infusion over 3 hours. 15mg/m2 every 8 hours for 3 days; repeat every 6 weeks. Regimen 2: Give by continuous IV infusion over 1 hour. 20mg/m2 once daily for 5 days; repeat every 4 weeks. Both: dose adjustment based on hematology values: see literature. Nonhematologic toxicities (eg, serum creatinine ≥2mg/dL; SGPT, total bilirubin ≥ 2 × ULN; active or uncontrolled infection): do not restart until toxicity resolved. Children: Not recommended. Warnings/Precautions: Renal or hepatic impairment. Obtain CBC and platelet counts before each dosing cycle and as needed. Monitor hepatic function (do baseline liver chemistries and serum creatinine). Pregnancy (Cat.D); use appropriate contraception (both men and women). Nursing mothers: not recommended. Adverse reactions: Neutropenia, thrombocytopenia, anemia, leukopenia, fatigue, pyrexia, nausea, cough, petechiae, constipation, diarrhea, hyperglycemia. How supplied: Single-use vial–1

DEPOCYT Sigma-Tau

℞

Antimetabolite. Cytarabine 50mg/vial; liposomal suspension for intrathecal administration; preservative-free. Indications: Intrathecal treatment of lymphomatous meningitis. Adults: See literature. Give intrathecally over 1–5 minutes. Administer dexamethasone 4mg twice daily for 5 days with each cycle of treatment. Induction: 50mg every 14 days for 2 doses (weeks 1 and 3). Consolidation: 50mg every 14 days for 3 doses (weeks 5, 7 and 9) followed by 1 additional dose at week 13. Maintenance: 50mg every 28 days for 4 doses (weeks 17, 21, 25 and 29). Reduce dose to 25mg if neurotoxicity develops and discontinue if it persists. Children: Not recommended. Contraindications: Active meningeal infection. Warnings/Precautions: Chemical arachnoiditis; reduce symptoms with

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GAZYVA® (obinutuzumab)

Injection, for intravenous infusion Initial U.S. Approval: 2013 This is a brief summary of information about GAZYVA. Before prescribing, please see full Prescribing Information. WARNING: HEPATITIS B VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY • Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.1)]. • Progressive Multifocal Leukoencephalopathy (PML) including fatal PML, can occur in patients receiving GAZYVA [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE GAZYVA, in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL) [see Clinical Studies (14.1)]. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatitis B Virus Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies such as GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels and, in severe cases, increase in bilirubin levels, liver failure, and death. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy. Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA. HBV reactivation has been reported for other CD20-directed cytolytic antibodies following completion of therapy. In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy, and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation. 5.2 Progressive Multifocal Leukoencephalopathy JC virus infection resulting in progressive multifocal leukoencephalopathy (PML), which can be fatal, was observed in patients treated with GAZYVA. Consider the diagnosis of PML in any patient presenting with new onset or changes to preexisting neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. 5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions. Two thirds of patients experienced a reaction to the first 1000 mg infused of GAZYVA. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, laryngeal edema). Other common symptoms include nausea, vomiting, diarrhea, hypertension, flushing, headache, pyrexia, and chills [see Adverse Reactions (6.1)]. Premedicate patients with acetaminophen, antihistamine and a glucocorticoid. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred [see Dosage and Administration (2)].

02-12478_R01_GAUS_BriefSummary_A_size.indd 1

For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy. For patients with Grade 1, 2 or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms [see Dosage and Administration (2)]. For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication.

The data described in Tables 3–6 below are based on a safety population of 773 previously untreated patients with CLL. Patients were treated with chlorambucil alone, GAZYVA in combination with chlorambucil, or rituximab in combination with chlorambucil. The Stage 1 analysis compared GAZYVA in combination with chlorambucil vs. chlorambucil alone, and Stage 2 compared GAZYVA in combination with chlorambucil vs. rituximab in combination with chlorambucil. Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil (6 cycles of 28 days each in total). In the last 140 patients enrolled, the first dose of GAZYVA was split between day 1 (100 mg) and day 2 (900 mg) [see Dosage and Administration (2.1)]. In total, 81% of patients received all 6 cycles (of 28 days each) of GAZYVA-based therapy. Table 3 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 1) Adverse Reactions (MedDRAa) System Organ Class

5.4 Tumor Lysis Syndrome Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia from Tumor Lysis Syndrome (TLS) can occur within 12–24 hours after the first infusion. Patients with high tumor burden and/or high circulating lymphocyte count (> 25 x 109/L) are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics (e.g., allopurinol) and hydration beginning 12–24 hours prior to the infusion of GAZYVA [see Dosage and Administration (2.2)]. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated.

Injury, poisoning, and procedural complications Infusion 69 21 0 0 reactions Blood and lymphatic system disordersb Neutropenia 41 35 18 16 Thrombocytopenia 15

Anemia 12 5 10 4 Leukopenia 7 5 0 0 General disorders and administration site conditions Pyrexia 10 < 1 7 0 Respiratory, thoracic, and mediastinal disorders Cough 10 0 7 <1

5.6 Neutropenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 neutropenia in 33% of patients in the trial. Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection.

Infections and infestations Urinary tract 6 2 infection

Musculoskeletal and connective tissue disorder Back pain 5 < 1 2 0

Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days).

Table 4 Summary of Adverse Reactions Reported in ≥ 5% of Patients and at Least 2% Greater in the GAZYVA Treated Arm (Stage 2) Adverse Reactions (MedDRAa) System Organ Class

5.7 Thrombocytopenia GAZYVA in combination with chlorambucil caused Grade 3 or 4 thrombocytopenia in 10% of patients in the trial. In 4% of patients, GAZYVA caused acute thrombocytopenia occurring within 24 hours after the GAZYVA infusion. Fatal hemorrhagic events during Cycle 1 have also been reported in patients treated with GAZYVA.

GAZYVA + Chlorambucil n = 336

Rituximab + Chlorambucil n = 321

All Grades All Grades Grades % 3–4 % Grades % 3–4 %

Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chlorambucil or dose reductions of chlorambucil. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors, anticoagulants), especially during the first cycle.

Injury, poisoning and procedural complications Infusion 66 20 38 4 reactions Blood and lymphatic system disordersb Neutropenia 38 33 32 28 Thrombocytopenia 14

Leukopenia 6 4 2 < 1 General disorders and administration site conditions Pyrexia 9 < 1 7 <1

5.8 Immunization The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy has not been studied. Immunization with live virus vaccines is not recommended during treatment and until B-cell recovery. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Hepatitis B reactivation [see Warnings and Precautions (5.1)] • Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.2)] • Infusion reactions [see Warnings and Precautions (5.3)] • Tumor lysis syndrome [see Warnings and Precautions (5.4)] • Infections [see Warnings and Precautions (5.5)] • Neutropenia [see Warnings and Precautions (5.6)] • Thrombocytopenia [see Warnings and Precautions (5.7)]

Chlorambucil n = 116

All Grades All Grades Grades % 3–4 % Grades % 3–4 %

5.5 Infections Serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. Fatal infections have been reported with GAZYVA. Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection.

Patients with neutropenia are strongly recommended to receive antimicrobial prophylaxis throughout the treatment period. Antiviral and antifungal prophylaxis should be considered.

GAZYVA + Chlorambucil n = 241

Gastrointestinal disorders Diarrhea 10 2

Constipation 8 0 5 0 Infections and infestations Nasopharyngitis 6 < 1 3 0 Urinary tract infection a

MedDRA coded adverse reactions as reported by investigators.

Adverse events reported under “Blood and lymphatic system disorders” reflect those reported by investigator as clinically significant.

The most common adverse reactions (incidence ≥ 10%) were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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Infusion reactions: The incidence of infusion reactions was 69% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 21% with 8% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and <1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on Day 28 postpartum, obinutuzumab was detected in offspring and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 45 patients for whom these mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 1000 mg and <2% thereafter [see Dosage and Administration (2)].

8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GAZYVA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the importance of the drug to the mother.

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 40% in the GAZYVA treated arm and 18% in the chlorambucil alone arm with the incidence of serious adverse events being 1% and 0%, respectively (Table 3). Cases of late onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the chlorambucil alone arm.

8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients has not been established.

Infection: The incidence of infections was similar between arms. Thirty-eight percent of patients in the GAZYVA treated arm experienced an infection, 9% were Grade 3-4, and none were fatal. Thrombocytopenia: The incidence of thrombocytopenia reported as an adverse reaction was 15% in the GAZYVA treated arm and 7% in the chlorambucil alone arm (Table 3). Five percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the chlorambucil arm. Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders, including pain (System Organ Class) have been reported with GAZYVA with higher incidence than in the comparator arm (17% vs. 13%). 6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Approximately 13% (9/70) of GAZYVA treated patients tested positive for anti-GAZYVA antibodies at one or more time points during the 12 month follow-up period. Neutralizing activity of anti-GAZYVA antibodies has not been assessed. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known. 6.3 Additional Clinical Trial Experience Progressive multifocal leukoencephalopathy: PML has been reported with GAZYVA [see Warnings and Precautions (5.2)]. Worsening of Pre-Existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. Hepatitis B reactivation: Hepatitis B virus reactivation has been reported with GAZYVA [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic

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8.5 Geriatric Use Of 240 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 196 patients (82%) were ≥ 65 years of age and 109 patients (45%) were ≥ 75 years of age. The median age was 74 years. Of the 109 patients ≥ 75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients <75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) an adverse event leading to death. Similar rates were observed in the comparator arm. No significant differences in efficacy were observed between patients ≥ 75 years of age and those <75 years of age [see Clinical Studies (14.1)]. 8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CLcr) >30mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr<30mL/min. [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment. 10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy. 17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. • Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. • Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]. • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)]. • New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)]. Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6, and 5.7) and Adverse Reactions (6.1)]. • Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)]. • Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

GAZYVA™ [obinutuzumab] Manufactured by: Genentech, Inc. A Member of the Roche Group South San Francisco, CA 94080-4990 U.S. License No: 1048

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER dexamethasone. Previous irradiation, cytotoxic chemotherapy. Monitor blood counts and for development of neurotoxicity. Renal and hepatic impairment. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Increased risk of neurotoxicity with concomitant cranial/spinal irradiation or other intrathecal antineoplastics. Adverse reactions: See literature. Arachnoiditis, GI upset, headache, fever, neurological toxicity (myelopathy), hydrocephalus, elevated CSF protein and WBC, weakness, back pain, insomnia, blurred vision, anaphylactic reactions; others. How supplied: Single-use vials (5mL)–1

DOXIL Janssen Biotech

℞

Anthracycline. Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free. Indications: Multiple myeloma, in combination with bortezomib, in patients not previously treated with bortezomib and who have received at least one prior therapy. Adults: Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 30mg/m2 on Day 4 of each cycle following bortezomib (see full labeling for bortezomib dose); may treat for up to 8 cycles. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling. Children: Not established. Warnings/Precautions: Not substitutable on a mg/mg basis with other doxorubicin products. Cardiotoxicity, acute infusion-related reactions, myelosuppression may occur. Have resuscitative/ antiallergic equipment and expertise available. Hepatic impairment. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (esp. myocardial biopsy). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity. Adverse reactions: Asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea,

constipation, hand and foot syndrome, rash, neutropenia, thrombocytopenia, anemia; infusion reactions, cardiovascular events (eg, cardiomyopathy, CHF, acute LV failure), recall of skin reaction from prior radiation therapy, toxoplasmosis, urine discoloration (red/orange). How supplied: Single-use vials (10mL, 25mL)–1

DTIC-DOME Bayer

℞

Alkylating agent. Dacarbazine 200mg/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol. Indications: Metastatic malignant melanoma. Second-line therapy for Hodgkin’s disease, in combination with other agents. Adults: Give by IV infusion. Malignant melanoma: 2–4.5mg/kg/day for 10 days, may repeat every 4 weeks; or 250mg/m2 daily for 5 days, may repeat every 3 weeks. Hodgkin’s disease (in combination with other drugs): 150mg/m2 daily for 5 days, may repeat every 4 weeks; or 375mg/m2 on Day 1, then repeat every 15 days. Children: Not recommended. Warnings/Precautions: Monitor CBCs, platelets; may need to discontinue or suspend therapy if hemopoietic toxicity occurs. Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Myelosuppression (eg, leukopenia, thrombocytopenia, anemia), anorexia, nausea, vomiting, flu-like syndrome, alopecia, facial flushing/paresthesia, inj site reactions, anaphylaxis; rare: hepatic necrosis, photosensitivity reactions. How supplied: Vials (20mL)–12

ERWINAZE Jazz

℞

Asparagine-specific enzyme. Asparaginase Erwinia chrysanthemi 10,000 IU; per vial; lyophilized pwd for IM or IV inj after reconstitution. Indications: As a component of a multi-agent chemotherapeutic regimen for the treatment of patients with acute lymphoblastic leukemia (ALL) who have developed hypersensitivity to E. coliderived asparaginase. Adults and Children: Give by IM inj (max 2mL/inj site) or IV (infuse over 1hr). To substitute for a pegaspargase dose: 25,000 IU/m2 three times weekly (M/W/F) for 6 doses for each planned pegaspargase dose. To substitute for a native E. coli asparaginase dose: 25,000 IU/m2 for each scheduled native E. coli asparaginase dose within a treatment. When IV use: consider monitoring nadir serum asparaginase activity (NSAA) levels; switch to IM inj if levels are inadequate.

Contraindications: History of serious pancreatitis, thrombosis, hemorrhagic events with prior L-asparaginase therapy. Warnings/Precautions: Have resuscitation equipment available and other agents necessary to treat anaphylaxis. Discontinue if serious hypersensitivity reactions occur. Monitor for pancreatitis; discontinue if severe or hemorrhagic pancreatitis manifested by abdominal pain >72hrs and amylase elevation ≥2×ULN occurs. Withhold therapy if mild pancreatitis; may resume after resolution. Monitor glucose levels at baseline and during therapy. Discontinue if thrombotic or hemorrhagic event occurs; may resume after resolution. Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Systemic hypersensitivity, hyperglycemia, abnormal transaminases, fever, pancreatitis, local reactions, vomiting, nausea, thrombosis, hyperbilirubinemia, abdominal pain/ discomfort, diarrhea. How supplied: Vials (3mL)–5

FLUDARA Genzyme

℞

Antimetabolite. Fludarabine phosphate 50mg/vial; lyophilized pwd for IV infusion after reconstitution and dilution; preservative-free; contains mannitol. Indications: B-cell chronic lymphocytic leukemia (CLL) in patients who have not responded to or whose disease progressed during treatment with at least 1 alkylating-agent containing regimen. Adults: Give by IV infusion over 30 minutes. 25mg/m2 daily for 5 days every 28 days. Renal dysfunction (CrCl 30–70mL/min): reduce dose by 20%; CrCl <30mL/min: not recommended. Give for 3 cycles after the max response. Reduce or delay dose if toxicity occurs. Children: Not recommended. Warnings/Precautions: Myelosuppression. Evaluate and monitor for hemolysis. Monitor blood (esp CBC, platelets). Use irradiated blood products if transfusions are required. May need to prophylax for tumor lysis syndrome with large tumors. Renal insufficiency. Delay or stop therapy if neurotoxicity occurs. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Severe pulmonary toxicity with pentostatin (not recommended). Adverse reactions: Myelosuppression (severe/cumulative), bone marrow hypoplasia, autoimmune hemolytic anemia (fatal/ severe), infection, fever, chills, GI upset, malaise, fatigue, CNS effects (eg, weakness, agitation, confusion, visual disturbances, coma,

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER peripheral neuropathy), pneumonia, pulmonary hypersensitivity (eg, dyspnea, interstitial pulmonary infiltrate), stomatitis, GI bleeding, edema, tumor lysis syndrome, rash, hemorrhagic cystitis (rare); others. How supplied: Single-dose vials–5

FOLOTYN Allos

℞

Folate analogue inhibitor. Pralatrexate 20mg/mL; soln for IV inj; preservative-free. Indications: Relapsed or refractory peripheral T-cell lymphoma. Adults: Prior to administration: mucositis should be ≤Grade 1, platelets should be ≥100,000/μL for first dose and ≥50,000/μL for subsequent doses, absolute neutrophil count should be ≥1000/ μL. Give by IV push over 3–5min. 30mg/m2 once weekly for 6 weeks in 7-week cycles; may reduce to 20mg/m2 or interrupt treatment to manage toxicity (see literature for adjustment criteria). Continue until disease progression or unacceptable toxicity develops. Supplement with vitamin B12 (1mg IM every 8–10 weeks, starting within 10 weeks before first Folotyn dose) and folic acid (1–1.25mg orally daily, beginning 10 days before starting Folotyn and for 30 days after stopping). Children: Not recommended. Warnings/Precautions: End stage renal disease (including dialysis): avoid, unless benefit justifies potential risk for toxicity. Adjust dose to manage toxicities (eg, hematological, mucositis, hepatic impairment); see literature. Monitor CBC and for mucositis weekly. Monitor serum chemistry, renal and hepatic function before the 1st and 4th dose per cycle. Monitor for dermatological reactions; withhold dose or discontinue if severe. Renal or hepatic impairment. Pregnancy (Cat.D) (may cause fetal harm), nursing mothers: not recommended. Interactions: May be potentiated by probenecid, NSAIDs, trimethoprim/sulfamethoxazole, other renally-excreted drugs. Adverse reactions: Mucositis, thrombocytopenia, neutropenia, anemia, abnormal liver function tests, nausea, fatigue, pyrexia, dehydration, sepsis, dyspnea; dermatological reactions (eg, skin exfoliation, ulceration, toxic epidermal necrolysis), tumor lysis syndrome. How supplied: Single-use vials (1mL, 2mL)–1

GAZYVA Genentech

℞

Cytolytic monoclonal antibody (CD20-directed). Obinutuzumab 25mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Treatment of patients with previously untreated chronic lymphocytic leukemia (CLL), in combination with chlorambucil. Adults: Premedicate (eg, glucocorticoid, APAP, antihistamine) before each infusion. Give by IV infusion for 6 treatment cycles (28 days duration). Cycle 1: 100mg on Day 1

at 25mg/hr over 4 hours; 900mg on Day 2 at 50mg/hr, may increase at 50mg/hr every 30mins (max 400mg/hr); 1000mg on Days 8 and 15 at 100mg/hr, may increase by 100mg/hr increments every 30mins (max 400mg/hr); Cycles 2–6: 1000mg on Day 1 at 100mg/hr, may increase by 100mg/hr increments every 30mins (max 400mg/hr). Infusion rate and premedication adjustments: see full labeling. Children: Not established. Warnings/Precautions: Risk of hepatitis B virus (HBV) reactivation; immediately discontinue and any concomitant chemotherapy if occurs. Screen for HBV infection prior to initiation; if positive evidence, monitor and consider antiviral therapy. Discontinue treatment and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressives if PML develops. Monitor closely for infusion reactions; if Grade 4: discontinue permanently; if Grade 3: interrupt until resolved; if Grade 1 or 2: interrupt or reduce the infusion rate and manage symptoms. Preexisting cardiac or pulmonary conditions: monitor more frequently during and post-infusion period for severe reactions. Risk of TLS in high tumor burden and/or high circulating lymphocyte count (>25 × 109/L): prophylaxis with antihyperuricemics and hydration. Active infection: do not administer. Monitor for bleeding; obtain blood and platelet counts frequently. Risk of neutropenia; give antimicrobial prophylaxis; consider antiviral and antifungal prophylaxis. Hepatic or renal impairment (CrCl <30mL/min). Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Concomitant live viral vaccines: not recommended. Consider withholding antihypertensives for 12hrs prior to, during, and for 1hr after infusion until BP is stable. Consider withholding drugs that may increase bleeding risk (eg, platelet inhibitors, anticoagulants) esp. during 1st cycle. Adverse reactions: Infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, musculoskeletal disorders. How supplied: Single-use vial (40mL)–1

GLEEVEC Novartis

℞

Kinase inhibitor. Imatinib (as mesylate) 100mg, 400mg; scored tabs. Indications: Philadelphia-chromosome (+) chronic myeloid leukemia (CML): in newlydiagnosed adults and children in chronic phase; in patients in blast crisis, accelerated phase, or chronic phase after failure of interferon-alpha therapy. Adults with relapsed or refractory Ph (+) acute lymphoblastic leukemia (ALL). Children with newly diagnosed Ph+ ALL in combination with chemotherapy. Adults with myelodysplastic/ myeloproliferative diseases (MDS/MPD) associated with PDGFR (platelet-derived growth factor receptor) gene rearrangements. Adults with hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukemia (CEL) who have the

FIP1L1-PDGFRα fusion kinase and for patients with HES and/or CEL who are FIP1L1-PDGFRα fusion kinase negative or unknown. Adults: Take with food and water. May disperse tab in water or apple juice and take promptly. ≥18yrs: Chronic phase CML: 400mg once daily; may increase to 600mg if clinically indicated. Accelerated phase or blast crisis: 600mg once daily; may increase to 800mg (given as 400mg twice daily) if clinically indicated. Relapsed/ refractory Ph+ ALL: 600mg once daily. MDS/ MPD: 400mg once daily. HES/CEL: 400mg once daily. HES/CEL w. FIP1L1-PDGFRα fusion kinase: initially 100mg once daily; may increase to 400mg once daily if insufficient response. If severe non-hematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction. Severe hepatic impairment: reduce dose by 25%. Renal or hematologic reactions: see full labeling. Avoid concomitant strong CYP3A4 inducers (eg, rifampin): if needed, increase imatinib dose by at least 50%. Children: Take with food and water in 1 or 2 divided doses; may disperse tab in water or apple juice and take promptly. <1yrs: not recommended. ≥1yrs: Newly diagnosed Ph+CML: 340mg/m2 per day (max 600mg). Newly diagnosed Ph+ALL: 340mg/m2 per day (max 600mg); give with chemotherapy. If severe nonhematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction. Renal or hematologic reactions: see full labeling. Avoid concomitant strong CYP3A4 inducers (eg, phenytoin): if needed, increase imatinib dose by at least 50%; monitor closely. Warnings/Precautions: Hepatic or renal impairment. Monitor weight and for fluid retention regularly; CBCs weekly for 1st month, bi-weekly for 2nd month, then periodically (eg, every 2–3 months); liver function at baseline then monthly or as needed; GI symptoms at baseline. Cardiovascular disease or risk factors; monitor. Immunosuppression and potential toxicities (liver, kidney, cardiac) from long-term use. Monitor for tumor lysis syndrome; correct clinically significant dehydration and treat high uric acid levels before initiating therapy. Monitor growth in children. Possible cardiogenic shock/LV dysfunction in conditions with high eosinophil levels (eg, HES/CEL, MDS/MPD, ASM); consider concomitant systemic steroid prophylaxis (1–2mg/kg) for 1 or 2 wks if abnormal ECG or serum troponin. Monitor TSH levels in thyroidectomy patients undergoing levothyroxine replacement. Pregnancy (Cat.D); avoid. Use highly effective contraception during treatment. Nursing mothers: not recommended. Interactions: Avoid grapefruit juice. Potentiated by CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, nefazodone, clarithromycin, telithromycin). Antagonized by strong CYP3A4 inducers (eg, dexamethasone, fosphenytoin, phenytoin, phenobarbital, carbamazepine, oxcarbamazepine, primidone, St. John’s wort,

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER rifampin, rifabutin, rifampicin); consider alternatives. May potentiate drugs metabolized by CYP3A4 (eg, benzodiazepines, dihydropyridine calcium channel blockers, cyclosporine, ergots, alfentanil, fentanyl, pimozide, quinidine, certain statins, sirolimus, tacrolimus), CYP2D6, or CYP2C9 (use heparin instead of warfarin). Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain, diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, Stevens-Johnson syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction. Testing considerations: BCR-Abl t(9;22) in Ph+CML patients How supplied: 100mg–90; 400mg–30

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps. Indications: Resistant chronic myelocytic leukemia. Adults: See literature. 20–30mg/kg/day as single dose. Renal impairment: reduce dose. Children: Not recommended. Contraindications: Marked bone marrow depression. Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated urease, uricase, lactate dehydrogenase. Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer. Note: Wear disposable gloves when handling caps or bottle. How supplied: Caps–100

ICLUSIG ARIAD

℞

Kinase inhibitor. Ponatinib 15mg, 45mg; tabs; contains lactose. Indications: Treatment of adults with T315Ipositive chronic, accelerated, or blast phase chronic myeloid leukemia (CML) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Treatment of adults with chronic, accelerated, or blast phase CML or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated. Adults: Swallow whole. ≥18yrs: initially 45mg once daily; consider reducing dose in chronic and accelerated phase CML if major cytogenic response achieved. Consider discontinuing if no response occurred by 3 months. Concomitant strong CYP3A inhibitors: reduce to 30mg once daily. Dose modification for hematologic and nonhematologic toxicity: see full labeling. Children: <18yrs: not established. Warnings/Precautions: Risk of vascular occlusion (eg, arterial and venous thrombosis, fatal MI, stroke, stenosis of arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures) in patients with or without CV risk factors (including ≤50yrs old, or increasing age, history of ischemia, HTN, diabetes, hyperlipidemia); monitor and interrupt or discontinue if occurs. Monitor for signs/symptoms of heart failure; interrupt or consider discontinuing if develops or worsens. Monitor hepatic function at baseline, then at least monthly or as needed; interrupt, reduce or discontinue as clinically indicated. Moderate-to-severe hepatic impairment: not recommended. Monitor and manage BP elevations; interrupt, reduce dose or discontinue if not controlled. Risk of pancreatitis; check serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated; do not restart until complete resolution and lipase levels <1.5×ULN. Monitor for neuropathy; consider interrupting and evaluate if suspected. Conduct eye exams at baseline and periodically during treatment. Interrupt therapy and evaluate for serious/severe hemorrhage or cardiac arrhythmias. Monitor for fluid retention; interrupt, reduce, or discontinue as indicated. Obtain CBCs every 2 weeks for the first 3 months, then monthly or as indicated. Tumor lysis syndrome; ensure adequate hydration and treat uric levels prior to therapy. Compromised wound healing (withhold for 1 week prior to major surgery) and GI perforation. Elderly. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Potentiated by strong CYP3A inhibitors (eg, boceprevir, clarithromycin,

conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole); see Adult dose. Avoid concomitant strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort), or drugs that elevate gastric pH (eg, PPIs, H2 blockers, antacids). Caution with concomitant P-gp and ABCG2 substrates. Adverse reactions: Hypertension, rash, abdominal pain, fatigue, headache, dry skin, constipation, arthralgia, nausea, pyrexia, anemia, thrombocytopenia, leukopenia, neutropenia, lymphopenia; vascular occlusion, heart failure, hepatotoxicity, ocular toxicities, hemorrhage, myelosuppression. How supplied: Tabs 15mg–60, 180; 45mg–30, 90

IDAMYCIN Pfizer

℞

Anthracycline. Idarubicin HCl 20mg/vial; lyophilized pwd for IV infusion after reconstitution. ℞ Also: IDAMYCIN PFS Idarubicin 1mg/mL; soln for IV infusion; preservative-free. Indications: Acute myeloid leukemia. Adults: Give by slow IV infusion (over 10–15 minutes). 12mg/m2 daily for 3 days (in combination with cytarabine). May give 2nd course if needed; if toxicity develops after 1st course, delay until resolved; reduce dose by 25%. Hepatic and renal impairment: consider reduce dose. Children: Not recommended. Warnings/Precautions: Pre-existing bone marrow suppression. Cardiovascular disease. Thoracic irradiation. Previous anthracycline therapy at high cumulative doses. Renal or hepatic impairment. Monitor CBCs, cardiac, renal and hepatic function prior to and during treatment. Avoid extravasation. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Adverse reactions: Myelosuppression, GI upset, mucositis, abdominal pain, alopecia, rash, inj site reactions, hepatotoxicity, renal toxicity, cardiotoxicity (eg, CHF, arrhythmias, chest pain, MI, asymptomatic declines in LVEF), hyperuricemia. How supplied: Single-dose vials–1 PFS: Single-dose vials (5mL, 10mL, 20mL)–1

IMBRUVICA

℞

Pharmacyclics and Janssen Biotech

Bruton’s tyrosine kinase (BTK) inhibitor. Ibrutinib 140mg; caps. Indications: Mantle cell lymphoma (MCL) in patients who have received at least one prior

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER therapy. Chronic lymphocytic leukemia (CLL) in patients who have received at least one prior therapy. CLL in patients with 17p deletion. Adults: Swallow whole with water. MCL: 560mg once daily. CLL: 420mg once daily. Concomitant moderate CYP3A inhibitors: 140mg once daily. Dose modifications for toxicities: see full labeling. Children: Not established. Warnings/Precautions: Risk of hemorrhage; consider the benefit/risk of withholding treatment for 3–7 days pre-and post-surgery. Monitor for fever and infections; evaluate promptly if occurs. Monitor for myelosuppression; obtain CBCs monthly. Periodically monitor for atrial fibrillation (esp. in those with cardiac risk factors, acute infections, history of atrial fibrillation); do ECG if arrhythmic symptoms or new onset dyspnea develop. Risk of second primary malignancies (eg, skin cancer or other carcinomas). Hepatic or renal impairment. Maintain adequate hydration. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Concomitant strong CYP3A inhibitors taken chronically (eg, ritonavir, indinavir, nelfinavir, saquinavir, boceprevir, telaprevir, nefazodone): not recommended; for shortterm (≤7days) use of strong CYP3A inhibitors (eg, ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin); consider interrupting ibrutinib therapy. If concomitant moderate CYP3A inhibitors must be used (eg, fluconazole, darunavir, erythromycin, diltiazem, atazanavir, aprepitant, amprenavir, fosamprevir, crizotinib, imatinib, verapamil, ciprofloxacin): reduce ibrutinib dose (see Adults). Avoid grapefruit and Seville oranges during treatment. Avoid concomitant strong CYP3A inducers (eg, carbamazepine, rifampin, phenytoin, St. John’s Wort); consider alternatives. Increased risk of hemorrhage with concomitant antiplatelets or anticoagulants. Adverse reactions: Thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting, decreased appetite, pyrexia. How supplied: Caps–90, 120

INTRON A Merck

℞

Interferon alfa-2b, recombinant; 10 million, 18 million, or 50 million IU per vial; pwd; for inj after reconstitution/dilution; preservative-free. ℞ Also: INTRON A SOLN Interferon alfa-2b, recombinant; 10 million IU, 18 million IU, 25 million IU; per vial; for inj; contains m-cresol. Indications: Hairy cell leukemia. Initial treatment of clinically aggressive follicular Non-Hodgkin’s lymphoma in conjunction with anthracyclinecontaining combination chemotherapy. Adults: Use SC route if platelets <50,000/mm3. Hairy cell leukemia: 2 million IU/m2 IM or SC 3 times a week for up to 6 months. Follicular

lymphoma: 5 million IU SC 3 times a week for up to 18 months in conjunction with anthracyclinecontaining chemotherapy regimen and following completion of the chemotherapy regimen. See literature for appropriate preparation and route and for dose adjustments. Children: Not recommended. Contraindications: Hepatitis: decompensated liver disease. Autoimmune disorders. Warnings/Precautions: May cause or exacerbate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue if they worsen. Severe psychiatric disorders (esp. depression). Cardiovascular or pulmonary disease. Severe myelosuppression. Uncontrolled thyroid abnormalities. Diabetes. Coagulation disorders. Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and during therapy; EKG in cardiovascular disease and cancer patients. Psoriasis. Renal dysfunction. Transplant recipients. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Caution with myelosuppressives, and drugs that can exacerbate depression. May potentiate theophylline (may double its levels). Adverse reactions: Flu-like symptoms (fever, headache, myalgia, fatigue); hepatic, hematologic, respiratory, skin, genitourinary system, CNS, cardiovascular, endocrine (esp thyroid), GI, or visual disorders; colitis, hypertriglyceridemia, pancreatitis, infections, injection site reactions; others (see literature). How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial–1; Soln (vials): 10million IU/vial–6 (kit w. supplies); Soln (multidose vials): 18million, 25million IU/vial–1

ISTODAX Celgene

℞

Histone deacetylase inhibitor. Romidepsin 10mg/vial; pwd for IV infusion after reconstitution and dilution; contains povidone. Indications: Cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy. Peripheral T-cell lymphoma in patients who have received at least one prior therapy. Adults: ≥18yrs: Give by IV infusion over 4hrs. 14mg/m2 on days 1, 8, and 15 of a 28-day cycle; repeat cycle every 28 days; continue as tolerated and as beneficial. May interrupt, reduce dose to 10mg/m2, or discontinue based on toxicities (see full labeling). Children: <18yrs: not established. Warnings/Precautions: Correct electrolyte imbalances (esp. K+, Mg++) before starting. Monitor ECG and electrolytes in congenital long QT syndrome, significant cardiovascular disease. Advanced stage disease and/or high tumor syndrome: monitor closely for tumor lysis syndrome. Moderate to severe hepatic impairment. End-stage renal disease. Monitor CBC with differential. Pregnancy (Cat.D; may

cause fetal harm). Nursing mothers: not recommended. Interactions: Caution with other drugs that can cause QT prolongation (monitor). Monitor PT/INR with warfarin. Potentiated by drugs that inhibit P-glycoprotein and CYP3A4; avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, clarithromycin, nefazodone). Caution with moderate CYP3A4 inhibitors. Avoid concomitant rifampin. May be antagonized by other strong CYP3A4 inducers (eg, dexamethasone, carbamazepine, phenytoin, phenobarbital, rifabutin, rifapentine, St. John’s Wort); avoid when possible. Adverse reactions: Nausea, vomiting, fatigue, infections, anorexia, anemia, thrombocytopenia, ECG T-wave changes, neutropenia, lymphopenia; tumor lysis syndrome. How supplied: Kit–1 (single-use vial + diluent and supplies)

JAKAFI Incyte

℞

Kinase inhibitor. Ruxolitinib 5mg, 10mg, 15mg, 20mg, 25mg; tabs. Indications: Treatment of intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Treatment of polycythemia vera (PV) in patients with inadequate response to, or intolerant of, hydroxyurea. Adults: Doses may be given by NG tube if unable to swallow tabs. Myelofibrosis: Platelets >200×109/L: initially 20mg twice daily. Platelets 100–200×109/L: initially 15mg twice daily. Platelets 50–<100×109/L: initially 5mg twice daily. May increase doses by 5mg twice daily to a max of 25mg twice daily; do not increase during the first 4 weeks of therapy and not more frequently than every 2 weeks. Discontinue treatment after 6 months if no reduction in spleen size or symptom improvement. Interrupt treatment if platelets <50×109/L or ANC <0.5×109/L. May restart after recovery of platelets or ANC (see full labeling for max allowable restarting doses). Consider dose reductions if platelets decrease but remain ≥50×109/L (see full labeling). Dose modifications for patients starting treatment with platelets 50–<100×109/L: see full labeling. PV: initially 10mg twice daily. May increase doses by 5mg twice daily to a max of 25mg twice daily; do not increase during the first 4 weeks of therapy and not more frequently than every 2 weeks. Consider dose reductions for Hgb and/or platelet decreases (see full labeling). Interrupt treatment if Hgb <8g/dL, platelets <50×109/L, or ANC <1.0×109/L. May restart after recovery of hematologic parameters (see full labeling for max allowable restarting doses). Concomitant strong CYP3A4 inhibitors (see Interactions) or fluconazole ≤200mg (Myelofibrosis): initially 10mg twice daily if platelets ≥100×109/L; if

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER platelets 50–<100×109/L: initially 5mg once daily; (PV): initially 5mg twice daily. Other reductions, hepatic or renal impairment, ESRD: see full labeling. Children: Not established. Warnings/Precautions: Monitor for thrombocytopenia, anemia, neutropenia; manage by reducing dose, interrupt, or transfusion if occur. Obtain CBC and platelets before initiating therapy, every 2–4 weeks until doses are stabilized, and then as clinically indicated. Risk of serious bacterial, mycobacterial, fungal, and viral infections; evaluate and treat if signs/ symptoms occur. Confirm resolution of active infections before starting. May exacerbate myelofibrosis following treatment interruption or discontinuation. Risk of non-melanoma skin cancer; perform periodic skin exams. Avoid abrupt cessation. Renal or hepatic impairment. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Avoid concomitant fluconazole doses >200mg daily. Potentiated by strong CYP3A4 inhibitors (eg, boceprevir, clarithromycin, conivaptan, grapefruit juice, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) and mild or moderate CYP3A4 inhibitors (eg, erythromycin). Antagonized by strong CYP3A4 inducers (eg, rifampin). Adverse reactions: Thrombocytopenia, anemia, bruising, dizziness, headache; herpes zoster, tuberculosis (monitor promptly and test for latent infection), progressive multifocal leukoencephalopathy (discontinue if occurs). How supplied: Tabs–60

KYPROLIS Onyx

℞

Proteasome inhibitor. Carfilzomib 60mg/vial; lyophilized pwd for IV inj after reconstitution; preservative-free. Indications: Treatment of patients with multiple myeloma who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Adults: See literature. Premedicate with dexamethasone prior to all Cycle 1 doses, during 1st dose escalation and if infusion reactions occur. Give by IV over 2–10 minutes, on two consecutive days each week for 3 weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (Days 17–28). In Cycle 1: 20mg/m2 per each dose, if tolerated increase to 27mg/m2 starting in Cycle 2 and subsequent cycles; continue until disease progression or unacceptable toxicity occurs. On

dialysis: give dose after session. Toxicity dose modification: see literature. Children: Not established. Warnings/Precautions: Risk of cardiac complications (eg, CHF, MI, pulmonary edema); monitor and manage promptly if occurs. Pulmonary hypertension; if suspected, withold therapy until resolved; may consider restarting after reevaluate. Monitor for dyspnea or tumor lysis syndrome, and manage promptly if occurs; interrupt therapy until resolved. Maintain adequate hydration. Monitor platelets frequently during therapy. Hepatic impairment (monitor enzymes). Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Adverse reactions: Fatigue, anemia, nausea, thrombocytopenia, dyspnea, diarrhea, pyrexia; cardiac events, pulmonary HTN, infusion reactions, tumor lysis syndrome, hepatic toxicity/failure. How supplied: Single use vial–1

LEUKERAN GlaxoSmithKline

℞

Alkylating agent. Chlorambucil 2mg; tabs. Indications: Palliative treatment of chronic lymphatic (lymphocytic) leukemia and malignant lymphomas (including lymphosarcoma, giant follicular lymphoma, and Hodgkin’s disease). Adults: See literature. 0.1–0.2mg/kg per day for 3–6 weeks. Reduce dose if leukocyte or platelet counts fall below normal values and discontinue if more severe depression occurs. Do not give full dose within 4 weeks of radio- or chemotherapy. Children: Not recommended. Warnings/Precautions: Compromised bone marrow function. History of seizure disorder or head trauma. Monitor blood weekly (during first 3–6 weeks, do WBC count 3–4 days after each weekly CBC). Discontinue if skin reactions occur. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Avoid live vaccines. Myelosuppressives, radiotherapy potentiate antineoplastic effect. Caution with drugs that lower seizure threshold. Adverse reactions: Bone marrow suppression, seizures, fever, rash, hypersensitivity, urticaria, azoospermia, amenorrhea, sterility, hepato- and pulmonary toxicity, secondary malignancies, GI upset. How supplied: Tabs–50

MARQIBO Spectrum

℞

Vinca alkaloid. Vincristine sulfate liposome injection; after preparation, each vial contains 0.16mg/mL; for IV infusion. Indications: Philadelphia chromosome-negative (Ph–) acute lymphoblastic leukemia (ALL) in

second or greater relapse or has progressed following ≥2 anti-leukemia therapies. Adults: 2.25mg/m2 IV over 1hr once every 7 days. Dose modifications for peripheral neuropathy: see full labeling. Children: Not established. Contraindications: Demyelinating conditions, including Charcot-Marie-Tooth syndrome. Intrathecal administration (death has occurred). Warnings/Precautions: For IV use only; fatal if given by other routes. Discontinue and treat if extravasation is suspected. Preexisting neuromuscular disorders. Monitor for symptoms of neuropathy before and during therapy; if occurs or worsens, delay, reduce or discontinue dose. Monitor CBCs prior to each dose; if Grade 3 or 4 myelosuppression develops, consider dose modification or reduction. Monitor for tumor lysis syndrome; manage if occurs. Institute a prophylactic bowel regimen to mitigate potential constipation, bowel obstruction, and/or paralytic ileus; consider dietary fiber intake, hydration, stool softeners. Monitor liver function tests; if hepatotoxicity occurs, reduce or interrupt dosing. Elderly. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Drugs known to interact with non-liposomal vincristine sulfate (eg, phenytoin: increased seizure risk). Avoid concomitant strong CYP3A inhibitors (eg, ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) or strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John’s Wort). Avoid concomitant potent P-gp inhibitors or inducers. Adverse reactions: Constipation, nausea, pyrexia, fatigue (may be severe; adjust dose or discontinue), peripheral neuropathy, febrile neutropenia, diarrhea, anemia, decreased appetite, insomnia. How supplied: Kit–1, 3 (vials + supplies)

MATULANE Sigma-Tau

℞

Alkylating agent. Procarbazine (as HCl) 50mg; caps. Indications: Stage III and IV Hodgkin’s disease as part of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) regimen. Adults: Initially 2–4mg/kg per day for the first week, then 4–6mg/kg per day until max response is obtained or until WBCs <4,000cells/mm3 or platelets <100,000cells/mm3. Maintain at 1–2mg/kg per day once max response attained. In MOPP regimen: 100mg/m2 daily for 14 days. Children: Individualize. Initially 50mg/m2 per day for the first week, then 100mg/m2 per day until max response is obtained or leukopenia or

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER thrombocytopenia occurs. Maintain at 50mg/m2 per day once max response attained. Contraindications: Inadequate marrow reserve. Warnings/Precautions: Discontinue if CNS effects (eg, paresthesias, neuropathies, confusion), leukopenia, thrombocytopenia, hypersensitivity reactions, stomatitis, diarrhea, hemorrhage or bleeding tendencies occur. Hepatic or renal impairment. Obtain baseline CBCs with differential, hemoglobin, hematocrit, reticulocytes, platelets prior to therapy, then monitor at least every 3–4 days. Do renal and hepatic function tests before starting therapy, then repeated weekly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid sympathomimetics, tricyclic antidepressants (eg, amitriptyline, imipramine), foods with high tyramine content (eg, wine, yogurt, ripe cheese, bananas). CNS depression with barbiturates, antihistamines, narcotics, hypotensive agents, phenothiazines. Disulfiramlike reactions with alcohol. Separate radiation or other myelosuppressives by at least 1 month (allow for bone marrow recovery). Adverse reactions: Leukopenia, anemia, thrombopenia, GI upset, bleeding tendencies, CNS effects, dysphagia, anorexia, abdominal pain, hypotension, tachycardia, syncope, cough, alopecia, dermatitis, pain, others. How supplied: Caps–100

Mitoxantrone HCl (various)

℞

Topoisomerase II inhibitor. Mitoxantrone (as HCl) 2mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Acute nonlymphocytic leukemia (ANLL) in combination with other approved drugs. Adults: Give by IV infusion. See full labeling for cytarabine dose. Induction therapy: 12mg/m2 daily on Days 1–3 + cytarabine on days 1–7; if 2nd induction course needed, give for 2 days + cytarabine for 5 days using same daily dosage levels. Consolidation therapy: 12mg/m2 on Days 1–2 + cytarabine on Days 1–5 for 2 courses (1st course given 6 weeks after the final induction course and the 2nd course given 4 weeks after the 1st course). Children: Not established. Warnings/Precautions: Risk of myelosuppression esp. in high doses (>14mg/m2 daily for 3 days); do not administer if baseline neutrophil count <1500 cell/mm3, except in ANLL. Increased risk of cardiotoxicity with pre-existing cardiovascular disease, prior radiotherapy to mediastinal/pericardial area, or previous anthracycline therapy. Assess cardiac history, physical exam, ECG, and LVEF prior to therapy. Increased risk of secondary acute myeloid leukemia. Hepatic impairment. Monitor CBCs, platelets, liver function tests prior to each course. Monitor for signs of infection. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Caution with concomitant cardiotoxic drugs.

Adverse reactions: Myelosuppression, nausea, vomiting, infection, fever, fatigue, alopecia, dyspnea, hypersensitivity reactions, bluishgreen urine, sclera discoloration, hyperuricemia (monitor), menstrual disorders, amenorrhea, interstitial pneumonitis; cardiotoxicity (eg, CHF). How supplied: Contact supplier.

MUSTARGEN Recordati

℞

Nitrogen mustard. Mechlorethamine HCl 10mg/vial; pwd for IV or intracavitary inj after reconstitution. Indications: Palliative treatment of Hodgkin’s disease (stages III and IV), lymphosarcoma, chronic myelocytic or chronic lymphocytic leukemia, polycythemia vera, mycosis fungoides. Palliative treatment of metastatic carcinoma resulting in effusion. Adults: By IV infusion, per therapeutic course: 0.4mg/kg (lean body weight) as single dose or in divided doses of 0.1–0.2mg/kg per day. See literature for intracavitary (eg, intrapleural) administration. Do not exceed recommended dose. Repeat course only after hematological recovery (eg, every 3 weeks). Children: See literature. Contraindications: Infectious diseases. Warnings/Precautions: Drug is highly toxic; verify potential benefits outweigh risks; avoid inadvertent contact with powder or vapor. Do not use if foci of acute and chronic suppurative inflammation are present. Ensure adequate hydration. Avoid extravasation. Chronic lymphatic leukemia. Bone marrow suppression. Previous X-ray, cytotoxic chemotherapy. Infection. Hemorrhagic tendency. Monitor renal, hepatic and bone marrow function. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Adverse reactions: Bone marrow suppression, hyperheparinemia, GI upset (may be severe), anorexia, weakness, thrombosis, thrombophlebitis, hypersensitivity, jaundice, alopecia, vertigo, auditory disturbances, hemolytic anemia, skin reactions, infection, amyloidosis, hyperuricemia, gonad damage. How supplied: Vials–4

MYLERAN GlaxoSmithKline

℞

Alkylating agent. Busulfan 2mg; tabs. Indications: Palliative treatment of chronic myelogenous leukemia. Adults: Remission induction: 4–8mg/day or 60micrograms/kg or 1.8mg/m2, daily. Reserve doses >4mg/day for severe cases. Reduce dose or discontinue at first sign of reduced bone marrow reserve. Discontinue before leukocyte count normalizes; see literature. Normal leukocyte counts usually achieved in 12–20 weeks. If remission <3 months, maintenance therapy of 1–3mg/day may be advisable. Children: Remission induction: 60micrograms/kg or 1.8mg/m2, daily. Reduce dose or discontinue at first sign of reduced bone marrow reserve. Discontinue before leukocyte count normalizes.

Normal leukocyte counts usually achieved in 12–20 weeks. See literature. Warnings/Precautions: Confirm diagnosis. Monitor hepatic and bone marrow function. Obtain CBCs and differential weekly; monitor for anemia. Previously compromised bone marrow (irradiation, chemotherapy). Seizure disorder or risk. Head trauma. Elderly. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Myelosuppression increased with other myelosuppressives. Increased pulmonary toxicity with other cytotoxic drugs. Potentiated by itraconazole, cyclophosphamide (see literature). May be antagonized by phenytoin. Hepatotoxicity possible with long-term continuous thioguanine therapy. Caution with drugs that lower seizure threshold. Adverse reactions: See literature. Bone marrow suppression (eg, pancytopenia, anemia, leukopenia, thrombocytopenia, aplastic anemia), pulmonary toxicity, cellular dysplasia, malignant tumors, acute leukemias, cardiac tamponade (esp. in thalassemia), hyperpigmentation, adrenal insufficiency, seizures, hepatic veno-occlusive disease, infection (eg, pneumonia, sepsis), mucositis, myasthenia gravis, gonadal suppression, rash; rare: cataracts, bronchopulmonary dysplasia (discontinue if occurs). How supplied: Tabs–25

ONCASPAR Sigma-Tau

℞

Enzyme. Pegaspargase 750 IU/mL; soln for IV or IM inj; preservative-free. Indications: First-line acute lymphoblastic leukemia (including patients with asparaginase hypersensitivity). Adults and Children: Give by IV inj over 1–2 hours or by IM inj (max 2mL/inj site). 2500 IU/m2 no more frequently than every 14 days. Contraindications: History of pancreatitis, serious hemorrhage, or thrombosis with prior L-asparaginase therapy. Warnings/Precautions: Have resuscitation equipment available and observe patient for 1 hour post-dose. Monitor coagulation parameters. Discontinue if serious allergic reactions, thrombotic events, or pancreatitis occurs. Monitor for hepatotoxicity and abnormal liver function. Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Allergic reactions (including anaphylaxis), hyperglycemia, pancreatitis, CNS thrombosis, coagulopathy, hyperbilirubinemia, hepatotoxicity, elevated transaminases, hyperlipidemia. How supplied: Single-use vial (5mL)–1

ONTAK Eisai

℞

Interleukin 2-diphtheria toxin fusion protein. Denileukin diftitox 150mcg/mL; soln for IV infusion after thawing and dilution. Indications: Persistent or recurrent cutaneous T-cell lymphoma in which malignant cells express the CD25 component of the IL-2 receptor.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER Adults: Premedicate with an antihistamine or acetaminophen prior to each infusion. Give by IV infusion over 30–60 minutes. 9 or 18mcg/kg per day for 5 consecutive days every 21 days for 8 cycles. Children: Not recommended. Warnings/Precautions: Ensure CD25 expression before starting therapy. Have resuscitative equipment available during administration. Permanently discontinue if serious infusion reactions occur. Monitor for signs/symptoms of capillary leak syndrome (hypotension, edema, hypoalbuminemia) and weight gain. Monitor serum albumin levels prior to each treatment course; withhold treatment if serum albumin <3g/dL. Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Fever, fatigue, rigors, GI upset, headache, edema, cough, dyspnea, pruritus, rash, hypotension, back pain, myalgia, chest pain, tachycardia, hypoalbuminemia, asthenia, elevated transaminases; capillary leak syndrome (may be fatal), serious infusion reactions, visual impairment (monitor). Testing considerations: CD25 expression How supplied: Single-use vials (2mL)–6

POMALYST Celgene

℞

Immunomodulator. Pomalidomide 1mg, 2mg, 3mg, 4mg; capsules. Indications: Multiple myeloma, in patients who have received at least two prior therapies (including lenalidomide and bortezomib), and have shown disease progression on or within 60 days of completion of the last therapy. Clinical benefit, such as improvement in survival or symptoms, has not been verified. Adults: Swallow whole; may be taken with water. Take without food. 4mg once daily on Days 1–21 of repeated 28-day cycles until disease progression; may give with dexamethasone. Dose modification for hematologic and other Grade 3/4 toxicities: see full labeling. Children: <18yrs: not established. Contraindications: Pregnancy (Cat.X): avoid during and for at least 4 weeks after completing therapy. Warnings/Precautions: Females of reproductive potential must commit either to abstain from heterosexual sex or to use two methods of reliable contraception, beginning 4 weeks prior to initiating, during therapy, dose interruptions and for 4 weeks after discontinuation. Obtain two negative pregnancy tests prior to initiating therapy: perform first test within 10–14 days, and second test within 24 hours prior to prescribing, and then weekly

during first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks if irregular cycles. Males: must use latex or synthetic condom during therapy and up to 28 days after discontinuing, even after successful vasectomy; do not donate sperm. Patients must not donate blood during therapy and for 1 month after discontinuation. Venous thromboembolism; consider anticoagulation prophylaxis. Monitor for hematologic toxicities (esp. neutropenia); obtain CBCs weekly for first 8 weeks and monthly thereafter; may need dose interruption and/or modification. Renal impairment (serum creatinine >3mg/dL) or hepatic impairment (serum bilirubin >2mg/dL and AST/ALT >3x ULN): avoid. Risk of hypersensitivity or second primary malignancies. Nursing mothers: not recommended. Interactions: May be potentiated by strong CYP1A2, CYP3A (eg, ketoconazole), or P-gp inhibitors; avoid. May be antagonized by strong CYP1A2, CYP3A (eg, rifampin), or P-gp inducers; avoid. Smoking may reduce efficacy. Adverse reactions: Fatigue, asthenia, neutropenia, anemia, constipation, nausea, diarrhea, dyspnea, upper-respiratory tract infections, back pain, pyrexia; venous thromboembolism, dizziness, confusion, neuropathy, pneumonia, thrombocytopenia. Note: Available only through Pomalyst REMS program. How supplied: Caps–21, 100

PURINETHOL Teva

℞

Antimetabolite. Mercaptopurine (6-MP) 50mg; scored tabs. Indications: Maintenance therapy of acute lymphatic leukemia as part of a combination regimen. Adults and Children: 1.5–2.5mg/kg per day as a single dose. Concomitant allopurinol: reduce dose of mercaptopurine to 1/3–1/4 of the usual dose. TPMT-deficient, renal or hepatic impairment: reduce dose, see literature. Contraindications: Prior resistance to mercaptopurine. Warnings/Precautions: Not effective in CNS leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, the lymphomas (including Hodgkin’s disease), or solid tumors. Renal impairment. Monitor liver function tests weekly at start of therapy, then monthly thereafter; discontinue if hepatotoxicity occurs. Preexisting liver disease (monitor more frequently). Obtain CBCs with differential, hemoglobin, hematocrit, platelets; discontinue if severe bone marrow suppression occurs. Thiopurine-Smethyltransferase (TPMT) deficient: increased

risk of myelosuppression, consider genotypic/ phenotypic testing. Pregnancy (Cat.D); esp. 1st trimester, nursing mothers: not recommended. Interactions: Increased risk of bone marrow suppression with allopurinol, aminosalicylate derivatives (eg, olsalazine, mesalazine, sulphasalazine), trimethoprim-sulfamethoxazole. Antagonizes warfarin. Caution with concomitant hepatotoxic agents. Adverse reactions: Myelosuppression, hyperuricemia/hyperuricosuria, GI upset, intestinal ulceration, rash, hyperpigmentation, alopecia, oligospermia; hepatotoxicity, infection, immunosuppression. How supplied: Tabs–60

PURIXAN Rare Disease

℞

Antimetabolite. Mercaptopurine (6-MP) 20mg/mL; oral susp; contains fruit extract, aspartame. Indications: Maintenance therapy of acute lymphoblastic leukemia as part of a combination regimen. Adults and Children: Shake bottle vigorously for at least 30 secs. Initially 1.5–2.5mg/kg (50–75mg/m2) per day as a single dose. Monitor subsequent doses to maintain desirable ANC level and adjust for excessive hematological toxicity. Thiopurine-S-methyltransferase (TPMT)deficient: if homozygous, may require up to a 90% dose reduction; if heterozygous, some may require dose reduction based on toxicities. Renal or hepatic impairment: use lower starting doses; monitor for toxicity. See full labeling. Warnings/Precautions: Myelosuppression; monitor CBCs and adjust dose for severe neutropenia and thrombocytopenia. Consider testing for TPMT gene polymorphism in patients who experience repeated severe bone marrow toxicities. Monitor serum transaminase, alkaline phosphatase, and bilirubin levels at weekly intervals when starting therapy, then monthly thereafter; interrupt treatment if evidence of hepatotoxicity occurs. Concomitant other hepatotoxic drugs or with pre-existing liver disease; monitor LFTs more frequently. Immunosuppression. Increased risk of secondary malignancies. Renal or hepatic impairment. Elderly. Pregnancy (Cat.D); esp. 1st trimester, nursing mothers: not recommended. Interactions: Avoid concomitant allopurinol. Increased risk of bone marrow suppression with allopurinol, aminosalicylate derivatives (eg, olsalazine, mesalamine, sulfasalazine), trimethoprim-sulfamethoxazole. Possibly decreased effectiveness with concomitant warfarin; monitor PT or INR; may need warfarin

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER dose adjustments. Concomitant live virus vaccines: may get suboptimal response and risk of infection. Adverse reactions: Myelosuppression, nausea, vomiting, anorexia, diarrhea, malaise, rashes, oral lesions, elevated transaminases and bilirubin, intestinal ulceration; hepatotoxicity. How supplied: Susp–100mL

REVLIMID Celgene

℞

Immunomodulator. Lenalidomide 2.5mg, 5mg, 10mg, 15mg, 20mg, 25mg; caps. Indications: In combination with dexamethasone for treatment of patients with multiple myeloma (MM) who have received at least one prior therapy. Treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. Limitations of use: not for treating patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials. Adults: Swallow whole with water. ≥18yrs: initially 25mg once daily on Days 1–21 of each 28-day cycle. Renal impairment: Moderate (CrCL 30–60mL/min): 10mg per day. Severe (CrCL <30mL/min without dialysis): 15mg every 48hrs. ESRD (CrCL <30mL/min with dialysis): 5mg once daily; administer after dialysis (on dialysis days). Dose adjustments if thrombocytopenia or neutropenia develops: see full labeling. Children: <18yrs: not established. Contraindications: Pregnancy (Cat.X). Women who may become pregnant. Warnings/Precautions: Must register patient in Revlimid REMS program; patient must understand toxicity with fetal exposure. Counsel patient on need for contraception; female: use 2 forms of contraception 1 month before, during, and 1 month after therapy; male: use condom during and 1 month after therapy; obtain 2 negative pregnancy tests (one within 10–14 days, and then another within 24hrs prior to starting therapy), repeat at least weekly for 1st month then every 4 weeks; get informed consent. Monitor for signs/symptoms of thromboembolic events. For MM: obtain CBCs every 2 weeks for first 3 months, then monthly. For MCL: obtain CBCs weekly for the first cycle, every 2 weeks during cycles 2–4, and then monthly thereafter. Renal impairment (monitor). Monitor for tumor lysis syndrome in those with high tumor burden. Monitor liver enzymes; discontinue if elevation occurs. Monitor for second primary malignancies. Maximum 1 month per ℞. Nursing mothers: not recommended. Interactions: Monitor digoxin. Concomitant warfarin; monitor PT, INR. May increase risk of thrombosis with dexamethasone, erythropoietic agents, or estrogen containing therapies. Adverse reactions: Birth defects, thrombocytopenia, neutropenia, anemia, leukopenia, constipation, diarrhea, nausea, vomiting, pruritus, rash, fatigue, arthralgia,

pyrexia, back pain, cough, dizziness, headache, dyspnea, upper respiratory tract infection, tremor, blurred vision, muscle cramp, peripheral edema; thrombosis/embolism, allergic reactions (discontinue if occurs; do not resume), tumor flare reaction (monitor; esp. in treating MCL), hepatotoxicity. Note: Available only through Revlimid REMS program. Report any suspected fetal exposure to the FDA at (800) FDA-1088 and Celgene at (888) 423-5436. How supplied: Caps 2.5mg, 5mg, 10mg–28, 100; 15mg, 20mg, 25mg–21, 100

RITUXAN Genentech

℞

CD20-directed cytolytic monoclonal antibody. Rituximab 10mg/mL; soln for IV infusion; preservative-free. Indications: Relapsed or refractory, low-grade or follicular, CD20(+), B-cell non-Hodgkin’s lymphoma (NHL). Previously untreated follcular, CD20(+), B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to Rituxan in combination with chemotherapy, as singleagent maintenance therapy. Non-progressing (including stable disease), low-grade, CD20(+), B-cell NHL as a single agent after first-line CVP chemotherapy. Previously untreated diffuse large B-cell, CD20(+) NHL (DLBCL) in combination with CHOP or other anthracycline-based chemotherapy regimens. CD20(+) chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide. Limitation of use: not recommended for use in patients with severe, active infections. Adults: Give by IV infusion. Premedicate with an antihistamine and acetaminophen prior to each infusion. First infusion: initially at a rate of 50mg/hr; may increase infusion rate in 50mg/hr increments every 30 mins. Subsequent infusions: initially at a rate of 100mg/hr; may increase infusion rate in 100mg/hr increments every 30 mins. Both: max 400mg/hr if infusion reactions do not occur. Previously untreated follicular NHL and DLBCL patients: if no Grade 3 or 4 infusion related adverse events during Cycle 1, a 90-minute infusion may be given in Cycle 2 with a glucocorticoid-containing chemotherapy regimen (see full labeling). NHL: 375mg/m2 once weekly for 4 or 8 doses. Retreatment therapy: 375mg/m2 once weekly for 4 doses. Previously untreated, follicular, CD20(+), B-cell NHL: 375mg/m2 on Day 1 of each cycle of CVP chemotherapy for up to 8 doses. In patients with complete or partial response, initiate Rituxan maintenance 8 weeks following completion of Rituxan in combination with chemotherapy. Administer Rituxan as a single-agent every 8 weeks for 12 doses. Low-grade, CD20(+), B-cell NHL after CVP chemotherapy: 375mg/m2 once weekly for 4 doses every 6 months for up to 16 doses. Diffuse large B-cell NHL: 375mg/m2 on

Day 1 of each cycle for up to 8 infusions. CLL: 375mg/m2 the day prior to FC chemotherapy, then 500mg/m2 on Day 1 of cycles 2–6 (every 28 days). Give PCP and antiherpetic viral prophylaxis during and up to 12 months after CLL therapy. As a component of Zevalin regimen: see full labeling. Children: Not established. Warnings/Precautions: Discontinue if severe infusion or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, MI, ventricular fibrillation, cardiogenic shock, paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid or vesiculobullous dermatitis, toxic epidermal necrolysis). Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Tumor lysis syndrome (esp. with high tumor burden); monitor for renal toxicity, fluid balance, electrolyte abnormalities (correct if occurs); discontinue if SCr rises or oliguria occurs. Monitor for new-onset neurologic manifestations; discontinue if progressive multifocal leukoencephalopathy (PML) develops. Discontinue and treat if serious infections (eg, bacterial, fungal, viral) occur. Pre-existing cardiovascular disease; monitor during and after treatment. Monitor CBCs, platelet counts during treatment, then periodically. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Live virus vaccines: not recommended. Renal toxicity with cisplatin. Adverse reactions: Fever, chills, rigors, nausea, vomiting, diarrhea, asthenia, fatigue, headache, throat irritation, flushing, rash, pruritus, urticaria, angioedema, cough, rhinitis, bronchospasm, dizziness, myalgia, arthralgia, hypotension, hypertension, chest tightness; myelosuppression (eg, lymphopenia, neutropenia, leukopenia, anemia, thrombocytopenia), infusion reactions (may be fatal), mucocutaneous reactions (may be fatal), PML, serious infections, tumor lysis syndrome, renal toxicity, bowel obstruction/ perforation, HBV reactivation with fulminant hepatitis, cardiac arrhythmias (discontinue if serious). Testing considerations: FCGR3A genotype testing How supplied: Single-use vial (10mL, 50mL)–1

SPRYCEL Bristol-Myers Squibb

℞

Tyrosine kinase inhibitor. Dasatinib 20mg, 50mg, 70mg, 80mg, 100mg, 140mg; tabs. Indications: Newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. Chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib. Philadelphia chromosome-positive acute lymphoblastic

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER leukemia (Ph+ ALL) with resistance or intolerance to prior therapy. Adults: Swallow whole. ≥18yrs: Chronic phase CML: 100mg once daily. Doses of up to 140mg once daily have been used. Accelerated phase CML, myeloid or lymphoid blast CML, Ph+ ALL: 140mg once daily. Doses of up to 180mg once daily have been used. Concomitant CYP3A4 inhibitors (see Interactions): consider reducing dose. Concomitant CYP3A4 inducers (see Interactions): consider increasing dose. See full labeling for dose adjustments with toxicity. Children: <18yrs: not established. Warnings/Precautions: History of QT prolongation. Proarrhythmic conditions. Cumulative high-dose anthracycline therapy. Monitor for signs/symptoms of cardiac dysfunction; treat appropriately if occur. Hypokalemia, hypomagnesemia; correct electrolyte imbalances before starting therapy. Monitor for pleural effusions. Increased risk of pulmonary arterial hypertension (PAH); evaluate for signs/symptoms of underlying cardiopulmonary disease before and during treatment; permanently discontinue if occurs. Obtain CBCs weekly for the first 2 months, then monthly thereafter. Hepatic impairment. Elderly. Pregnancy (Cat.D; use adequate contraception); nursing mothers: not recommended. Interactions: Avoid potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, ritonavir, atazanavir, indinavir, nefazodone, nelfinavir, saquinavir, telithromycin, voriconazole), grapefruit juice. May be antagonized by strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital), St. John’s wort: not recommended. Separate dosing of antacids by at least 2hrs; H2 blockers, proton pump inhibitors: not recommended. May potentiate drugs metabolized by CYP3A4 (eg, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, ergot alkaloids). Caution with concomitant anticoagulants or drugs that inhibit platelet function. Caution with antiarrhythmics or other drugs that may lead to QT prolongation. Adverse reactions: Myelosuppression (eg, severe thrombocytopenia, neutropenia, anemia), fluid retention (eg, ascites, edema, pleural and pericardial effusions), diarrhea, headache, dyspnea, musculoskeletal pain, rash, fatigue, nausea, severe hemorrhage (eg, CNS, GI); QT prolongation, cardiac events (eg, cardiomyopathy, CHF, fatal MI, left ventricular dysfunction), PAH. How supplied: Tabs 20mg, 50mg, 70mg–60; 80mg, 100mg, 140mg–30

SYNRIBO Teva

℞

Protein synthesis inhibitor. Omacetaxine mepesuccinate 3.5mg/vial; lyophilized powder for SC injection after reconstitution; contains mannitol; preservative-free. Indications: Treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to two or more tyrosine kinase inhibitors (TKI). Adults: Induction: 1.25mg/m2 by SC injection twice daily for 14 consecutive days every 28 days, over a 28-day cycle. Repeat cycles every 28 days until hematologic response achieved. Maintenance: 1.25mg/m2 by SC injection twice daily for 7 consecutive days every 28 days, over a 28-day cycle, as long as clinically beneficial. Dose adjustments and modifications: see full labeling. Children: Not established. Warnings/Precautions: Risk of myelosuppression (thrombocytopenia, neutropenia, anemia), hemorrhage (cerebral, GI). Monitor CBCs with platelets weekly during induction, initial maintenance cycles, and every 2 weeks during later cycles. Monitor glucose levels (esp. in diabetics). Avoid in poorly controlled diabetes until glycemic control is established. Elderly. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Avoid concomitant anticoagulants, aspirin, NSAIDs if platelets <50,000/microliters; may increase risk of bleeding. Adverse reactions: Thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, lymphopenia; bleeding, hyperglycemia. How supplied: Single-use vial–1

TABLOID GlaxoSmithKline

℞

Antimetabolite. Thioguanine 40mg; tabs; scored. Indications: Remission induction and remission consolidation treatment of acute nonlymphocytic leukemias. Treatment of the chronic phase of chronic myelogenous leukemia (see literature). Adults and Children: See literature. Initially, 2mg/kg per day. If, after 4 weeks, with no improvement, no leukocyte or platelet depression, may increase to 3mg/kg per day. Total daily dose may be given at one time. Contraindications: Allergy to mercaptopurine. Warnings/Precautions: Not recommended for maintenance therapy or long-term continuous treatments; increased risk of liver toxicity (discontinue if occurs). Pre-existing liver disease. Monitor liver function tests weekly at start of

therapy, then monthly thereafter. Thiopurine methyltransferase (TPMT) enzyme deficiency (may need to reduce dose to avoid severe bone marrow suppression); consider testing for TPMT deficiency. Obtain hemoglobin, hematocrit, WBCs with differential, platelets frequently during therapy. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid live vaccines (if immunocompromised). Caution with drugs that inhibit TPMT (eg, olsalazine, mesalazine, or sulphasalazine). Adverse reactions: Myelosuppression, hyperuricemia, GI upset, anorexia, stomatitis, hepatotoxicity, elevated liver enzymes, jaundice (discontinue if occurs). How supplied: Tabs–25

TARGRETIN Eisai

℞

Retinoid. Bexarotene 75mg; caps. Indications: Cutaneous manifestations of cutaneous T-cell lymphoma in patients who are refractory to at least one prior systemic therapy. Adults: Take with food. Initially 300mg/m2 once daily; may increase after 8 weeks to 400mg/m2 once daily if no tumor response and if well tolerated; monitor carefully. If toxicity occurs, reduce to 200mg/m2 then 100mg/m2 once daily, or suspend therapy. Children: Not recommended. Contraindications: Pregnancy (Cat.X). Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Pancreatitis or risk of pancreatitis (eg, history of pancreatitis, uncontrolled hyperlipidemia, excess alcohol consumption, uncontrolled diabetes, biliary tract disease, drugs that can cause pancreatitis). Counsel patients monthly about need for contraception. Women of childbearing potential: obtain reliable negative pregnancy test within 1 week of start; repeat monthly. Start therapy on 2nd or 3rd day of normal menstrual period. Use two effective forms of contraception 1 month prior to, during, and for 1 month after therapy. Max 1 month/℞. Men with partners who are or may become pregnant: use condoms during and for at least 1 month after therapy. Monitor lipids before treatment, weekly until stable, then every 8 weeks; try to keep triglycerides <400mg/dL; treat hyperlipidemia, or reduce or suspend bexarotene if needed. Hepatic or renal insufficiency. Monitor liver function at baseline, 1, 2, and 4 weeks after start, then (if stable) at least every 8 weeks during therapy; consider suspending or discontinuing treatment if SGOT/ AST, SGPT/ALT, or bilirubin >3×ULN occurs. Monitor WBC with differential and thyroid

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER function at baseline and during treatment; treat hypothyroidism if needed. Avoid sun and UV light. Nursing mothers: not recommended. Interactions: Concomitant gemfibrozil: not recommended. Levels may be increased by CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice). Levels may be reduced by CYP3A4 inducers (eg, rifampin, phenobarbital, phenytoin). May potentiate antihyperglycemics (eg, insulin, sulfonylureas, thiazolidinediones); monitor. May potentiate or be potentiated by protein-bound drugs. May antagonize tamoxifen, hormonal contraceptives, other CYP3A4 substrates. Limit Vit. A supplements to avoid toxicity. May increase CA125 assay values. Adverse reactions: Lipid abnormalities, headache, hypothyroidism, asthenia, leukopenia, anemia, rash, GI disturbances, peripheral edema, dry skin, exfoliative dermatitis, alopecia, insomnia, fatigue, abnormal liver function tests, pancreatitis, pruritus, photosensitivity. How supplied: Caps–100

TARGRETIN GEL Eisai

℞

Retinoid. Bexarotene 1%; gel. Indications: Cutaneous lesions in patients with CTCL (Stage IA and IB) who have refractory or persistent disease after other therapies or who have not tolerated other therapies. Adults: Apply once every other day for the 1st week; then increase frequency at weekly intervals to once daily, then twice daily, then 3 times daily, then 4 times daily based on lesion tolerance. Usual dosing frequency: 2–4 times daily; may reduce if application site toxicity occurs. Allow gel to dry. Do not occlude. Children: Not recommended. Contraindications: Pregnancy (Cat.X). Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Counsel patients monthly about need for contraception. Women of childbearing potential: obtain reliable negative pregnancy test within 1 week of start; repeat monthly. Start therapy on 2nd or 3rd day of normal menstrual period. Use two effective forms of contraception 1 month prior to, during, and for 1 month after therapy. Max 1 month/℞. Men with partners who are or may become pregnant: use condoms during and for at least 1 month after therapy. Hepatic or renal insufficiency. Discontinue temporarily if severe irritation occurs. Avoid sun, UV light, and mucosal membranes. Nursing mothers: not recommended. Interactions: Avoid concomitant products that contain DEET. May be potentiated by CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, grapefruit juice). Caution with gemfibrozil. Limit Vit. A supplements to avoid toxicity. Adverse reactions: Application site reactions (eg, rash, pruritus, skin disorders, pain, contact dermatitis). How supplied: Gel–60g

TASIGNA Novartis

℞

Kinase inhibitor. Nilotinib (as HCl monohydrate) 150mg, 200mg; caps; contains lactose. Indications: Newly diagnosed adults with Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) in chronic phase. Chronic and accelerated phase Ph+ CML in adults resistant or intolerant to imatinib. Adults: Take on an empty stomach. Swallow whole with water; if unable, may disperse capsule contents in 1 tsp of applesauce, then take immediately (within 15 mins). Newly diagnosed Ph+ CML: 300mg every 12hrs. Hepatic impairment (mild, moderate, severe): initially 200mg twice daily, followed by dose increase to 300mg twice daily if tolerated. Resistant or intolerant Ph+ CML: 400mg every 12hrs. Hepatic impairment (mild or moderate): initially 300mg twice daily, followed by dose increase to 400mg twice daily if tolerated; severe: initially 200mg twice daily, followed by sequential dose increase to 300mg twice daily, and then 400mg twice daily if tolerated. May give concomitant hematopoietic growth factors, hydroxyurea, or anagrelide if clinically indicated. See full labeling for dose adjustments in QT prolongation, hematological and nonhematological toxicities, concomitant strong CYP3A4 inhibitors and inducers. Children: Not established. Contraindications: Hypokalemia. Hypomagnesemia. Long QT syndrome. Warnings/Precautions: Prolongs QT interval, sudden deaths have been reported; correct electrolyte abnormalities before starting; monitor. Monitor ECG at baseline, after 7 days, then periodically and after dose changes. Hereditary galactose intolerance, severe lactase deficiency, glucose-galactose malabsorption: not recommended. Hepatic impairment. History of pancreatitis. Cardiovascular disorders. Monitor for myelosuppression; withhold or reduce dose if occurs; perform CBCs every 2 weeks for 1st 2 months then once monthly. Monitor serum lipase, liver function monthly. Total gastrectomy (monitor frequently); consider dose increase or alternative therapy. Tumor lysis syndrome possible; maintain adequate hydration, correct uric acid levels prior to initiating therapy. Pregnancy (Cat.D) (use adequate contraception), nursing mothers: not recommended. Interactions: Avoid concomitant food (for at least 2hrs before and 1hr after dose), antiarrhythmics (eg, amiodarone, disopyramide, procainamide, quinidine, sotalol), or other drugs that may prolong QT interval (eg, chloroquine, haloperidol, methadone, moxifloxacin, pimozide). Avoid strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), grapefruit; if necessary, interrupt therapy or consider dose reduction of nilotinib; if unavoidable, monitor

closely for QT prolongation. Avoid strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital), St. John’s wort. May affect, or be affected by, other drugs metabolized by CYP3A4, 2B6, 2C8, 2C9, 2D6, UGT1A1, P-glycoprotein. Concomitant proton pump inhibitors: not recommended. Administer H2-blockers at least 10hrs before or 2hrs after nilotinib dose. Separate dosing of antacids by at least 2hrs of nilotinib dose. Adverse reactions: Rash, pruritus, nausea, fatigue, headache, myalgia, nasopharyngitis, constipation, diarrhea, abdominal pain, vomiting, arthralgia, pyrexia, upper respiratory tract infection, back pain, cough, asthenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, reversible myelosuppression (thrombocytopenia, neutropenia, anemia); QT prolongation, elevated serum lipase, electrolyte disturbances (hypophosphatemia, hypo- and hyperkalemia, hypocalcemia, hyponatremia), sudden death, hepatotoxicity. Testing considerations: BCR-Abl t(9;22) How supplied: Blister pack (28 caps)–1, 4

THALOMID Celgene

℞

Immunomodulator. Thalidomide 50mg, 100mg, 150mg, 200mg; caps. Indications: Newly diagnosed multiple myeloma in combination with dexamethasone. Treatment, suppression and prevention of cutaneous manifestations of erythema nodosum leprosum (ENL). Adults: Take at bedtime, at least 1 hour after evening meal. Multiple myeloma: 200mg once daily in combination with dexamethasone in 28-day treatment cycles. ENL: initially 100–300mg/day; <50kg: start with lower dose; continue until signs/symptoms of active reaction have subsided (usually at least 2 weeks), then taper off in 50mg decrements every 2–4 weeks. Severe ENL: may start at higher doses; max 400mg/day. Moderate to severe neuritis with severe ENL: give concomitant corticosteroids (see full labeling). Children: Not established. Contraindications: Pregnancy (Cat.X). Nursing mothers. Women who may become pregnant. Warnings/Precautions: Must register patient in STEPS program; patient must understand toxicity with fetal exposure. Counsel patient on need for contraception; female: use 2 forms of contraception 1 month before, during, and 1 month after therapy; male: use condom during and 1 month after therapy; obtain negative pregnancy test within 24 hours prior to starting treatment; repeat at least weekly for 1st month then every 4 weeks; get informed consent. Monitor for neuropathy monthly for first 3 months; discontinue if symptoms develop. Monitor for signs/symptoms of thromboembolic events, neutropenia, bradycardia, syncope, orthostatic hypotension, tumor lysis syndrome.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER Reevaluate if ANC <750/mm2; consider withholding if neutropenia persists. Measure HIV viral load after 1st and 3rd months, and every 3 months thereafter. Discontinue if pregnancy or severe skin rash occurs. History of seizure. Avoid contact with non-intact capsule or powder content. Maximum 1 month per ℞. Interactions: Increased sedative effect with barbiturates, alcohol, chlorpromazine, reserpine. Caution with drugs associated with peripheral neuropathy. Avoid drugs (eg, rifampin, carbamazepine, St. John’s wort) that decrease effectiveness of hormonal contraceptives. Increased risk of thromboembolism with concomitant erythropoietic agents, or estrogencontaining therapies in those receiving thalidomide with dexamethasone. Adverse reactions: Fatigue, birth defects, somnolence, skin rash (eg, Stevens-Johnson Syndrome, toxic epidermal necrolysis), headache, bradycardia, peripheral neuropathy, seizures, drowsiness, dizziness, orthostatic hypotension, leukopenia, anorexia, nausea, anxiety, asthenia, tremor, fever, weight loss, dry skin, neutropenia, increased HIV viral load, constipation, confusion, hypocalcemia, edema, dyspnea, thrombosis/ embolism. Note: Available only through STEPS program. Suspected fetal exposure must be reported to the FDA at (800) FDA-1088 and Celgene at (888) 423-5436. How supplied: Blister packs (50mg)–1, 28; (100mg, 150mg, 200mg)–28

TREANDA Teva

℞

Alkylating agent. Bendamustine HCl 90mg/mL; soln for IV infusion after dilution; preservativefree. Indications: Chronic lymphocytic leukemia (CLL). Indolent B-cell non-Hodgkin’s lymphoma (NHL) that has progressed during or within 6 months of treatment with rituximab or a rituximab–containing regimen. Adults: CLL: Give by IV infusion over 30 minutes. 100mg/m2 on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Hematologic toxicity (≥Grade 3): reduce dose to 50mg/m2 on Days 1 and 2 of each cycle; if toxicity recurs, reduce dose to 25mg/m2 on Days 1 and 2. Non-hematologic toxicity (clinically significant ≥Grade 3): reduce dose to 50mg/m2 on Days 1 and 2 of each cycle. Subsequent cycles: may consider dose re-escalation. NHL: Give by IV infusion over 60 minutes. 120mg/m2 on Days 1 and 2 of a 21-day cycle, up to 8 cycles. Hematologic toxicity (Grade 4) or non-hematologic toxicity (≥Grade 3): reduce

dose to 90mg/m2 on Days 1 and 2 of each cycle; if toxicity recurs, reduce dose to 60mg/m2 on Days 1 and 2. Delay treatment for Grade 4 hematologic toxicity or clinically significant ≥Grade 2 nonhematologic toxicity. Severe renal impairment (CrCl <40mL/min) or moderate to severe hepatic impairment: not recommended. Children: Not established. Warnings/Precautions: Myelosuppression; monitor leukocytes, platelets, hemoglobin, neutrophils closely; restart treatment based on ANC and platelet count recovery. Renal or hepatic impairment. Monitor for infection, infusion or skin reactions, tumor lysis syndrome. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: May be potentiated or antagonized by CYP1A2 inhibitors, inducers; consider alternatives. Adverse reactions: Lymphopenia, anemia, leukopenia, thrombocytopenia, neutropenia, pyrexia, nausea, vomiting, diarrhea, asthenia, fatigue, malaise, dry mouth, somnolence, cough, constipation, headache, mucosal inflammation, stomatitis, increased bilirubin, increased AST or ALT; infection, infusion reactions (discontinue if severe), tumor lysis syndrome, skin reactions (if severe or progressive, withhold dose or discontinue), other malignancies (eg, myelodysplastic syndrome, acute myeloid leukemia, bronchial carcinoma). How supplied: Single-use vial (45mg/0.5mL, 180mg/2mL)–1

TREXALL Teva

℞

intrathecally (max 15mg) at intervals of 2–5 days; see literature for prophylaxis treatment. Burkitt’s tumor (stage I–II): 10–25mg per day orally for 4–8 days. Lymphosarcomas (stage III): 0.625–2.5mg/kg daily. Mycosis fungoides (cutaneous T cell lymphoma): 5–50mg once weekly. Children: See literature. Contraindications: Pregnancy (Cat.X). Nursing mothers. Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration). Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer. Ulcerative colitis. Infection. Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated. Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, non-absorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin). Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome, skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome). How supplied: Tabs–30; soln (2mL, 4mL, 8mL, 10mL)–10 (single-use vials); pwd (1 gram)–1 (single-use vial)

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NEW—LIQUID FORMULATION

Start with TREANDA® (bendamustine HCI) Injection for established front-line CLL therapy

Preparing for IV administration is:

Fast

Precise

Convenient

Less preparation time

No reconstitution necessary

Fewer steps prior to admixing

Important Safety Information Contraindication: TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. Myelosuppression: TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppression-related adverse reactions. If myelosuppression occurs, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Infections: Infection, including pneumonia, sepsis, septic shock, and death have occurred. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Anaphylaxis and Infusion Reactions: Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus, and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe (Grade 3-4) reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Consider measures to prevent severe reactions, including antihistamines, antipyretics, and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Tumor Lysis Syndrome: Tumor lysis syndrome associated with TREANDA treatment has occurred. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. There may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Learn more at TREANDAHCP.com

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

Skin Reactions: Skin reactions have been reported with TREANDA treatment and include rash, toxic skin reactions, and bullous exanthema. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab. Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. Other Malignancies: There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia, and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation Injury: TREANDA extravasations have been reported in postmarketing resulting in hospitalizations from erythema, marked swelling, and pain. Ensure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Embryo-fetal Toxicity: TREANDA can cause fetal harm when administered to a pregnant woman. Women should be advised to avoid becoming pregnant while using TREANDA. Most Common Adverse Reactions: The most common non-hematologic adverse reactions for CLL (frequency ≥15%) are pyrexia, nausea, and vomiting. The most common hematologic abnormalities (frequency ≥15%) are anemia, thrombocytopenia, neutropenia, lymphopenia, and leukopenia. Please see accompanying brief summary of Full Prescribing Information on the following pages.

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Job Number: 20972 Revision No: 0 Date: 10/29/14

NEW—LIQUID FORMULATION

Start with TREANDA® (bendamustine HCI) Injection for established front-line CLL therapy

Preparing for IV administration is:

Fast

Precise

Convenient

Less preparation time

No reconstitution necessary

Fewer steps prior to admixing

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first-line therapies other than chlorambucil has not been established.

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Job Number: 20972 Revision No: 0 Date: 10/29/14

TREANDA® (bendamustine hydrochloride) Injection

™

Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia 1 INDICATIONS AND USAGE 1.1 Chronic Lymphocytic Leukemia (CLL) TREANDA® is indicated for the treatment of patients with chronic lymphocytic leukemia. Efficacy relative to first line therapies other than chlorambucil has not been established. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Instructions for CLL Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 non-hematologic toxicity. Once nonhematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions (5.1)] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle. Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician. 2.3 Preparation for Intravenous Administration Each vial of TREANDA Injection is intended for single use only. Aseptically withdraw the volume needed for the required dose from the 90 mg/mL solution. Immediately transfer the solution to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2 - 0.7 mg/mL. The admixture should be a clear colorless to yellow solution. Use either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. 2.4 Admixture Stability TREANDA Injection contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored under refrigerated conditions at 2°-8°C (36°-46°F) or for 2 hours when stored at room temperature (15°-30°C or 59°-86°F) and room light. Administration of TREANDA must be completed within this period. 3 DOSAGE FORMS AND STRENGTHS TREANDA Injection is supplied in single-use vials containing either 45 mg/0.5mL or 180 mg/2mL of bendamustine HCl. 4 CONTRAINDICATIONS TREANDA is contraindicated in patients with a known hypersensitivity (e.g., anaphylactic and anaphylactoid reactions) to bendamustine. [See Warnings and Precautions (5.3)] 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression TREANDA caused severe myelosuppression (Grade 3-4) in 98% of patients in the two NHL studies. Three patients (2%) died from myelosuppressionrelated adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils frequently. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Myelosuppression may require dose delays and/or subsequent dose reductions if recovery to the recommended values has not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration (2.1)] 5.2 Infections Infection, including pneumonia, sepsis, septic shock, and death have occurred in adult and pediatric patients in clinical trials and in postmarketing

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reports. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Advise patients with myelosuppression following TREANDA treatment to contact a physician if they have symptoms or signs of infection. 5.3 Anaphylaxis and Infusion Reactions Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy. Monitor clinically and discontinue drug for severe reactions. Ask patients about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experience Grade 3 or worse allergic-type reactions should not be rechallenged. Consider measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids in subsequent cycles in patients who have experienced Grade 1 or 2 infusion reactions. Discontinue TREANDA for patients with Grade 4 infusion reactions. Consider discontinuation for Grade 3 infusions reactions as clinically appropriate considering individual benefits, risks, and supportive care. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome associated with TREANDA treatment has occurred in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include vigorous hydration and close monitoring of blood chemistry, particularly potassium and uric acid levels. Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly [see Warnings and Precautions (5.5)]. 5.5 Skin Reactions Skin reactions have been reported with TREANDA treatment in clinical trials and postmarketing safety reports, including rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Monitor patients with skin reactions closely. If skin reactions are severe or progressive, withhold or discontinue TREANDA. 5.6 Other Malignancies There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. 5.7 Extravasation Injury TREANDA extravasations have been reported in post marketing resulting in hospitalizations from erythema, marked swelling, and pain. Assure good venous access prior to starting TREANDA infusion and monitor the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. 5.8 Embryo-fetal Toxicity TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights. 6 ADVERSE REACTIONS The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression (5.1); Infections (5.2); Anaphylaxis and Infusion Reactions (5.3); Tumor Lysis Syndrome (5.4); Skin Reactions (5.5); Other Malignancies (5.6); Extravasation injury (5.7). The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.1 Clinical Trials Experience in CLL The data described below reflect exposure to TREANDA in 153 patients with CLL studied in an active-controlled, randomized trial.The population was 45-77 years of age, 63% male, 100% white, and were treatment naïve. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on Days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. Nonhematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%).

Job Number: 20972 Revision No: 0 Date: 10/29/14

TREANDA® (bendamustine hydrochloride) Injection

Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the CLL trial and in none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study. Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients

In the CLL trial, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients. Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that further deterioration does not occur. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including phlebitis, pruritus, irritation, pain, and swelling; pneumocystis jiroveci pneumonia and pneumonitis. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions (5.5)] 10 OVERDOSAGE The intravenous LD50 of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. 15 REFERENCES 1. OSHA Hazardous Drugs. OSHA. [Accessed on June 19, 2013, from http://www.osha.gov/SLTC/hazardousdrugs/index.html] 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 Safe Handling and Disposal As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA Injection. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. TREANDA is a cytotoxic drug. Follow special handling and disposal procedures1. 16.2 How Supplied TREANDA (bendamustine hydrochloride) Injection is supplied as a 90 mg/mL clear colorless to yellow solution as follows: NDC 63459-395-02: 45 mg/0.5 mL of solution in an amber single-use vial NDC 63459-396-02: 180 mg/2 mL of solution in an amber single-use vial Vials are supplied in individual cartons. 16.3 Storage TREANDA Injection must be stored refrigerated between 2°-8°C (36°-46°F). Retain in original package until time of use to protect from light.

Number (%) of patients TREANDA (N=153) System organ class Preferred term Total number of patients with at least 1 adverse reaction Gastrointestinal disorders Nausea Vomiting Diarrhea General disorders and administration site conditions Pyrexia Fatigue Asthenia Chills Immune system disorders Hypersensitivity Infections and infestations Nasopharyngitis Infection Herpes simplex Investigations Weight decreased Metabolism and nutrition disorders Hyperuricemia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash Pruritus

Chlorambucil (N=143)

All Grades

Grade 3/4

All Grades

Grade 3/4

121 (79)

52 (34)

96 (67)

25 (17)

31 (20) 24 (16) 14 (9)

1 (<1) 1 (<1) 2 (1)

21 (15) 9 (6) 5 (3)

1 (<1) 0 0

36 (24) 14 (9) 13 (8) 9 (6)

6 (4) 2 (1) 0 0

8 (6) 8 (6) 6 (4) 1 (<1)

2 (1) 0 0 0

7 (5)

2 (1)

3 (2)

10 (7) 9 (6) 5 (3)

0 3 (2) 0

12 (8) 1 (<1) 7 (5)

0 1 (<1) 0

11 (7)

5 (3)

11 (7)

3 (2)

2 (1)

6 (4)

1 (<1)

7 (5)

1 (<1)

12 (8) 8 (5)

4 (3) 0

7 (5) 2 (1)

3 (2) 0

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil. Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA N=150

Chlorambucil N=141

Laboratory Abnormality

All Grades n (%)

Grade 3/4 n (%)

All Grades n (%)

Grade 3/4 n (%)

Hemoglobin Decreased

134 (89)

20 (13)

115 (82)

12 (9)

Platelets Decreased

116 (77)

16 (11)

110 (78)

14 (10)

Leukocytes Decreased

92 (61)

42 (28)

26 (18)

4 (3)

Lymphocytes Decreased

102 (68)

70 (47)

27 (19)

6 (4)

Neutrophils Decreased

113 (75)

65 (43)

86 (61)

30 (21)

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Distributed By: Teva Pharmaceuticals USA, Inc. North Wales, PA 19454 TREANDA is a trademark of Cephalon, Inc. or its affiliates. ©2008-2014 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. or its affiliates. All rights reserved. (Label Code: 00016287.06) 9/2013 TRE-40161 This brief summary is based on TRE-009 TREANDA full Prescribing Information.

Job Number: 20972 Revision No: 0 Date: 10/29/14

DRUG MONOGRAPHS

HEMATOLOGIC CANCER TRISENOX Teva

℞

Antineoplastic. Arsenic trioxide 1mg/mL; soln for IV inj after dilution; preservative-free. Indications: Induction of remission and consolidation in acute promyelocytic leukemia (APL) refractory to or relapsed from retinoid and anthracycline chemotherapy, and whose APL has the t(15;17) translocation or PML/RAR-alpha gene expression. Adults: Give by IV infusion over 1–2 hours; may extend infusion up to 4 hours if acute vasomotor symptoms occur. Induction: 0.15mg/kg per day until bone marrow remission; max 60 doses. Consolidation treatment (begin 3–6 weeks after completion of induction therapy): 0.15mg/kg per day for 25 doses for up to 5 weeks. Children: See literature. <5yrs: not recommended. 5–16yrs: doses of 0.15mg/kg per day have been used. Warnings/Precautions: Renal or hepatic dysfunction. History of torsades de pointes. Preexisting QT interval prolongation. CHF. Monitor hematology, renal function, and electrolytes at least twice weekly, perform ECG at baseline then weekly (hospitalize if cardiac irregularities develop); unstable patients: monitor more frequently. Correct electrolyte imbalances before starting therapy (maintain K+ above 4mEq/dL and Mg++ above 1.8mg/dL). Pregnancy: (Cat.D), nursing mothers: not recommended. Interactions: Caution with drugs that can cause QT prolongation (discontinue these before starting therapy, if possible) or electrolyte imbalances. Adverse reactions: Leukocytosis, GI upset, fatigue, edema, hyperglycemia, cough, rash, headache, dizziness, paresthesia, arthralgia, renal failure, electrolyte disorders (eg,hypokalemia, hypomagnesemia), abnormal LFTs; APL differentiation syndrome (eg, fever, dyspnea, weight gain, pulmonary infiltrates, pericardial effusion; give high-dose IV steroids at 1st sign), hyperleukocytosis, QT interval prolongation/heart block, atrial dysrhythmias, tachycardia, others (see literature). How supplied: Single-use amps (10mL)–10

UVADEX Therakos

℞

Photoactive agent. Methoxsalen 20mcg/mL; sterile soln. Indications: Extracorporeal administration with the UVAR Photopheresis System in the palliative treatment of skin manifestations of cutaneous T-cell lymphoma that is unresponsive to other forms of treatment. Adults: Consult UVAR Photopheresis System Operator’s Manual before administering. Give on two consecutive days every 4 weeks for minimum of 7 treatment cycles (6 months). 200mcg per photopheresis treatment. Accelerated treatment schedule: see literature. Children: Not recommended.

Contraindications: Idiosyncratic reactions to psoralen compounds. History of light sensitive disease. Lupus erythematosus. Porphyria cutanea tarda. Erythropoietic protoporphyria. Variegate porphyria. Xeroderma pigmentosum. Albinism. Aphakia. Warnings/Precautions: Exposure to sun or UV light may cause actinic degeneration, skin burning, cataracts; wear UVA-absorbing, wraparound sunglasses and cover exposed skin (or use sunblock: SPF ≥15) for 24hrs after treatment. Basal cell carcinomas (monitor and treat if occur). Pregnancy (Cat.D); nursing mothers: not recommended. Interactions: Increased photosensitivity with anthralin, coal tar, griseofulvin, phenothiazines, nalidixic acid, halogenated salicylanilides, sulfonamides, tetracyclines, thiazides, organic staining dyes. Adverse reactions: Hypotension secondary to changes in extracorporeal volume. How supplied: Vials (10mL)–12

VALCHLOR Actelion

℞

Nitrogen mustard. Mechlorethamine 0.016%; topical gel; contains propylene glycol, isopropyl alcohol. Indications: Treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy. Adults: Apply a thin film once daily to affected areas of the skin. Apply to completely dry skin ≥4 hours before or 30 minutes after showering or washing. Allow treated areas to completely dry for 5–10 minutes after applying. Wash hands thoroughly after application. Discontinue if any grade of skin ulceration, blistering, or moderately-to-severe, or severe dermatitis occur; restart at reduced frequency of once every 3 days upon improvement; if reintroduction is tolerated for at least 1 week, can increase to every other day for 1 week and then once daily if tolerated. Children: Not established. Warnings/Precautions: Mucosal (oral, nasal) or eye exposure; blindness and severe irreversible anterior eye injury may occur; immediately irrigate for ≥15 minutes with copious amounts of water. Secondary exposure; avoid direct skin contact with patient. Risk of dermatitis (eg, face, genitalia, anus, and intertriginous skin); monitor for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections. Monitor for nonmelanoma skin cancer during and after treatment. Flammable (avoid fire and flame until gel has dried). Pregnancy (Category D); may cause fetal harm. Nursing mothers: not recommended. Adverse reactions: Dermatitis, pruritus, bacterial skin infection, skin ulceration or blistering, hyperpigmentation. How supplied: Gel–60g

VELCADE Millennium

℞

Proteasome inhibitor. Bortezomib 3.5mg/vial; lyophilized pwd for IV or SC inj after reconstitution; contains mannitol. Indications: Multiple myeloma. Mantle cell lymphoma. Adults: Give as a 3–5 second IV bolus inj or as SC inj into thigh or abdomen (rotate sites). Previously untreated multiple myeloma: Treat for nine 6-week cycles in combination with oral melphalan and oral prednisone. Cycles 1–4: 1.3mg/m2 twice weekly (Days 1, 4, 8, 11, 22, 25, 29, 32); Cycles 5–9: 1.3mg/m2 once weekly (Days 1, 8, 22, 29). Previously untreated mantle cell lymphoma: Treat for six 3-week cycles in combination with IV rituximab, cyclophosphamide, doxorubicin, and oral prednisone. 1.3mg/m2 twice weekly for 2 weeks (Days 1, 4, 8, 11) then 10 day rest period (Days 12–21); if response first documented at Cycle 6, two more cycles are recommended. Relapsed multiple myeloma or mantle cell lymphoma: Standard schedule: 1.3mg/m2 twice weekly for 2 weeks (Days 1, 4, 8, 11) then 10 day rest period (Days 12–21); Extended therapy (if using >8 cycles): may use standard schedule, or maintenance schedule: 1.3mg/m2 once weekly for 4 weeks (Days 1, 8, 15, 22) then 13-day rest period (Days 23–35). Multiple myeloma patients who have previously responded to bortezomib (alone or in combination) and have relapsed at least 6 months after completing prior bortezomib therapy: may retreat starting at last tolerated dose, given twice weekly every 3 weeks (Days 1, 4, 8, 11); max 8 cycles. Allow at least 72hrs between consecutive doses. May be given as a single agent or in combination with dexamethasone. Dose modifications: see full labeling. SC inj may be considered for patients with pre-existing or at high-risk of peripheral neuropathy. Moderate-tosevere hepatic impairment: reduce to 0.7mg/m2 in 1st cycle; may consider dose increase to 1mg/m2 or further decrease to 0.5mg/m2 in subsequent cycles based on tolerance. Children: Not established. Contraindications: Boron or mannitol sensitivity. Intrathecal administration. Warnings/Precautions: Hepatic impairment. Pre-existing severe neuropathy; treat only after careful risk-benefit assessment. Monitor for development or worsening of peripheral neuropathy; consider dose and/or schedule adjustment. Diabetes (closely monitor blood glucose). History of syncope. Avoid dehydration; give fluids and electrolytes. Heart disease (monitor for CHF). Interrupt therapy and evaluate if new or worsening cardiopulmonary symptoms develop. Monitor CBC frequently during therapy and platelets prior to each dose; adjust dose/schedule for thrombocytopenia (see full labeling). Monitor for toxicities. High tumor burden (monitor for tumor lysis syndrome). Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER Interactions: Concomitant strong CYP3A4 inducers (eg, rifampin): not recommended; efficacy may be reduced. Avoid St. John’s Wort. Potentiated by strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir); consider reducing bortezomib dose. Caution with hypotensives and hypoglycemics. Adverse reactions: GI toxicity (eg, nausea, diarrhea, constipation, vomiting; interrupt therapy if severe), thrombocytopenia, neutropenia, anemia, leukopenia, lymphopenia, peripheral neuropathy, fatigue, neuralgia, rash, pyrexia, anorexia, asthenia, herpes reactivation, insomnia, dyspnea, paresthesia, headache, decreased appetite, dizziness, blurred vision, edema, arthralgia, pain, dysesthesia, psychiatric disorders, cough, pruritus, orthostatic hypotension, CHF, decreased LVEF, hepatotoxicity; rare: posterior reversible encephalopathy syndrome (discontinue if occurs). How supplied: Single-dose vial–1

VESANOID Roche

℞

Retinoid. Tretinoin 10mg; soft gelatin caps; contain parabens. Indications: Induction of remission in patients with acute promyelocytic leukemia (APL), French-American-British (FAB) classification M3 (including the M3 variant), characterized by the presence of the t(15;17) translocation and/or the presence of the PML/RARα gene who are refractory to, or who have relapsed from, anthracycline chemotherapy, or for whom anthracycline-based chemotherapy is contraindicated. Adults: Use only for induction of remission. 45mg/m2 per day in two divided doses until complete remission is documented. Discontinue 30 days after complete remission or after 90 days of treatment, whichever occurs first. Children: See literature. Warnings/Precautions: Confirm APL diagnosis. Monitor for Retinoic Acid-APL (RA-APL) syndrome, leukocytosis, pseudotumor cerebri, or respiratory compromise. Consider temporarily interrupting therapy if moderate to severe RA-APL syndrome develops. Monitor blood counts, coagulation profile, lipids, liver function; consider temporary withdrawal if tests >5×ULN. Pregnancy (Cat.D); obtain negative pregnancy test 1 week before starting treatment, counsel patient about need to use 2 effective methods of contraception during, and 1 month after therapy. Nursing mothers: not recommended. Interactions: Do not administer with Vitamin A. May be potentiated or antagonized by CYP450 enzyme inducers or inhibitors. Caution with anti-fibrinolytic agents; and other agents known

to cause pseudotumor cerebri/intracranial hypertension. Adverse reactions: Headache, fever, skin/ mucous membrane dryness, bone pain, GI upset, rash, mucositis, pruritus, increased sweating, visual disturbances, alopecia; RA-APL syndrome, leukocytosis, pseudotumor cerebri, hypercholesterolemia/hypertriglyceridemia, others. How supplied: Caps–100

VIDAZA Celgene

℞

Cytidine analogue. Azacitidine 100mg/vial; lyophilized pwd for SC inj after reconstitution or IV inj after reconstitution and dilution; contains mannitol; preservative-free. Indications: Myelodysplastic syndromes (refractory anemias, chronic myelomonocytic leukemia). Adults: Premedicate for nausea & vomiting. Initially 75mg/m2 SC (doses >4mL divide equally into 2 syringes and inject into 2 separate sites) or IV (infuse over 10–40 mins, must complete within 1hr of reconstitution) daily for 7 days; repeat cycle every 4 weeks. May increase to 100mg/m2 after 2 cycles if no response and no toxicity. Treat for at least 4–6 cycles. Adjust subsequent doses on blood counts and toxicities (eg, neutropenia, thrombocytopenia, decreased serum bicarbonate). Children: Not established. Contraindications: Advanced malignant hepatic tumors. Warnings/Precautions: Renal or hepatic impairment. High tumor burden. Obtain CBC counts before each dosing cycle and as needed. Monitor serum bicarbonate and renal and hepatic function (do baseline liver chemistries and serum creatinine). Elderly. Pregnancy (Cat.D); use appropriate contraception (both men and women). Nursing mothers: not recommended. Adverse reactions: Nausea, vomiting, diarrhea, blood dyscrasias (esp. anemia, thrombocytopenia, neutropenia, leukopenia), fever, fatigue, inj site reactions, constipation, ecchymosis, petechiae, rigors, dyspnea, arthralgia, headache, anorexia, renal failure/ tubular acidosis, hypokalemia, hepatic coma, others (see full labeling). How supplied: Single-use vial–1

VUMON Bristol-Myers Squibb

℞

Topoisomerase inhibitor. Teniposide 10mg/mL; soln for IV infusion after dilution; contains benzyl alcohol, Cremophor EL (polyoxyethylated castor oil), dehydrated alcohol. Indications: Refractory childhood acute lymphoblastic leukemia.

Adults and Children: See literature. Give as slow IV infusion (at least 30–60 minutes). Patients failing induction therapy with a cytarabine-containing regimen: 165mg/m2 + cytarabine twice weekly for 8 to 9 doses. Refractory to vincristine/prednisone-containing regimen: 250mg/m2 + vincristine weekly for 4 to 8 weeks + oral prednisone for 28 days. Warnings/Precautions: Severe myelosuppression. Monitor for hypersensitivity reactions following infusion; have epinephrine available. Risk of hypotension with rapid IV administration. Hepatic dysfunction. Monitor and obtain CBCs with differential, hemoglobin, platelets, renal and hepatic functions before, during, and after therapy. Down syndrome (use reduced dose). Monitor children with hypoalbuminemia. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Potentiated by tolbutamide, sodium salicylate, and sulfamethizole. Concomitant vincristine sulfate may cause neuropathy. Concomitant antiemetics in patients given high doses of teniposide may increase risk of CNS depression, hypotension. Adverse reactions: Myelosuppression (leukopenia, neutropenia, thrombocytopenia, anemia), mucositis, GI upset, infection, alopecia, bleeding, rash, fever, hypotension, CNS depression, hypersensitivity reactions (may be fatal). How supplied: Ampules (5mL)–1

ZEVALIN Spectrum

℞

Radionuclide (B-lymphocyte-restricted differentiation antigen [CD20] inhibitor). Ibritumomab tiuxetan 3.2mg/2mL; soln for IV inj; contains albumin; preservative-free. Indications: B-cell non-Hodgkin’s lymphoma (relapsed or refractory, low grade or follicular). Previously untreated follicular non-Hodgkin’s lymphoma in patients who achieve a partial or complete response to first-line chemotherapy. Adults: See literature. Prepare In-111 Zevalin and Y-90 Zevalin as directed. Initiate Zevalin therapy after recovery of platelets to ≥150000/mm3 at least 6 weeks, but no more than 12 weeks, after the last dose of first-line chemotherapy. Administered in two steps. Step 1: Single infusion of rituximab followed by a fixed dose of 5mCi (1.6mg total antibody dose) of In-111 Zevalin given as a 10-minute IV push. Step 2 (7–9 days after Step 1): Second rituximab infusion followed by 0.4mCi/kg of Y-90 Zevalin given as a 10-minute IV push; if platelet count 100000–149000cells/mm3, reduce dose to 0.3 mCi/kg. Do not treat if platelets <100000cells/mm3. Max Y-90 Zevalin dose: 32mCi. Children: Not recommended.

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DRUG MONOGRAPHS

HEMATOLOGIC CANCER Contraindications: Hypersensitivity to murine proteins. Warnings/Precautions: See literature. Use only if trained in radionuclide therapy. Do not treat patients with altered biodistribution. ≥25% lymphoma marrow involvement and/or impaired bone marrow reserve (eg, prior myeloablative therapies, platelet count <100000cells/mm3, neutrophil count <1500cells/mm3), or history of failed stem cell collection: not recommended. Monitor for cytopenias and complications (eg, febrile neutropenia, hemorrhage) for up to 3 months after treatment. Obtain CBCs, platelets weekly until levels recover. Avoid extravasation. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Caution with anticoagulants, platelet aggregation inhibitors, or live viral vaccines. Separate growth factor treatment by 2 weeks before and after Zevalin therapy. Adverse reactions: Neutropenia, leukopenia, thrombocytopenia, anemia, infections, asthenia, musculoskeletal symptoms, GI upset, abdominal pain, fatigue, nasopharyngitis, cough, dizziness, hemorrhage, altered biodistribution; infusion reactions, severe cutaneous/mucocutaneous reactions: both may be fatal, discontinue if occurs; leukemia and myelodysplastic syndrome. Note: Indium-11 chloride sterile solution must be ordered separately at the time the In-11 Zevalin kit is ordered. Yttrium-90 chloride sterile solution will be shipped directly upon placement of order for Y-90 Zevalin kit. How supplied: In-111 Zevalin kit (ibritumomab tiuxetan 3.2mg/2mL vial + sodium acetate vial + formulation buffer vial + empty reaction vial)–1 Y-90 Zevalin kit (ibritumomab tiuxetan 3.2mg/2mL vial + sodium acetate vial + formulation buffer vial + empty reaction vial)–1

ZOLINZA Merck

℞

Histone deacetylase inhibitor. Vorinostat 100mg; caps. Indications: Refractory cutaneous T-cell lymphoma. Adults: Take with food. Swallow whole. 400mg once daily. If not tolerated, may reduce to 300mg once daily, then to 300mg once daily 5 days/week if needed. Continue until disease progression or not tolerated. Children: <18yrs: not recommended. Warnings/Precautions: Renal or hepatic impairment. Monitor for DVT, pulmonary embolism. Correct electrolyte disturbances before starting therapy. Maintain adequate hydration. Diabetes. Monitor CBC, platelets, blood glucose, serum creatinine, electrolytes (esp. potassium, calcium, magnesium) every 2 weeks for 1st 2 months, then monthly. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Increased risk of thrombocytopenia and GI bleed with other HDAC inhibitors (eg, valproic acid). Concomitant warfarin: monitor PT, INR.

Adverse reactions: GI upset, fatigue, chills; thrombocytopenia, anemia (may need to modify dose or discontinue); anorexia, dysgeusia, pulmonary embolism, DVT, hyperglycemia. How supplied: Caps–120

ZOMETA Novartis

℞

Bisphosphonate. Zoledronic acid 4mg/5mL concentrated soln for IV infusion after dilution; 4mg/100mL ready-to-use soln for IV infusion. Indications: Adjunct in multiple myeloma and bone metastases of solid tumors. Limitation of use: not established for use in hyperparathyroidism or nontumor-related hypercalcemia. Adults: Give by IV infusion over at least 15 minutes. CrCl >60mL/min: 4mg; CrCl 50–60mL/min: 3.5mg; CrCl 40–49mL/min: 3.3mg; CrCl 30–39mL/min: 3mg; CrCl <30mL/min: see full labeling; all: every 3–4 weeks (give oral multivitamin supplement with calcium 500mg + Vit. D 400 IU daily). Children: Not recommended. Warnings/Precautions: Not recommended for use in patients with bone metastases with severe renal impairment. Renal or hepatic insufficiency. Check serum creatinine before each dose: withhold until serum creatinine is within 10% of baseline if serum creatinine increases by 0.5 mg/dL from a normal pre-treatment level, or by 1 mg/dL from an abnormal pre-treatment level, within 2 weeks of next dose. Assure adequate hydration when treating hypercalcemia of malignancy. Correct hypocalcemia before initiating treatment; supplement with calcium and vitamin D. Closely monitor electrolytes (esp. calcium, magnesium, phosphate), CBC/ differential, hematocrit, hemoglobin. Evaluate if thigh or groin pain develops and consider discontinuing if atypical femur fracture is suspected. Aspirin-sensitive asthma. Avoid dental surgery (do preventative dental work before therapy). Elderly. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Avoid concomitant other bisphosphonates. Additive hypocalcemic effect with aminoglycosides, loop diuretics. Caution with other nephrotoxic drugs (eg, thalidomide). Adverse reactions: Nausea, fatigue, anemia, musculoskeletal pain (discontinue if severe), constipation, fever, vomiting, dyspnea, flu-like syndrome, electrolyte disturbances, hypotension, CNS effects, rigors, headache, paresthesia, renal toxicity; jaw osteonecrosis, atypical subtrochanteric, diaphyseal femoral fractures, severe hypocalcemia. How supplied: Single-use vial, ready-to-use bottle–1

ZYDELIG Gilead

℞

Phosphatidylinositol 3-kinase inhibitor. Idelalisib 100mg, 150mg; tabs. Indications: Relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab,

in patients for whom rituximab alone would be considered appropriate due to other co-morbidities. Relapsed follicular B-cell nonHodgkin lymphoma (FL) in patients who have received at least 2 prior systemic therapies. Relapsed small lymphocytic lymphoma (SLL) in patients who have received at least 2 prior systemic therapies. Adults: Swallow whole. ≥18yrs: initially 150mg twice daily; continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling. Children: <18yrs: not established. Contraindications: History of serious allergic reactions including anaphylaxis and toxic epidermal necrolysis. Warnings/Precautions: Risk of fatal/ serious hepatotoxicity: monitor ALT/AST every 2 weeks for the first 3 months, every 4 weeks for the next 3 months, then every 1–3 months thereafter; if ALT/AST >3×ULN, monitor weekly until resolved; if ALT/AST >5×ULN, withhold and continue monitoring weekly until resolved. Monitor for diarrhea or colitis; withhold if severe and discontinue if lifethreatening. Risk of fatal/serious pneumonitis; monitor for pulmonary symptoms, interstitial infiltrates, or a decline by >5% in oxygen saturation; if suspected, interrupt or discontinue as indicated. Risk of fatal/serious intestinal perforation; discontinue permanently if occurs. Monitor for severe cutaneous or serious allergic reactions; discontinue if occur. Monitor CBCs at least every 2 weeks for the first 3 months, and at least weekly if neutrophils <1.0Gi/L. Pregnancy (Cat.D); avoid. Use effective contraception during treatment and for at least 1 month after last dose. Nursing mothers: not recommended. Interactions: Avoid concomitant drugs that may cause hepatotoxicity or diarrhea. Avoid concomitant strong CYP3A inducers (eg, rifampin, phenytoin, St. John’s wort, carbamazepine) or CYP3A substrates (eg, oral midazolam). Concomitant strong CYP3A inhibitors (eg, ketoconazole); monitor for idelalisib toxicity. Adverse reactions: Diarrhea, pyrexia, fatigue, nausea, cough, pneumonia, abdominal pain, chills, rash, neutropenia, hypertriglyceridemia, hyperglycemia, ALT/AST elevations. How supplied: Tabs–60

ADVERSE REACTIONS Those adverse reactions listed within product monographs represent the potential for adverse effects based upon the active ingredient(s) and/or the drug class. It is not meant to be an inclusive list of responses.

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DRUG MONOGRAPHS

LUNG CANCER ABRAXANE Celgene

℞

Taxane antimicrotubule. Paclitaxel [bound to albumin (human)] 100mg/vial; pwd for IV infusion after reconstitution; solvent-free. Indications: First-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC), in combination with carboplatin, in patients who are not candidates for curative surgery or radiation therapy. Adults: Do not treat if neutrophil count <1,500 cells/mm3 or platelets <100,000 cells/mm3. In combination with carboplatin: 100mg/m2 IV over 30 minutes on Days 1, 8, and 15 of each 21-day cycle. Dose reductions for hematologic and neurologic adverse reactions, hepatic impairment: see full labeling. Avoid extravasation. Children: Not evaluated. Contraindications: Baseline neutrophil count <1,500 cells/mm3. Prior severe hypersensitivity reaction (do not rechallenge). Warnings/Precautions: Do not substitute for, or with, other paclitaxel products (due to formulation differences). Do frequent complete blood cell counts. Monitor for sensory neuropathy, sepsis, or pneumonitis. Hepatic or renal dysfunction. Contains human albumin; remote risk of viral transmission. Use appropriate contraception (men and women). Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: May potentiate or be potentiated by CYP2C8 and/or CYP3A4 inducers (eg, rifampin, carbamazepine, phenytoin, efavirenz, nevirapine) and/or inhibitors (eg, ketoconazole, other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, nelfinavir). Adverse reactions: Bone marrow suppression (eg, neutropenia, anemia), infections, alopecia, sensory neuropathy (may require dose reduction or interruption), peripheral neuropathy, GI upset, mucositis, fatigue/asthenia, myalgia/arthralgia, abnormal ECG; alkaline phosphatase or AST elevation; dyspnea, edema, hypotension, rash (may be serious); rare: thrombotic events. How supplied: Single-use vial–1

ALIMTA Lilly

℞

Antifolate. Pemetrexed 100mg/vial, 500mg/vial; pwd for IV inj after reconstitution and dilution; preservative-free. Indications: Locally advanced or metastatic nonsquamous non-small cell lung cancer (NSCLC): in combination with cisplatin as initial treatment, or as maintenance in patients whose disease has not progressed after 4 cycles of platinum-based 1st-line chemotherapy; or as a single agent after prior chemotherapy. Malignant

pleural mesothelioma (MPM): in combination with cisplatin in patients whose disease is either unresectable or who are otherwise not candidates for curative surgery. Limitations of use: not for the treatment of squamous cell NSCLC. Adults: See full labeling. 500mg/m2 by IV infusion over 10 mins on Day 1 of each 21-day cycle. Adjust dose if toxicity (esp. myelosuppression) develops. Combination therapy: Give cisplatin beginning 30 mins after pemetrexed infusion. Supplement with oral folic acid and intramuscular vitamin B12 prior to initiating pemetrexed and continue during treatment. Pretreat with corticosteroid the day before, the day of, and day after pemetrexed. Children: Not recommended. Warnings/Precautions: See full labeling. Renal impairment (CrCl <45mL/min): not recommended. Discontinue if Grade 3 or 4 neurotoxicity occurs, or if any Grade 3 or 4 toxicity occurs after two dose reductions. Do not start a treatment cycle unless ANC is ≥1500cells/mm3, platelets ≥100,000cells/mm3 and CrCl ≥45mL/min. Hepatic impairment. Monitor CBCs, platelets, renal and hepatic function. Clinically significant third space fluid: consider draining effusion first. Pregnancy (Cat.D); avoid, use effective contraception. Nursing mothers: not recommended. Interactions: May be potentiated by nephrotoxic agents, drugs eliminated by renal tubular secretion (eg, probenecid). Concomitant NSAIDs: use caution in patients with mild to moderate renal insufficiency (esp. ibuprofen). Adverse reactions: Fatigue, nausea, anorexia, vomiting, stomatitis, pharyngitis, constipation, fever, infection with neutropenia, rash, desquamation, neutropenia, leukopenia, anemia, thrombocytopenia, elevated creatinine, chest pain, neuropathy; rare: renal failure. Testing considerations: TS (thymidylate synthase) expression for response and toxicity How supplied: Single-use vial–1

AVASTIN Genentech

CYRAMZA Lilly ℞

Angiogenesis inhibitor. Bevacizumab 100mg, 400mg; per vial; soln for IV infusion after dilution; preservative-free. Indications: First-line treatment of unresectable, locally advanced, recurrent or metastatic nonsquamous, non-small cell lung cancer (NSCLC), in combination with carboplatin and paclitaxel. Adults: Give by IV infusion. Infuse 1st dose over 90 mins; if tolerated, infuse 2nd dose over 60 mins, and subsequent doses over 30 mins. 15mg/kg every 3 weeks with carboplatin/ paclitaxel. Children: Not established.

℞

Human IgG1 monoclonal antibody. Ramucirumab 10mg/mL; per vial; soln for IV infusion after dilution; preservative-free. Indications: In combination with docetaxel, for treatment of metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy; patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDAapproved therapy prior to initiation. Adults: Give by IV infusion over 60 mins. Premedicate with IV histamine H1-antagonist (eg, diphenhydramine) prior to each infusion; or with dexamethasone and acetaminophen in

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DRUG MONOGRAPHS

LUNG CANCER those who have experienced Grade 1 or 2 infusion reaction. 10mg/kg on Day 1 of a 21-day cycle prior to docetaxel; continue until disease progression or unacceptable toxicity. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Increased risk of hemorrhage; permanently discontinue if severe bleeding occurs. Control hypertension prior to initiating. Monitor blood pressure every 2 weeks or more frequently as indicated; if severe hypertension develops, temporarily suspend until medically controlled. Monitor for infusionrelated reactions during therapy. Have emergency resuscitative equipment available. Permanently discontinue if severe arterial thromboembolic events, severe uncontrolled hypertension (despite antihypertensives), hypertensive crisis or encephalopathy, Grade 3 or 4 infusion-related reactions, urine protein >3g/24hrs, nephrotic syndrome, or GI perforation occurs. Impaired wound healing: withhold Cyramza prior to surgery. Clinical deterioration in patients with Child-Pugh B or C cirrhosis (eg, new or worsening encephalopathy, ascites, hepatorenal syndrome). Discontinue if reversible posterior leukoencephalopathy syndrome develops. Pregnancy (Cat.C); avoid; use effective contraception during therapy and for ≥3 months after completion. Nursing mothers: not recommended. Adverse reactions: Hypertension, diarrhea, headache, fatigue, hyponatremia, anemia, intestinal obstruction, neutropenia, epistaxis, stomatitis/mucosal inflammation, rash, arterial thromboembolic events, proteinuria, GI perforation, infusion-related reactions. How supplied: Single-dose vial (10mL, 50mL)–1

Etoposide Capsules (various)

℞

Topoisomerase inhibitor. Etoposide 50mg; contain parabens. Indications: Small cell lung cancer. Adults: Round dose to nearest 50mg increment. Range: 70mg/m2 per day for 4 days to 100mg/m2 per day for 5 days. Repeat course every 3 to 4 weeks after recovery (esp myelosuppression). Renal impairment (CrCl ≤50mL/min): reduce dose (see literature). Consider dose reduction with existing myelosuppression due to previous radiation or chemotherapy. Children: Not recommended. Warnings/Precautions: Monitor blood (esp CBC/differential, platelets, hemoglobin) before each cycle and during therapy; renal function. Withhold dose if platelet count <50,000/mm3 or ANC <500/mm3. Hypoalbuminemia. Elderly. Pregnancy (Cat.D); nursing mothers: not recommended. Interactions: Potentiated by cyclosporine. Additive toxicity with radiation, other cytotoxic therapies. Adverse reactions: GI upset, mucositis, myelosuppression (esp. neutropenia, thrombocytopenia; may be fatal), alopecia, fever,

infections, peripheral neurotoxicity; hypersensitivity reactions, acute leukemia (rare); others. How supplied: Contact supplier.

GILOTRIF Boehringer Ingelheim

℞

Tyrosine kinase inhibitor. Afatinib 20mg, 30mg, 40mg; tabs. Indications: First-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitutions as detected by an FDAapproved test. Limitations of use: safety and efficacy of Gilotrif have not been established in patients whose tumors have other EGFR mutations. Adults: Take on an empty stomach at least 1 hour before or 2 hours after a meal. 40mg once daily until disease progression or not tolerated. Concomitant P-gp inhibitors: reduce afatinib daily dose by 10mg if not tolerated; resume previous dose after discontinuing the P-gp inhibitor. Concomitant P-gp inducers: increase afatinib by 10mg as tolerated; resume previous dose 2–3 days after discontinuing the P-gp inducer. Dose modification: see full labeling. Children: Not established. Warnings/Precautions: Permanently discontinue for life-threatening bullous, blistering, or exfoliative skin lesions, confirmed interstitial lung disease, severe drug-induced hepatic impairment, persistent ulcerative keratitis, symptomatic left ventricular dysfunction, or severe/intolerable adverse reactions (at dose 20mg/day). Withhold for severe or prolonged diarrhea Grade ≥2 lasting for ≥2 consecutive days while taking antidiarrheal, prolonged cutaneous reaction Grade ≥2 (lasting >7 days) or intolerable, renal dysfunction Grade ≥2, or worsening liver function. History of keratitis, ulcerative keratitis, or severe dry eye. Monitor closely in moderate-to-severe renal impairment or severe hepatic impairment; adjust dose if not tolerated. Embryofetal toxicity: females of reproductive potential should use highly effective contraception during treatment and for at least 2 weeks after last afatinib dose. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Potentiated by P-gp inhibitors (eg, ritonavir, cyclosporine A, ketoconazole, itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir, amiodarone). Antagonized by P-gp inducer (eg, rifampicin, carbamazepine, phenytoin, phenobarbital, St. John’s wort). Adverse reactions: Diarrhea, rash/dermatitis acneiform, stomatitis, paronychia, dry skin, decreased appetite, pruritus. How supplied: Tabs–30

HYCAMTIN GlaxoSmithKline

℞

Topoisomerase inhibitor. Topotecan (as HCl) 4mg/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free. Indications: Small cell lung cancer sensitive disease after failure of 1st line chemotherapy. Adults: Confirm baseline neutrophils >1,500cells/mm3 and platelets >100,000cells/mm3

prior to 1st course of therapy. Give by IV infusion over 30 minutes. 1.5mg/m2 daily for 5 consecutive days starting on Day 1 of a 21-day cycle. Dose adjustments, renal impairment: see literature. Children: Not recommended. ℞ Also: HYCAMTIN CAPSULES Topotecan (as HCl) 0.25mg, 1mg; caps. Indications: Relapsed small cell lung cancer with prior complete or partial response and at least 45 days from the end of 1st line chemotherapy. Adults: Confirm baseline neutrophils >1,500cells/mm3 and platelets >100,000cells/mm3 prior to 1st course of therapy. Swallow whole. 2.3mg/m2/day once daily for 5 consecutive days; repeat every 21 days. Dose adjustments, renal impairment: see literature. Children: Not recommended. Contraindications: Severe bone marrow depression. Pregnancy (Cat.D). Nursing mothers. Warnings/Precautions: Monitor peripheral blood cell counts during therapy; hold subsequent doses until neutrophils >1,000cells/mm3, platelets >100,000cells/mm3, and hemoglobin ≥9g/dL. History of interstitial lung disease, pulmonary fibrosis, lung cancer, thoracic exposure to radiation, use of pneumotoxic drugs and/or colony stimulating factors: increased risk of interstitial lung disease; monitor, discontinue if occurs. Moderate to severe renal impairment. Caps: severe diarrhea; may need to reduce dose. IV: avoid extravasation. Elderly. Interactions: Myelosuppression potentiated with platinum agents. IV: Neutropenia potentiated by G-CSF. Caps: Avoid concomitant P-glycoprotein inhibitors (eg, cyclosporine A, elacridar, ketoconazole, ritonavir, saquinavir). Adverse reactions: See literature. Neutropenia, leukopenia, thrombocytopenia, anemia, GI upset, anorexia, abdominal pain, stomatitis, headache, dyspnea, cough, pyrexia, alopecia, fatigue; infection, sepsis, interstitial lung disease, neutropenic colitis (may be fatal). How supplied: Single-use vials–1, 5 Caps–10

MUSTARGEN Recordati

℞

Nitrogen mustard. Mechlorethamine HCl 10mg/vial; pwd for IV or intracavitary inj after reconstitution. Indications: Palliative treatment of bronchogenic carcinoma. Adults: By IV infusion, per therapeutic course: 0.4mg/kg (lean body weight) as single dose or in divided doses of 0.1–0.2mg/kg per day. See literature for intracavitary (eg, intrapleural) administration. Do not exceed recommended dose. Repeat course only after hematological recovery (eg, every 3 weeks). Children: See literature. Contraindications: Infectious diseases. Warnings/Precautions: Drug is highly toxic; verify potential benefits outweigh risks; avoid inadvertent contact with powder or vapor. Do not use if foci of acute and chronic suppurative

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B:8.75 in T:8.5 in S:7 in

DID YOU KNOW?

CLIENT: Lilly 27020_ELRALU_NowApproved_LUNG_JournAd_Sprd_SnglPg_A_M14.indd 1 JOB#: ELRALU 27020

FINISH SIZE: 17” wide x 10.875” high

LOCATION: Mechanicals

COLLECT DATE:

R|O|U|T|I|N|G| |S|T|A|G|E ED

1/6/15 5:30 PM

ARTIST: MC, DL

M14 C PM

ACD

ins er v

B:11.25 in

NSCLC=non-small cell lung cancer.

T:10.875 in

S:9.625 in

SINCE THE APPROVAL OF DOCETAXEL IN 1999, NO SECOND-LINE REGIMEN HAS EXTENDED OVERALL SURVIVAL VERSUS DOCETAXEL ACROSS A BROAD POPULATION OF METASTATIC NSCLC PATIENTS1-3

B:8.75 in

T:8.5 in

S:7 in

CYRAMZA PLUS DOCETAXEL DEMONSTRATED A STATISTICALLY SIGNIFICANT IMPROVEMENT IN OVERALL SURVIVAL VS DOCETAXEL4

NEW FDA APPROVAL

OVERALL SURVIVAL: MEDIAN - MONTHS (95% CI) CYRAMZA (ramucirumab), in combination with docetaxel, is indicated for the treatment of patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Patients with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. ®

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)4

15% INCREASE IN MEDIAN OS

MONTHS

(9.5, 11.2) Hazard Ratio (95% CI)=0.86 (0.75, 0.98); P=0.024

0.6

CYRAMZA + docetaxel

0.4

Placebo + docetaxel

9.1

0.2

Placebo + docetaxel (n=625)

MONTHS (8.4, 10.0)

0.0 0

CYRAMZA is the first antiangiogenic agent FDA approved in combination with docetaxel for the second-line treatment of metastatic NSCLC, including nonsquamous and squamous histologies.4

10.5

0.8

OS PROBABILITY

ADVANCING THE SECONDLINE TREATMENT OF METASTATIC NSCLC4

CYRAMZA + docetaxel (n=628)

1.0

MAJOR OUTCOME MEASURE

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

• The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively 4

527

415

329

231

156

103

501

386

306

197

129

• Median PFS with CYRAMZA plus docetaxel was 4.5 months (95% CI: 4.2, 5.4) vs 3.0 months (95% CI: 2.8, 3.9) with placebo plus docetaxel (hazard ratio 0.76 [95% CI: 0.68, 0.86]; P<0.001) — The percentage of events at the time of analysis was 89% (558 patients) and 93% (583 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively • ORR with CYRAMZA plus docetaxel was 23% (95% CI: 20, 26) vs 14% (95% CI: 11, 17) with placebo plus docetaxel (P<0.001)* CI=confidence interval; OS=overall survival; PFS=progressionfree survival; ORR=objective response rate. *ITT population. Disease progression and tumor response were assessed by investigators in accordance with Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.5 ORR is defined as complete plus partial response.

REVEL TRIAL DESIGN (N=1253)

Hemorrhage • CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 3, which evaluated CYRAMZA plus docetaxel in metastatic non-small cell lung cancer (NSCLC), the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDs or other antiplatelet therapy other than once-daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events • Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension • An increased incidence of severe hypertension occurred in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every 2 weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with

27020_ELRALU_NowApproved_LUNG_JournAd_Sprd_SnglPg_A_M14.indd 2-3

Infusion-Related Reactions • Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including 2 severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations • CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel versus 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing • CYRAMZA has not been studied in patients with serious or nonhealing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume CYRAMZA following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Child-Pugh B or C Cirrhosis • Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome, was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with ChildPugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.

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Reversible Posterior Leukoencephalopathy Syndrome (RPLS) • RPLS has been reported at a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death.

Most Common Adverse Reactions

• The most commonly reported adverse reactions (all grades; Grade 3/4) occurring in ≥5% of patients receiving CYRAMZA plus docetaxel and ≥2% higher than placebo plus docetaxel in Study 3 were neutropenia (55% vs 46%; 49% vs 40%), fatigue/asthenia (55% vs 50%; 14% vs 11%), stomatitis/mucosal inflammation (37% vs 19%; 7% vs 2%), epistaxis (19% vs 7%; <1% vs <1%), febrile neutropenia (16% vs 10%; 16% vs 10%), peripheral edema (16% vs 9%; 0% vs <1%), thrombocytopenia (13% vs 5%; 3% vs <1%), lacrimation increased (13% vs 5%; <1% vs 0%), and hypertension (11% vs 5%; 6% vs 2%). • The most common serious adverse events with CYRAMZA plus docetaxel in Study 3 were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colonystimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. • Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%). • Clinically relevant adverse reactions reported in ≥1% and <5% of CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel).

Drug Interactions

• No pharmacokinetic interactions were observed between ramucirumab and docetaxel.

Use in Specific Populations

• Pregnancy Category C: Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant, including use of adequate contraception, while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. Animal models link angiogenesis, VEGF and VEGF Receptor 2 to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. • Nursing Mothers: It is recommended to discontinue nursing or discontinue CYRAMZA due to the potential risks to the nursing infant. • Females of Reproductive Potential: Advise females of reproductive potential that CYRAMZA may impair fertility. Please see Brief Summary of Prescribing Information for CYRAMZA, including Boxed Warning for hemorrhage, on the next page. RB-L HCP ISI 17DEC2014 References: 1. Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomized controlled trial. Lancet Oncol. 2014;15:143-155. 2. Supplement to: Reck M, Kaiser R, Mellemgaard A, et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double-blind, randomized controlled trial. Lancet Oncol. 2014;15:143-155. 3. National Cancer Institute. Cancer drug information. FDA approval for docetaxel. http://www.cancer.gov/cancertopics/druginfo/ fda-docetaxel/print. Accessed August 26, 2014. 4. CYRAMZA (ramucirumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014. 5. Garon EB, Ciuleanu T-E, Arrieta O, et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014;384(9944):665-673.

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Warnings and Precautions

antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

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VISIT www.CYRAMZAHCP.com

IMPORTANT SAFETY INFORMATION FOR CYRAMZA WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding.

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The phase III REVEL trial evaluated the efficacy and safety of CYRAMZA plus docetaxel vs placebo plus docetaxel in patients with metastatic NSCLC with disease progression on or after platinum-based chemotherapy. Major efficacy outcome measure was OS. Supportive efficacy outcome measures were PFS and ORR. All patients were required to have Eastern Cooperative Oncology Group performance status 0 or 1. Patients were randomized 1:1 (N=1253) to receive either CYRAMZA 10 mg/kg or placebo, in combination with docetaxel at 75 mg/m2 every 21 days.4

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CYRAMZA PLUS DOCETAXEL DEMONSTRATED A STATISTICALLY SIGNIFICANT IMPROVEMENT IN OVERALL SURVIVAL VS DOCETAXEL4

NEW FDA APPROVAL

Demonstrated improvements across all three efficacy outcomes (OS, PFS, ORR)4

15% INCREASE IN MEDIAN OS

MONTHS

(9.5, 11.2) Hazard Ratio (95% CI)=0.86 (0.75, 0.98); P=0.024

0.6

CYRAMZA + docetaxel

0.4

Placebo + docetaxel

9.1

0.2

Placebo + docetaxel (n=625)

MONTHS (8.4, 10.0)

0.0 0

CYRAMZA is the first antiangiogenic agent FDA approved in combination with docetaxel for the second-line treatment of metastatic NSCLC, including nonsquamous and squamous histologies.4

10.5

0.8

OS PROBABILITY

ADVANCING THE SECONDLINE TREATMENT OF METASTATIC NSCLC4

CYRAMZA + docetaxel (n=628)

1.0

MAJOR OUTCOME MEASURE

TIME FROM RANDOMIZATION (MONTHS)

Number at Risk

CYRAMZA + docetaxel 628 Placebo + docetaxel 625

• The percentage of deaths at the time of analysis was 68% (428 patients) and 73% (456 patients) in the CYRAMZA plus docetaxel and placebo plus docetaxel arms, respectively 4

527

415

329

231

156

103

501

386

306

197

129

REVEL TRIAL DESIGN (N=1253)

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Most Common Adverse Reactions

Drug Interactions

• No pharmacokinetic interactions were observed between ramucirumab and docetaxel.

Use in Specific Populations

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Warnings and Precautions

antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.

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CYRAMZA® (ramucirumab) injection BRIEF SUMMARY: For complete safety, please consult the full Prescribing Information. WARNING: HEMORRHAGE CYRAMZA increased the risk of hemorrhage, including severe and sometimes fatal hemorrhagic events. Permanently discontinue CYRAMZA in patients who experience severe bleeding. INDICATIONS AND USAGE Non-Small Cell Lung Cancer: CYRAMZA, in combination with docetaxel, is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hemorrhage CYRAMZA increased the risk of hemorrhage and gastrointestinal hemorrhage, including severe and sometimes fatal hemorrhagic events. In Study 1, the incidence of severe bleeding was 3.4% for CYRAMZA and 2.6% for placebo. In Study 2, the incidence of severe bleeding was 4.3% for CYRAMZA plus paclitaxel and 2.4% for placebo plus paclitaxel. Patients with gastric cancer receiving nonsteroidal anti-inflammatory drugs (NSAIDs) were excluded from enrollment in Studies 1 and 2; therefore, the risk of gastric hemorrhage in CYRAMZA-treated patients with gastric tumors receiving NSAIDs is unknown. In Study 3, the incidence of severe bleeding was 2.4% for CYRAMZA plus docetaxel and 2.3% for placebo plus docetaxel. Patients with NSCLC receiving therapeutic anticoagulation or chronic therapy with NSAIDS or other anti-platelet therapy other than once daily aspirin or with radiographic evidence of major airway or blood vessel invasion or intratumor cavitation were excluded from Study 3; therefore, the risk of pulmonary hemorrhage in these groups of patients is unknown. Permanently discontinue CYRAMZA in patients who experience severe bleeding. Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATEs) including myocardial infarction, cardiac arrest, cerebrovascular accident, and cerebral ischemia occurred in clinical trials including 1.7% of 236 patients who received CYRAMZA as a single agent for gastric cancer in Study 1. Permanently discontinue CYRAMZA in patients who experience a severe ATE. Hypertension An increased incidence of severe hypertension occurred in patients receiving CYRAMZA as a single agent (8%) as compared to placebo (3%) and in patients receiving CYRAMZA plus paclitaxel (15%) as compared to placebo plus paclitaxel (3%) and in patients receiving CYRAMZA plus docetaxel (6%) as compared to placebo plus docetaxel (2%). Control hypertension prior to initiating treatment with CYRAMZA. Monitor blood pressure every two weeks or more frequently as indicated during treatment. Temporarily suspend CYRAMZA for severe hypertension until medically controlled. Permanently discontinue CYRAMZA if medically significant hypertension cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy. Infusion-Related Reactions Prior to the institution of premedication recommendations across clinical trials of CYRAMZA, infusion-related reactions (IRRs) occurred in 6 out of 37 patients (16%), including two severe events. The majority of IRRs across trials occurred during or following a first or second CYRAMZA infusion. Symptoms of IRRs included rigors/tremors, back pain/spasms, chest pain and/or tightness, chills, flushing, dyspnea, wheezing, hypoxia, and paresthesia. In severe cases, symptoms included bronchospasm, supraventricular tachycardia, and hypotension. Monitor patients during the infusion for signs and symptoms of IRRs in a setting with available resuscitation equipment. Immediately and permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Gastrointestinal Perforations CYRAMZA is an antiangiogenic therapy that can increase the risk of gastrointestinal perforation, a potentially fatal event. Four of 570 patients (0.7%) who received CYRAMZA as a single agent in clinical trials experienced gastrointestinal perforation. In Study 2, the incidence of gastrointestinal perforations was also increased in patients that received CYRAMZA plus paclitaxel (1.2%) as compared to patients receiving placebo plus paclitaxel (0.3%). In Study 3, the incidence of gastrointestinal perforation was 1% for CYRAMZA plus docetaxel and 0.3% for placebo plus docetaxel. Permanently discontinue CYRAMZA in patients who experience a gastrointestinal perforation. Impaired Wound Healing CYRAMZA has not been studied in patients with serious or non-healing wounds. CYRAMZA is an antiangiogenic therapy with the potential to adversely affect wound healing. Withhold CYRAMZA prior to surgery. Resume following the surgical intervention based on clinical judgment of adequate wound healing. If a patient develops wound healing complications during therapy, discontinue CYRAMZA until the wound is fully healed. Clinical Deterioration in Patients with Child-Pugh B or C Cirrhosis Clinical deterioration, manifested by new onset or worsening encephalopathy, ascites, or hepatorenal syndrome was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Use CYRAMZA in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration. CYRAMZA® (ramucirumab) injection RB-L HCP BS 17Dec2014

CYRAMZA RB-L HCP BS 17Dec2014 Brief Summary 7 x 10

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with a rate of <0.1% in clinical studies with CYRAMZA. Confirm the diagnosis of RPLS with MRI and discontinue CYRAMZA in patients who develop RPLS. Symptoms may resolve or improve within days, although some patients with RPLS can experience ongoing neurologic sequelae or death. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. CYRAMZA Administered in Combination with Docetaxel Study 3 was a multinational, randomized, double-blind study conducted in patients with NSCLC with disease progression on or after one platinum-based therapy for locally advanced or metastatic disease. Patients received either CYRAMZA 10 mg/kg intravenously plus docetaxel 75 mg/m2 intravenously every 3 weeks or placebo plus docetaxel 75 mg/m2 intravenously every 3 weeks. Due to an increased incidence of neutropenia and febrile neutropenia in patients enrolled in East Asian sites, Study 3 was amended and 24 patients (11 CYRAMZA plus docetaxel, 13 placebo plus docetaxel) at East Asian sites received a starting dose of docetaxel at 60 mg/m2 every 3 weeks. Study 3 excluded patients with an ECOG PS of 2 or greater, bilirubin greater than the upper limit of normal (ULN), uncontrolled hypertension, major surgery within 28 days, radiographic evidence of major airway or blood vessel invasion by cancer, radiographic evidence of intra-tumor cavitation, or gross hemoptysis within the preceding 2 months, and patients receiving therapeutic anticoagulation or chronic anti-platelet therapy other than once daily aspirin. The study also excluded patients whose only prior treatment for advanced NSCLC was a tyrosine kinase (epidermal growth factor receptor [EGFR] or anaplastic lymphoma kinase [ALK]) inhibitor. The data described below reflect exposure to CYRAMZA plus docetaxel in 627 patients in Study 3. Demographics and baseline characteristics were similar between treatment arms. Median age was 62 years; 67% of patients were men; 84% were White and 12% were Asian; 33% had ECOG PS 0; 74% had non-squamous histology and 25% had squamous histology. Patients received a median of 4.5 doses of CYRAMZA; the median duration of exposure was 3.5 months, and 195 (31% of 627) patients received CYRAMZA for at least six months. In Study 3, the most common adverse reactions (all grades) observed in CYRAMZA plus docetaxel-treated patients at a rate of ≥30% and ≥2% higher than placebo plus docetaxel were neutropenia, fatigue/asthenia, and stomatitis/mucosal inflammation. Treatment discontinuation due to adverse reactions occurred more frequently in CYRAMZA plus docetaxel-treated patients (9%) than in placebo plus docetaxel-treated patients (5%). The most common adverse events leading to treatment discontinuation of CYRAMZA were infusion-related reaction (0.5%) and epistaxis (0.3%). For patients with non-squamous histology, the overall incidence of pulmonary hemorrhage was 7% and the incidence of ≥Grade 3 pulmonary hemorrhage was 1% for CYRAMZA plus docetaxel compared to 6% overall incidence and 1% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. For patients with squamous histology, the overall incidence of pulmonary hemorrhage was 10% and the incidence of ≥Grade 3 pulmonary hemorrhage was 2% for CYRAMZA plus docetaxel compared to 12% overall incidence and 2% for ≥Grade 3 pulmonary hemorrhage for placebo plus docetaxel. The most common serious adverse events with CYRAMZA plus docetaxel were febrile neutropenia (14%), pneumonia (6%), and neutropenia (5%). The use of granulocyte colony-stimulating factors was 42% in CYRAMZA plus docetaxel-treated patients versus 37% in patients who received placebo plus docetaxel. In patients ≥65 years, there were 18 (8%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 9 (4%) deaths for placebo plus docetaxel. In patients <65 years, there were 13 (3%) deaths on treatment or within 30 days of discontinuation for CYRAMZA plus docetaxel and 26 (6%) deaths for placebo plus docetaxel. Table 4 provides the frequency and severity of adverse reactions in Study 3. Table 4: Adverse Reactions Occurring at Incidence Rate ≥5% and a ≥2% Difference Between Arms in Patients Receiving CYRAMZA in Study 3 CYRAMZA plus docetaxel Placebo plus docetaxel Adverse Reactions (N=627) (N=618) (MedDRA) System Organ All Grades Grade 3-4 All Grades Grade 3-4 Class (Frequency %) (Frequency %) (Frequency %) (Frequency %) Blood and Lymphatic System Disorders Febrile neutropenia 16 16 10 10 Neutropenia 55 49 46 40 Thrombocytopenia 13 3 5 <1 Gastrointestinal Disorders Stomatitis/Mucosal 37 7 19 2 inflammation Eye Disorders Lacrimation 13 <1 5 0 increased General Disorders and Administration Site Disorders Fatigue/Asthenia 55 14 50 11 Peripheral edema 16 0 9 <1 Respiratory, Thoracic, and Mediastinal Disorders Epistaxis 19 <1 7 <1 Vascular Disorders Hypertension 11 6 5 2 CYRAMZA® (ramucirumab) injection

RB-L HCP BS 17Dec2014

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Clinically relevant adverse drug reactions reported in ≥1% and <5% of the CYRAMZA plus docetaxel-treated patients in Study 3 were hyponatremia (4.8% CYRAMZA plus docetaxel versus 2.4% for placebo plus docetaxel) and proteinuria (3.3% CYRAMZA plus docetaxel versus 0.8% placebo plus docetaxel). Immunogenicity As with all therapeutic proteins, there is the potential for immunogenicity. In 19 clinical trials, 70/2131 (3.3%) of CYRAMZA-treated patients with post baseline serum samples tested positive for treatment-emergent anti-ramucirumab antibodies by an enzyme-linked immunosorbent assay (ELISA). Neutralizing antibodies were detected in 12 of the 70 patients who tested positive for treatment-emergent anti-ramucirumab antibodies. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to CYRAMZA with the incidences of antibodies to other products may be misleading. DRUG INTERACTIONS No pharmacokinetic (PK) interactions were observed between ramucirumab and docetaxel. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Risk Summary Based on its mechanism of action, CYRAMZA may cause fetal harm. Animal models link angiogenesis, VEGF and VEGF Receptor 2 (VEGFR2) to critical aspects of female reproduction, embryofetal development, and postnatal development. There are no adequate or well-controlled studies of ramucirumab in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Animal Data No animal studies have been specifically conducted to evaluate the effect of ramucirumab on reproduction and fetal development. In mice, loss of the VEGFR2 gene resulted in embryofetal death and these fetuses lacked organized blood vessels and blood islands in the yolk sac. In other models, VEGFR2 signaling was associated with development and maintenance of endometrial and placental vascular function, successful blastocyst implantation, maternal and feto-placental vascular differentiation, and development during early pregnancy in rodents and non-human primates. Disruption of VEGF signaling has also been associated with developmental anomalies including poor development of the cranial region, forelimbs, forebrain, heart, and blood vessels. Nursing Mothers It is not known whether CYRAMZA is excreted in human milk. No studies have been conducted to assess CYRAMZA’s impact on milk production or its presence in breast milk. Human IgG is excreted in human milk, but published data suggests that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted in human milk and because of the potential risk for serious adverse reactions in nursing infants from ramucirumab, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness of CYRAMZA in pediatric patients have not been established. In animal studies, effects on epiphyseal growth plates were identified. In cynomolgus monkeys, anatomical pathology revealed adverse effects on the epiphyseal growth plate (thickening and osteochondropathy) at all doses tested (5-50 mg/kg). Ramucirumab exposure at the lowest weekly dose tested in the cynomolgus monkey was 0.2 times the exposure in humans at the recommended dose of ramucirumab as a single agent. Geriatric Use Of the 563 CYRAMZA-treated patients in two randomized gastric cancer clinical studies, 36% were 65 and over, while 7% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Of the 1253 patients in Study 3, 455 (36%) were 65 and over and 84 (7%) were 75 and over. Of the 627 patients who received CYRAMZA plus docetaxel in Study 3, 237 (38%) were 65 and over, while 45 (7%) were 75 and over. In an exploratory subgroup analysis of Study 3, the hazard ratio for overall survival in patients less than 65 years old was 0.74 (95% CI: 0.62, 0.87) and in patients 65 years or older was 1.10 (95% CI: 0.89, 1.36). Renal Impairment No dose adjustment is recommended for patients with renal impairment based on population PK analysis. Hepatic Impairment No dose adjustment is recommended for patients with mild hepatic impairment (total bilirubin within upper limit of normal [ULN] and aspartate aminotransferase [AST] >ULN or total bilirubin >1.0-1.5 times ULN and any AST) based on population PK analysis. Clinical deterioration was reported in patients with Child-Pugh B or C cirrhosis who received single-agent CYRAMZA. Females and Males of Reproductive Potential Fertility Advise females of reproductive potential that CYRAMZA may impair fertility. Contraception Based on its mechanism of action, CYRAMZA may cause fetal harm. Advise females of reproductive potential to avoid getting pregnant while receiving CYRAMZA and for at least 3 months after the last dose of CYRAMZA. DOSAGE AND ADMINISTRATION Do not administer CYRAMZA as an intravenous push or bolus. CYRAMZA® (ramucirumab) injection RB-L HCP BS 17Dec2014

CYRAMZA RB-L HCP BS 17Dec2014 Brief Summary 7 x 10

Recommended Dose and Schedule The recommended dose of CYRAMZA is 10 mg/kg administered by intravenous infusion over approximately 60 minutes on day 1 of a 21-day cycle prior to docetaxel infusion. Continue CYRAMZA until disease progression or unacceptable toxicity Premedication Prior to each CYRAMZA infusion, premedicate all patients with an intravenous histamine H1 antagonist (e.g., diphenhydramine hydrochloride). For patients who have experienced a Grade 1 or 2 infusion reaction, also premedicate with dexamethasone (or equivalent) and acetaminophen prior to each CYRAMZA infusion. Dose Modifications Infusion-Related Reactions (IRR) • Reduce the infusion rate of CYRAMZA by 50% for Grade 1 or 2 IRRs. • Permanently discontinue CYRAMZA for Grade 3 or 4 IRRs. Hypertension • Interrupt CYRAMZA for severe hypertension until controlled with medical management. • Permanently discontinue CYRAMZA for severe hypertension that cannot be controlled with antihypertensive therapy. Proteinuria • Interrupt CYRAMZA for urine protein levels ≥2 g/24 hours. Reinitiate treatment at a reduced dose of 8 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. If the protein level ≥2 g/24 hours reoccurs, interrupt CYRAMZA and reduce the dose to 6 mg/kg every 2 weeks once the urine protein level returns to <2 g/24 hours. • Permanently discontinue CYRAMZA for urine protein level >3 g/24 hours or in the setting of nephrotic syndrome. Wound Healing Complications • Interrupt CYRAMZA prior to scheduled surgery until the wound is fully healed. Arterial Thromboembolic Events, Gastrointestinal Perforation, or Grade 3 or 4 Bleeding • Permanently discontinue CYRAMZA. For toxicities related to docetaxel, refer to the current respective prescribing information. PATIENT COUNSELING INFORMATION Advise patients: • That CYRAMZA can cause severe bleeding. Advise patients to contact their health care provider for bleeding or symptoms of bleeding including lightheadedness. • Of increased risk of an arterial thromboembolic event. • To undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if symptoms from hypertension occur including severe headache, lightheadedness, or neurologic symptoms. • To notify their health care provider for severe diarrhea, vomiting, or severe abdominal pain. • That CYRAMZA has the potential to impair wound healing. Instruct patients not to undergo surgery without first discussing this potential risk with their health care provider. • Of the potential risk for maintaining pregnancy, risk to the fetus, or risk to postnatal development during and following treatment with CYRAMZA and the need to avoid getting pregnant, including use of adequate contraception, for at least 3 months following the last dose of CYRAMZA. • To discontinue nursing during CYRAMZA treatment. Additional information can be found at www.CYRAMZAhcp.com.

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DRUG MONOGRAPHS

LUNG CANCER inflammation are present. Ensure adequate hydration. Avoid extravasation. Chronic lymphatic leukemia. Bone marrow suppression. Previous X-ray, cytotoxic chemotherapy. Infection. Hemorrhagic tendency. Monitor renal, hepatic and bone marrow function. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Adverse reactions: Bone marrow suppression, hyperheparinemia, GI upset (may be severe), anorexia, weakness, thrombosis, thrombophlebitis, hypersensitivity, jaundice, alopecia, vertigo, auditory disturbances, hemolytic anemia, skin reactions, infection, amyloidosis, hyperuricemia, gonad damage. How supplied: Vials–4

NAVELBINE Pierre Fabre

℞

Antimicrotubule agent. Vinorelbine (as tartrate) 10mg/mL; soln for IV inj after dilution; preservative-free. Indications: First-line treatment of ambulatory patients with unresectable, advanced non-small cell lung cancer (NSCLC), as a single agent or in combination with cisplatin. In Stage III NSCLC, use in combination with cisplatin. Adults: See literature. Give by IV inj over 6–10 minutes. Monotherapy: 30mg/m2 once weekly. Combination therapy: 25mg/m2 once weekly with cisplatin given every 4 weeks; or 30mg/m2 once weekly with cisplatin given on Days 1 and 29, then every 6 weeks. Dose adjustment for toxicities, hepatic impairment: see literature. Children: Not recommended. Contraindications: Pretreatment granulocyte counts <1000 cells/mm3. Warnings/Precautions: IV use only; fatal if given intrathecally. Discontinue if neurotoxicity ≥grade 2. Pre-existing pulmonary dysfunction or neuropathy. Prior irradiation or chemotherapy. Cardiovascular disease. Monitor for myelosuppression, infection, and/or fever; obtain CBCs with differentials prior to each dose. Avoid contamination of the eyes or injecting into an extremity with poor circulation (thrombosis possible). Hepatic injury or impairment. Avoid extravasation. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: May be potentiated by CYP3A inhibitors. Acute pulmonary reactions possible with mitomycin. Increased risk of granulocytopenia with cisplatin. May increase risk of neurotoxicity with paclitaxel. Prior or concomitant radiation therapy; may result in radiosensitizing effects. Adverse reactions: Myelosuppression (esp. granulocytopenia), inj site reactions, elevated liver enzymes, chest pain, fatigue, GI upset, alopecia, jaw pain, myalgia, arthralgia, rash, severe constipation, paralytic ileus, intestinal

obstruction, necrosis, and/or perforation; dyspnea, severe bronchospasm. How supplied: Single-use vial (1mL, 5mL)–1

PHOTOFRIN Pinnacle Biologics

TARCEVA Genentech

℞

Photosensitizing agent. Porfimer (as sodium) 75mg/vial; pwd for IV inj after reconstitution; preservative-free. Indications: Reduction of obstruction and palliation in patients with completely or partially obstructing endobronchial non-small-cell lung cancer (NSCLC). Treatment of microinvasive endobronchial NSCLC in patients for whom surgery and radiotherapy is not indicated. Adults: See literature. Give by slow IV inj over 3–5 minutes. 2mg/kg then illumination with laser light 40–50 hours following injection. 2nd course may be given at a minimum of 30 days after initial therapy; max 3 courses (separated by ≥30 days). Children: Not recommended. Contraindications: Porphyria. Existing tracheoesophageal or bronchoesophageal fistula. Tumors eroding into a major blood vessel. Emergency treatment of patients with severe acute respiratory distress caused by an obstructing endobronchial lesion. Esophageal or gastric varices. Esophageal ulcers >1cm in diameter. Warnings/Precautions: Avoid direct sunlight or bright indoor light; wear dark sunglasses when outdoors. Increased risk of fatal massive hemoptysis with large, centrally located tumors, cavitating tumors, extensive tumor extrinsic to the bronchus. Caution with endobronchial tumors in locations where treatment-induced inflammation could obstruct airway. Avoid extravasation. Pregnancy (Cat.C; use adequate contraception), nursing mothers: not recommended. Interactions: Increased risk of photosensitivity reactions with other photosensitizing agents (eg, tetracyclines, sulfonamides, phenothiazines, sulfonylurea hypoglycemic agents, thiazide diuretics, griseofulvin, fluoroquinolones). May be antagonized by dimethyl sulfoxide, β-carotene, ethanol, formate, mannitol, allopurinol, calcium channel blockers, prostaglandin synthesis inhibitors, drugs that decreased clotting, vasoconstriction or platelet aggregation (eg, thromboxane A2 inhibitors), glucocorticoid hormones. Separate radiotherapy by 2–4 weeks. Adverse reactions: Photosensitivity reactions (eg, erythema, swelling, itching, burning sensation, feeling hot, blisters), fluid imbalance, chest pain, fever, pain, abdominal pain, GI upset, constipation, mucositis, ocular sensitivity, dyspnea, pleural effusion, anemia, fistula formation, fatal massive hemoptysis, others. How supplied: Vial–1

℞

Human epidermal growth factor receptor type 1/ epidermal growth factor receptor tyrosine kinase inhibitor. Erlotinib (as HCl) 25mg, 100mg, 150mg; tabs. Indications: Maintenance treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) whose disease has not progressed after four cycles of platinum-based firstline chemotherapy. Treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) after failure of at least one prior chemotherapy regimen. Adults: Take on empty stomach. 150mg once daily. Use until disease progression or unacceptable toxicity occurs. Diarrhea unresponsive to loperamide, severe skin reactions, strong CYP3A4 inhibitors (see Interactions), hepatic impairment: reduce in 50mg decrements. CYP3A4 inducers (see Interactions): consider increased dose (see literature). Children: Not recommended. Warnings/Precautions: Discontinue if interstitial lung disease, hepatic failure, or GI perforation occurs; interrupt or discontinue therapy in patients with dehydration at risk for renal failure, or with severe bullous, blistering or exfoliative skin conditions, or with acute/worsening ocular disorders. Hepatic impairment. Monitor liver function tests periodically; if tests worsen, consider withholding or reducing dose; interrupt or discontinue therapy if severe changes (eg, total bilirubin >3×ULN, and/or transaminases >5×ULN) occur. Monitor renal function, serum electrolytes, pulmonary function, INR, prothrombin time. History of peptic ulcers or diverticular disease. Pregnancy (Cat.D); use adequate contraception (see literature). Nursing mothers: not recommended. Interactions: Potentiated by CYP3A4 inhibitors (eg, clarithromycin, ritonavir, ketoconazole). Plasma levels decreased by CYP3A4 inducers (eg, rifampicin, phenytoin, carbamazepine, phenobarbital, St. John’s wort), proton pump inhibitors or H2 blockers, and smoking. Antagonizes midazolam. Increased risk of GI perforation with concomitant anti-angiogenic agents, steroids, NSAIDs, taxane-based chemotherapy. Monitor for bleeding with oral anticoagulants, NSAIDs. Adverse reactions: Rash, diarrhea, GI upset, anorexia, fatigue, elevated LFTs, unexplained pulmonary symptoms (eg, dyspnea, cough, fever; discontinue and follow-up if occurs), stomatitis, infection; rare: GI perforation (may be fatal), ocular disorders (eg, conjunctivitis, keratitis, corneal ulceration/perforation), MI/ischemia, hemolytic anemia, cerebrovascular accidents, interstitial lung disease; hepatic or renal failure and hepatorenal

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DRUG MONOGRAPHS

LUNG CANCER syndrome (may be fatal); bullous, blistering and exfoliative skin conditions (eg, Stevens-Johnson syndrome, toxic epidermal necrolysis). Testing considerations: K-RAS mutation analysis, EGFR amplification analysis How supplied: Tabs–30

TREXALL Teva

skin reactions (may be fatal; eg, toxic epidermal necrolysis, Stevens-Johnson syndrome). How supplied: Tabs–30; soln (2mL, 4mL, 8mL, 10mL)–10 (single-use vials); pwd (1 gram)–1 (single-use vial)

XALKORI Pfizer ℞

Folic acid antagonist. Methotrexate sodium 5mg, 7.5mg, 10mg, 15mg; scored tabs. ℞ Also: Methotrexate injection Bedford Methotrexate 25mg/mL; soln for IV, IM, intraarterial, or intrathecal administration after dilution; preservative-free. ℞ Also: Methotrexate for injection Bedford Methotrexate 1g/vial; pwd for IV, IM, intra-arterial, or intrathecal administration after dilution; preservative-free. Indications: Lung cancer (squamous cell and small cell types). Adults: See literature. Children: Not established. Contraindications: Pregnancy (Cat.X). Nursing mothers. Warnings/Precautions: Be fully familiar with this drug’s toxicity before use. Discontinue if malignant lymphomas occur. Obtain baseline and monitor CBCs with differential, platelet counts, chest X-ray, and hepatic, renal and pulmonary function. During therapy monitor hematology monthly, renal and hepatic function every 1–2 months, more often if increasing dose or predisposed to toxicity (eg, dehydration). Discontinue immediately if blood counts drop significantly. Rule out pregnancy in women of childbearing potential; use effective contraception during therapy and for at least 1 ovulatory cycle afterwards for women and for at least 3 months afterwards for men. Interrupt therapy if vomiting, diarrhea, stomatitis, or pulmonary symptoms occur. Hepatic or renal impairment. Obesity. Diabetes. Peptic ulcer. Ulcerative colitis. Infection. Dehydration. Folate deficiency. Ascites, pleural effusions: evacuate fluid, monitor for toxicity and reduce dose or discontinue if needed. Elderly (use low doses and monitor closely). Debilitated. Interactions: Avoid live virus vaccines. Toxicity increased by NSAIDs, salicylates, phenytoin, sulfonylureas, sulfonamides, probenecid, folic acid antagonists. May be potentiated by penicillins (monitor), tetracyclines, chloramphenicol, nonabsorbable broad spectrum antibiotics. May be antagonized by folic acid. May potentiate theophylline, mercaptopurine. Increased risk of soft tissue necrosis and osteonecrosis with radiotherapy. Caution with other hepatotoxic drugs (eg, azathioprine, retinoids, sulfasalazine) and nephrotoxic agents (eg, cisplatin). Adverse reactions: Ulcerative stomatitis, leukopenia, nausea, GI upset, malaise, fatigue, chills, fever, dizziness, infection, myelosuppression, hepatotoxicity, renal toxicity, CNS toxicity, seizures (esp in children); interstitial pneumonitis, tumor lysis syndrome,

℞

Tyrosine kinase inhibitor. Crizotinib 200mg, 250mg; hard gel caps. Indications: Treatment of metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. Adults: Swallow whole. 250mg twice daily until disease progression or intolerance. Dose modification and/or dose reduction to 200mg twice daily may be required based on Grade 3 or 4 severity, then to 250mg once daily, or permanently discontinue if intolerable. Severe renal impairment (CrCl <30mL/min) not requiring dialysis: 250mg once daily. Dose reduction for hematologic and non-hematologic toxicities: see full labeling. Children: Not established. Warnings/Precautions: Confirm ALK-positive NSCLC with an FDA-approved test before treating. Monitor ALT and total bilirubin every 2 weeks during first 2 months, then monthly, and more frequently for elevated transaminases; temporarily suspend, reduce dose, or permanently discontinue as clinically indicated. Monitor CBCs with differential monthly and more frequently if Grade 3 or 4 abnormalities, fever or infection occurs. Risk of severe pneumonitis: monitor for pulmonary symptoms; permanently discontinue if occurs. Congenital long QT syndrome; avoid. History of or predisposition for QTc prolongation (eg, CHF, bradyarrhythmias, electrolyte abnormalities, concomitant drugs that prolong QT interval): consider monitoring ECG, electrolytes periodically. Torsade de pointes, ventricular tachycardia, serious arrhythmia: permanently discontinue if QTc >500ms or ≥60ms change from baseline. Monitor hr and BP regularly; discontinue if life-threatening bradycardia occurs. Hepatic impairment. Severe renal impairment. Pregnancy (Cat.D); avoid. Use adequate contraception during therapy and at least 90 days after completion. Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP3A inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole), grapefruit juice, or strong CYP3A inducers (eg, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates with narrow therapeutic indices (eg, alfentanil, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus); if needed, reduce doses. Avoid concomitant agents known to cause bradycardia (eg, beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin); adjust dose or discontinue. Caution with moderate CYP3A inhibitors. Dose reduction may be needed with coadministered drugs metabolized by CYP3A.

Adverse reactions: Vision disorder, nausea, diarrhea, vomiting, constipation, edema, fatigue, Grade 3–4 events: ALT increased, neutropenia; elevated total bilirubin, pneumonitis (may be fatal), QT prolongation, bradycardia, hepatotoxicity (may be fatal). How supplied: Caps–60

ZYKADIA Novartis

℞

Tyrosine kinase inhibitor. Ceritinib 150mg; hard gel caps. Indications: Treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. Not established for improvement in survival or disease-related symptoms. Adults: Take on an empty stomach (at least 2 hours before or after a meal). 750mg once daily until disease progression or unacceptable toxicity. Discontinue if 300mg once daily not tolerated. Moderate-to-severe hepatic impairment: not established. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: Monitor for severe or persistent GI toxicity; if occurs, withhold until improved; resume at reduced dose. Monitor ALT/AST and total bilirubin once monthly, and more frequently if elevated transaminases develop; withhold then reduce dose, or permanently discontinue as clinically indicated. Congenital long QT syndrome; avoid. CHF, bradyarrhythmias, electrolyte abnormalities; monitor ECG, electrolytes periodically. Permanently discontinue if QTc prolongation in combination with Torsade de pointes or polymorphic ventricular tachycardia or serious arrhythmia develop. Monitor hr and BP regularly; serum glucose and pulmonary symptoms as clinically indicated. Permanently discontinue if treatment-related interstitial lung disease (ILD)/pneumonitis, uncontrolled hyperglycemia, or life-threatening bradycardia occur. Pregnancy (Cat.D). Females of reproductive potential should use effective contraception during treatment and for at least 2 weeks after completion. Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, ritonavir, macrolides, ketoconazole, nefazodone), grapefruit juice; if unavoidable, reduce ceritinib dose by 1/3. Avoid concomitant strong CYP3A4 inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s Wort). Avoid concomitant CYP3A substrates (eg, alfentanil, cyclosporine, ergots, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) or CYP2C9 substrates (eg, phenytoin, warfarin) with narrow therapeutic indices; if unavoidable, reduce doses of these drugs. Avoid concomitant agents known to cause bradycardia (eg, beta-blockers, non-dihydropyridine CCBs, clonidine, digoxin). Adverse reactions: Diarrhea, nausea, vomiting, abdominal pain, constipation, elevated transaminases, fatigue, decreased appetite; bradycardia, hepatotoxicity, ILD/pneumonitis, QTc prolongation, hyperglycemia. How supplied: Caps–70

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SARCOMA Gastrointestinal Stromal Tumor (Gist) Treatment Regimens Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment. Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies. These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Adjuvant Therapy Following Complete Gross Resection of GIST1 Note: Chemotherapeutic regimens are used if GIST is unresectable, recurrent, or metastatic.1

REGIMEN

DOSING

Imatinib

Imatinib 400mg PO once daily; has been given for up to 1 year in a clinical trial.

2,3

Kit (CD117) Positive Unresectable and/or Metastatic Malignant GIST1 Imatinib2,4–7

Imatinib 400mg PO once daily; increase to 400mg twice daily if disease progression occurs or in patients with documented KIT exon 9 (or exon 11) mutation as clinically tolerated.

Intolerance to Imatinib or Disease Progression1 Sunitinib8–10

Sunitinib 50mg PO once daily. Given in 6-week cycles with 4 weeks on and 2 weeks off.* OR Sunitinib 37.5mg PO once daily without interruption.†

Disease Progression Despite Prior Imatinib or Sunitinib Therapy1 Regorafenib11,12

Regorafenib 160mg PO once daily. Given in 4-week cycles with 3 weeks on and 1 week off.‡

Disease Progression Despite Prior Imatinib, Sunitinib, or Regorafenib Therapy¶ None of the drugs listed below are FDA-approved for the treatment of GIST. Recommendations are based on limited data.

Sorafenib13-15

Sorafenib 400mg PO twice daily until disease progression or development of intolerance.

Nilotinib16,17

Nilotinib 400mg PO twice daily. Reduce to once daily in case of intolerance.

Dasatinib18

Dasatinib 70mg PO twice daily (for patients with D842V mutation).

* Consider dose reduction to a minimum of 37.5mg daily if given with a strong CYP3A4 inhibitor or dose increase to a maximum 87.5mg daily if given with a CYP3A4 inducer. † Consider dose reduction to a minimum of 25mg daily if given with a strong CYP3A4 inhibitor or a dose increase to a maximum 62.5mg daily if given with concomitant CYP3A4 inducer. ‡ For additional treatment caveats, please see the NCCN Soft Tissue Sarcoma Guidelines for Dosing and Administration of Regorafenib for GIST (v 1.2014, page 33)1 ¶ Imatinib, sunitinib, and regorafenib are the only three FDA agents approved for the treatment of GIST.

References 1. 2. 3. 4.

NCCN Clinical Practice Guidelines in Oncology™. Soft Tissue Sarcoma. v 1.2014. Available at: http://www.nccn.org/ professionals/ physician_gls/pdf/sarcoma.pdf. Accessed March 18, 2014. Gleevec [prescribing information]. East Hanover, NJ: Novartis Corp.; 2012. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localized, primary gastrointestinal stromal tumor: a randomised, double-blind, placebo-controlled trial. Lancet. 2009;373:1097–1104. Blanke CD, Rankin C, Demetri GD, et al. Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033. J Clin Oncol. 2008;26:626–632.

6. 7.

Heinrich MS, Owzar K, Corless CL, et al. Correlation of kinase genotype and clinical outcome in the North American Intergroup phase III trial of imatinib mesylate for treatment of advanced gastrointestinal stromal tumor: CALGB 150105 study by Cancer and Leukemia Group B and Southwest Oncology Group. J Clin Oncol. 2008;26:5360–5367. Debiec-Rychter M, Sciot R, Le Cesne A, et al. KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stomal tumors. Eur J Cancer. 2006;42:1093–1103. Gastrointestinal Stromal Tumor Meta-Analysis Group (MetaGIST). Comparison of two doses of imatinib for the treatment of unresectable or metastatic gastrointestinal stromal tumors: a meta-analysis of 1,640 patients. J Clin Oncol. 2010;28: 1247–125

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SARCOMA 8. 9. 10. 11. 12.

13.

Demetri GD, van Oosterom AT, Garrett CR, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumor after failure of imatinib: a randomised controlled trial. Lancet. 2006;368:1329–1338. Sutent [prescribing information]. New York, NY: Pfizer Corp.; 2011. George S, Blay JY, Casali PG, et al. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumor after imatinib failure. Eur J Cancer. 2009;45:1959–1968. Stivarga [prescribing information]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc; 2013. Demetri GD, Reichardt P, Kang YK, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumors after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381(9863):295–302. Montemurro M, Gelderblom H, Bitz U, et al. Sorafenib as third- or fourth-line treatment of advanced gastrointestinal stromal tumor and pretreatment including both imatinib and sunitinib, and nilotinib: A retrospective analysis. Eur J Cancer. 2013;49(5):1027–1031.

14.

15.

16. 17. 18.

Kindler HL, Campbell NP, Wroblewski K, et al. Sorafenib (SOR) in patients (pts) with imatinib (IM) and sunitinib (SU)-resistant (RES) gastrointestinal stromal tumors (GIST): Final results of a University of Chicago Phase II Consortium trial. J Clin Oncol. 2011;29:Abstract 10009. Park SH, Ryu MH, Ryoo BY, et al. Sorafenib in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors: a phase II study of Korean gastrointestinal stromal tumors study group. Invest New Drugs. 2012;30(6):2377–2383. Montemurro M, Schoffski P, Reichardt P, et al. Nilotinib in the treatment of advanced gastrointestinal stromal tumors resistant to both imatinib and sunitinib. Eur J Cancer. 2009;45: 2293–2297. Sawaki A, Nishida T, Doi T, et al. Phase 2 study of nilotinib as third-line therapy for patients with gastrointestinal stromal tumor. Cancer. 2011;117:4633–4641. Trent JC, Wathen K, von Mehren M, et al. A phase II study of dasatinib for patients with imatinib-resistant gastrointestinal stromal tumor (GIST). J Clin Oncol. 2011;29:Abstract 10006.

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DRUG MONOGRAPHS

SARCOMA DOXIL Janssen Biotech

℞

Anthracycline. Doxorubicin HCl (liposomal) 2mg/mL; dispersion for IV infusion after dilution; preservative-free. Indications: AIDS-related Kaposi’s sarcoma refractory to combination chemotherapy. Adults: Give by IV infusion at initial rate of 1mg/min; may increase rate to complete infusion over 1hr if no infusion reactions occur; may premedicate with antiemetics. 20mg/m2 once every 3 weeks. Hepatic dysfunction (serum bilirubin ≥1.2mg/dL), hand-foot syndrome, hematologic toxicity (esp. ANC, platelets), or stomatitis: reduce dose. Consider total anthracycline and anthracenedione doses and irradiation when calculating total cumulative dose. See full labeling. Children: Not established. Warnings/Precautions: Not substitutable on a mg/mg basis with other doxorubicin products. Cardiotoxicity, acute infusion-related reactions, myelosuppression may occur. Have resuscitative/ antiallergic equipment and expertise available. Hepatic impairment. Monitor blood (esp. CBC + platelets), hepatic (esp. SGOT/SGPT, alkaline phosphatase), and cardiac function (esp. myocardial biopsy). Monitor periodically for secondary oral cancers with long-term use. Avoid extravasation. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: Caution with cyclosporine, phenobarbital, phenytoin, streptozocin, digoxin, myelosuppressants, others. Previous mediastinal irradiation, cyclophosphamide, other cardiotoxic drugs: monitor for cardiotoxicity and hepatotoxicity. Adverse reactions: Asthenia, fatigue, fever, anorexia, nausea, vomiting, stomatitis, diarrhea,

INTRON A Merck

℞

Interferon alfa-2b, recombinant; 10 million, 18 million, or 50 million IU per vial; pwd; for inj after reconstitution/dilution; preservative-free. Also: INTRON A SOLN ℞ Interferon alfa-2b, recombinant; 10 million IU, 18 million IU, 25 million IU; per vial; for inj; contains m-cresol. Indications: AIDS-related Kaposi’s sarcoma. Adults: Use appropriate preparation and route: see literature. Use SC route if platelets <50,000/mm3. 30 million IU/m2 IM or SC three times weekly; continue until rapid disease progression or maximal response achieved after 16 weeks; reduce dose by ½ or suspend therapy if severe adverse reactions occur; discontinue if persists. Children: Not recommended. Contraindications: Hepatitis: decompensated liver disease. Autoimmune disorders. Warnings/Precautions: May cause or exacerbate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue if they worsen. Severe psychiatric disorders (esp. depression). Cardiovascular or pulmonary disease. Severe myelosuppression. Uncontrolled thyroid abnormalities. Diabetes. Coagulation disorders. Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and during

therapy; EKG in cardiovascular disease and cancer patients. Psoriasis. Renal dysfunction. Transplant recipients. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Caution with myelosuppressives, and drugs that can exacerbate depression. May potentiate theophylline (may double its levels). Adverse reactions: Flu-like symptoms (fever, headache, myalgia, fatigue); hepatic, hematologic, respiratory, skin, genitourinary system, CNS, cardiovascular, endocrine (esp thyroid), GI, or visual disorders; colitis, hypertriglyceridemia, pancreatitis, infections, injection site reactions; others (see literature). How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial–1; Soln (vials): 10million IU/vial–6 (kit w. supplies); Soln (multidose vials): 18million, 25million IU/vial–1

PANRETIN Eisai

℞

Retinoid. Alitretinoin 0.1%; gel. Indications: Cutaneous lesions of AIDS-related Kaposi’s sarcoma (KS). Adults: Apply twice daily to lesions (avoid mucous membranes and normal skin); do not occlude; may increase to 3-4 times daily as tolerated. Reduce frequency or suspend treatment if local toxicity occurs. Children: Not recommended. Warnings/Precautions: Not for use when systemic KS therapy required. Avoid sun, UV light. Flammable. Pregnancy (Cat.D), nursing mothers: not recommended. Interactions: Increases DEET toxicity (avoid). Adverse reactions: Photosensitivity, rash, pruritus, pain, exfoliative dermatitis, paresthesia, edema. How supplied: Gel–60g

DOSAGES FOR THE ELDERLY Special caution is advised when prescribing drugs for elderly patients. Keep the following points in mind when prescribing drugs for patients of approximately 60 years or older:

1. Renal Function: Glomerular filtration rate, renal tubular secretion and blood flow tend to decrease with advancing age, while the incidence of renal pathology increases. 2. Drug Sensitivity: Elderly patients may show unusual sensitivity or paradoxical reactions to a number of drugs. Refer to the complete prescribing information. 3. Drug Distribution: The ratio of fat to lean body weight may increase in the elderly, which affects the volume of distribution of fat-soluble drugs. Plasma albumin concentrations may be decreased in the elderly. This potentiates plasma-protein bound drugs and increases the potential for drug interactions caused by plasma-protein displacement. 4. Polypharmacy: It is important to determine the patient’s current medication use, including nonprescription products, before adding any medication to determine any possible interactions. 5. Hepatic Function: Reduced function of metabolic enzymes in the liver may occur in the elderly.

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DRUG MONOGRAPHS

SKIN CANCER EFUDEX Valeant

℞

Antimetabolite. Fluorouracil 2%, 5%; soln. ℞ Also: EFUDEX CREAM Fluorouracil 5%. Indications: Multiple actinic or solar keratoses. Superficial basal cell carcinoma when conventional therapy is impractical (5% only); see literature. Adults: Keratoses: Apply twice daily until erosion occurs (usually 2–4 wks). Basal cell carcinoma (5% only): Apply twice daily, usually for 3–6 weeks (obliteration may take 10–12 weeks). Children: Not recommended. Contraindications: Dihydropyrimidine dehydrogenase (DPD) deficiency. Pregnancy (Cat.X). Warnings/Precautions: Apply cautiously near eyes, nose, mouth. Avoid mucous membranes, occlusion, ulcerated/inflamed skin, exposure to UV light. Wash hands after application if fingers were used. Notify patients of expected skin reaction. Biopsy unresponsive lesions. Nursing mothers: not recommended. Adverse reactions: Pain or burning at application site, pruritus, irritation, hyperpigmentation. How supplied: Soln–10mL (w. drop dispenser); Crm–25g

ERIVEDGE Genentech

℞

Hedgehog pathway inhibitor. Vismodegib 150mg; caps. Indications: Treatment of adults with metastatic basal cell carcinoma, or locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation. Adults: Swallow whole. 150mg once daily, until disease progression or unacceptable toxicity. Children: Not established. Warnings/Precautions: Risk of embryo-fetal death and severe birth defects in pregnant women. Verify pregnancy status prior to initiation of therapy. Counsel patients (males and females) on the need for contraception during and after treatment. Advise patients not to donate blood or blood products while on therapy and for at least 7 months after last dose. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: May be potentiated by P-gp inhibitors (eg, clarithromycin, erythromycin, azithromycin). May be antagonized by drugs that affect gastric pH (eg, proton pump inhibitors, H2-receptor antagonists, antacids). Adverse reactions: Muscle spasms, alopecia, dysgeusia, weight loss, fatigue, GI upset, decreased appetite, constipation, arthralgias, ageusia. Note: Report immediately exposure to Erivedge during pregnancy by contacting the Genentech Adverse Event Line at (888) 835-2555. How supplied: Caps–28

GLEEVEC Novartis

℞

Kinase inhibitor. Imatinib (as mesylate) 100mg, 400mg; scored tabs. Indications: Adults with aggressive systemic mastocytosis (ASM) without the D816V c-Kit mutation or with c-Kit mutational status unknown. Adults with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP). Adults: Take with food and water. May disperse tab in water or apple juice and take promptly. ≥18yrs: ASM without D816V c-Kit mutation or status unknown: 400mg once daily. ASM associated with eosinophilia: initially 100mg once daily; may increase to 400mg once daily if insufficient response. If severe non-hematologic reactions develop: interrupt dose; resume at a lower dose in hepatic dysfunction. Severe hepatic impairment: reduce dose by 25%. Renal or hematologic reactions: see full labeling. Avoid concomitant strong CYP3A4 inducers (eg, rifampin): if needed, increase imatinib dose by at least 50%. Children: Not recommended. Warnings/Precautions: Hepatic or renal impairment. Monitor weight and for fluid retention regularly; CBCs weekly for 1st month, bi-weekly for 2nd month, then periodically (eg, every 2–3 months); liver function at baseline then monthly or as needed; GI symptoms at baseline. Cardiovascular disease or risk factors; monitor. Immunosuppression and potential toxicities (liver, kidney, cardiac) from long-term use. Monitor for tumor lysis syndrome; correct clinically significant dehydration and treat high uric acid levels before initiating therapy. Monitor growth in children. Possible cardiogenic shock/LV dysfunction in conditions with high eosinophil levels (eg, HES/CEL, MDS/MPD, ASM); consider concomitant systemic steroid prophylaxis (1–2mg/kg) for 1 or 2 wks if abnormal ECG or serum troponin. Monitor TSH levels in thyroidectomy patients undergoing levothyroxine replacement. Pregnancy (Cat.D); avoid. Use highly effective contraception during treatment. Nursing mothers: not recommended. Interactions: Avoid grapefruit juice. Potentiated by CYP3A4 inhibitors (eg, azole antifungals, protease inhibitors, nefazodone, clarithromycin, telithromycin). Antagonized by strong CYP3A4 inducers (eg, dexamethasone, fosphenytoin, phenytoin, phenobarbital, carbamazepine, oxcarbamazepine, primidone, St. John’s wort, rifampin, rifabutin, rifampicin); consider alternatives. May potentiate drugs metabolized by CYP3A4 (eg, benzodiazepines, dihydropyridine calcium channel blockers, cyclosporine, ergots, alfentanil, fentanyl, pimozide, quinidine, certain statins, sirolimus, tacrolimus), CYP2D6, or CYP2C9 (use heparin instead of warfarin). Adverse reactions: Edema (may be severe), nausea, vomiting, musculoskeletal pain,

diarrhea, muscle cramps, rash (may be severe; eg, erythema multiforme, Stevens-Johnson syndrome), fatigue, abdominal pain, dizziness, blurred vision, somnolence, fever, headache, cough, arthralgia/myalgia, dyspnea, hypokalemia, night sweats, anorexia, pruritus, hemorrhage, anemia, neutropenia, thrombocytopenia, weight gain, renal or hepatotoxicity, immunosuppression, hypothyroidism; rare: severe CHF, LV dysfunction. How supplied: 100mg–90; 400mg–30

HYDREA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 500mg; caps. Indications: Melanoma. Adults: See literature. Intermittant therapy for solid tumors: 80mg/kg as single dose every 3rd day. Continuous therapy for solid tumors: 20–30mg/kg/day as single dose. Renal impairment: reduce dose. Children: Not recommended. Contraindications: Marked bone marrow depression. Warnings/Precautions: Previous irradiation therapy or chemotherapy. Correct anemia before starting. Monitor hematologic, renal, hepatic function before and during treatment. Marked renal dysfunction. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop and use alternative agents. Elderly. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). Myelosuppressives potentiate antineoplastic effect. May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated urease, uricase, lactate dehydrogenase. Adverse reactions: Leukopenia, anemia, erythrocytic abnormalities, thrombocytopenia, GI upset, rash, erythema, fever, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer. Note: Wear disposable gloves when handling caps or bottle. How supplied: Caps–100

INTRON A Merck

℞

Interferon alfa-2b, recombinant; 10 million, 18 million, or 50 million IU per vial; pwd; for inj after reconstitution/dilution; preservative-free. ℞ Also: INTRON A SOLN Interferon alfa-2b, recombinant; 10 million IU, 18 million IU, 25 million IU; per vial; for inj; contains m-cresol. Indications: Malignant melanoma. Adults: Induction: 20million IU/m2 IV over 20 mins, 5 consecutive days per week, for 4 weeks. Maintenance: 10 million IU/m2 SC 3 times per week for 48 weeks. See literature for

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DRUG MONOGRAPHS

SKIN CANCER appropriate preparation and route and for dose adjustments. Children: Not recommended. Contraindications: Hepatitis: decompensated liver disease. Autoimmune disorders. Warnings/Precautions: May cause or exacerbate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, or infectious disorders: monitor closely, discontinue if they worsen. Severe psychiatric disorders (esp. depression). Cardiovascular or pulmonary disease. Severe myelosuppression. Uncontrolled thyroid abnormalities. Diabetes. Coagulation disorders. Maintain adequate hydration. Monitor blood, thyroid, visual and liver function before and during therapy; EKG in cardiovascular disease and cancer patients. Psoriasis. Renal dysfunction. Transplant recipients. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Caution with myelosuppressives, and drugs that can exacerbate depression. May potentiate theophylline (may double its levels). Adverse reactions: Flu-like symptoms (fever, headache, myalgia, fatigue); hepatic, hematologic, respiratory, skin, genitourinary system, CNS, cardiovascular, endocrine (esp thyroid), GI, or visual disorders; colitis, hypertriglyceridemia, pancreatitis, infections, injection site reactions; others (see literature). How supplied: Pwd (w. diluent): 10million, 18million, 50million IU/vial–1; Soln (vials): 10million IU/vial–6 (kit w. supplies); Soln (multidose vials): 18million, 25million IU/vial–1

KEYTRUDA Merck

℞

Human programmed death receptor-1 (PD-1)blocking antibody. Pembrolizumab 50mg; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free. Indications: Treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Adults: Give as IV infusion over 30mins. 2mg/kg every 3 weeks until disease progression or unacceptable toxicity. Dose modifications: see full labeling. Administer corticosteroids for most Grade ≥2 related immune-mediated reactions. Children: Not established. Warnings/Precautions: Monitor for signs/ symptoms of pneumonitis; withhold dose if Grade 2 pneumonitis; permanently discontinue if Grade 3 or 4 develops. Monitor for signs/ symptoms of colitis; withhold dose if Grade 2

or 3 colitis; permanently discontinue if Grade 4 develops. Monitor for changes in liver function; withhold dose or discontinue based on severity of elevated liver enzymes. Monitor for hypophysitis; withhold dose if Grade 2 hypophysitis; withhold or discontinue if Grade 3; permanently discontinue if Grade 4 develops. Monitor for changes in renal function; withhold dose if Grade 2 nephritis; permanently discontinue if Grade 3 or 4 develops. Monitor thyroid function at treatment initiation, during, and as clinically indicated; withhold if Grade 3 hyperthyroidism; permanently discontinue if Grade 4 develops. Permanently discontinue if any severe or Grade 3 immunemediated adverse reaction that recurs and for any life-threatening immune-mediated adverse reaction. Use highly effective contraception during treatment and for at least 4 months after the last dose. Pregnancy (Cat.D), nursing mothers: not recommended. Adverse reactions: Fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, diarrhea, sepsis; renal failure, dyspnea, pneumonia, cellulitis. How supplied: Single-use vial–1

MEKINIST GlaxoSmithKline

℞

Kinase inhibitor. Trametinib 0.5mg, 1mg, 2mg; tabs. Indications: As monotherapy or in combination with dabrafenib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDAapproved test. Limitation of use: as a single agent is not indicated for the treatment of patients who have received prior BRAF-inhibitor therapy. Adults: Confirm presence of BRAF V600E or V600K mutation prior to initiation. Take at least 1hr before or 2hrs after a meal. Monotherapy or in combination with dabrafenib: 2mg once daily; continue until disease progression or unacceptable toxicity occurs. In combination therapy: take at same time each day either with the AM or PM dose of dabrafenib. Dose modifications: see full labeling. Children: Not established. Warnings/Precautions: See full labeling for dabrafenib prior to starting combination therapy. Risk of cardiomyopathy; assess LVEF prior to initiation, after one month, and then at every 2–3 month intervals during treatment; withhold if absolute LVEF decreases by 10% from pre-treatment values and is less than the lower limit of normal; permanently discontinue if symptomatic cardiomyopathy or persistent

asymptomatic LVEF dysfunction is unresolved within 4 weeks. Perform eye exam at any time for visual disturbances and compare to baseline. Retinal pigment epithelial detachment; withhold if diagnosed; if resolved within 3 weeks, may resume at reduced dose. Withhold if new or progressive pulmonary symptoms or findings develop. Permanently discontinue if retinal vein occlusion, interstitial lung disease, or pneumonitis occurs. Monitor for skin toxicities and secondary infections. Embryo-fetal toxicity. Females of reproductive potential should use highly effective contraception during and for 4 months after treatment. Pregnancy (Cat.D). Nursing mothers: not recommended. Adverse reactions: Rash, diarrhea, lymphedema; combination with dabrafenib: pyrexia, chills, fatigue, rash, nausea, vomiting, constipation, abdominal pain, peripheral edema, cough, headache, arthralgia, night sweats, decreased appetite, myalgia; hemorrhage, thromboembolic events. How supplied: Tabs–30

PROLEUKIN Prometheus

℞

Interleukin-2, recombinant. Aldesleukin 22 million IU/vial; pwd for IV infusion after reconstitution and dilution; contains mannitol; preservative-free. Indications: Metastatic melanoma. Adults: ≥18yrs: 600,000 IU/kg (0.037mg/kg) every 8 hours by IV infusion over 15 minutes for a max of 14 doses, followed by 9 days rest, then repeat for another 14 doses (max 28 doses/ course), as tolerated. Retreatment and dose adjustments: see literature. Children: <18yrs: not established. Contraindications: Abnormal thallium stress test or pulmonary function tests. Organ allografts. Previous drug related toxicity (eg, sustained ventricular tachycardia [≥5 beats], uncontrolled or unresponsive arrhythmias, chest pain with ECG changes consistent with angina, or MI, cardiac tamponade, intubation >72hrs, renal failure requiring dialysis >72hrs, coma or toxic psychosis >48hrs, repetitive or difficult seizures, bowel ischemia or perforation, GI bleeding requiring surgery). Warnings/Precautions: See literature. History of cardiac or pulmonary disease. Renal, hepatic, or CNS impairment. Seizure disorder. Bacterial infections (treat prior to starting therapy; esp. patients with indwelling central lines). Withhold dose if organ perfusion is not maintained, urine output is reduced, systolic BP <90mmHg, CHF, cardiac ischemia or arrhythmias occur; or if moderate-to-severe lethargy or

Access Cancer Therapy Advisor treatment regimens in a user-friendly format. CancerTherapyAdvisor.com/TreatmentRegimens.

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DRUG MONOGRAPHS

SKIN CANCER somnolence (continuing may result in coma) develops. Evaluate and treat CNS metastases; obtain negative scan before starting treatment. Do thallium stress test; monitor vital signs, weight, fluid intake and output daily. Correct hypovolemia or fluid accumulations if occur. Obtain CBCs, differential and platelets, blood chemistries (electrolytes, renal and hepatic function tests), chest X-rays, serum creatinine (should be ≤1.5mg/dL before starting therapy), pulmonary function tests, arterial blood gases. Monitor for capillary leak syndrome, mental status changes, thyroid changes, diabetes onset. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Psychotropics may increase CNS toxicity. Increased toxicity with other nephrotoxic, hepatotoxic, myelotoxic, or cardiotoxic drugs. Hypersensitivity reactions with other antineoplastics. Myocardial injury and rhabdomyolysis risk increased with interferonalfa. Antagonized by glucocorticoids (avoid). β-blockers and other antihypertensives may potentiate hypotension. Delayed reactions to iodinated contrast media. May increase risk of allograft rejection. Adverse reactions: Hypotension, GI upset, oliguria, flu-like syndrome, respiratory disorders (eg, dyspnea), CNS effects (eg, confusion, somnolence), rash, metabolic and nutritional disorders (eg, bilirubinemia, increased creatinine), hyperglycemia, thyroid disorder, thrombocytopenia, anemia, impaired neutrophil function, capillary leak syndrome, cardiotoxicity, exacerbation of autoimmune and inflammatory disease, eosinophilia, possible antibody formation; others. How supplied: Single-use vials–1

SYLATRON Merck

℞

Alpha interferon. Peginterferon alfa-2b 296mcg, 444mcg, 888mcg; per vial; pwd for SC inj after reconstitution. Indications: Adjuvant treatment of melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy. Adults: ≥18yrs: Give by SC inj. Rotate inj sites. Premedicate with acetaminophen. 6mcg/kg/ week for 8 doses, followed by 3mcg/kg/week for up to 5 years. Withhold dose if ANC <0.5×109/L, platelets <50×109/L, ECOG PS ≥2, or for non-hematologic toxicity ≥ Grade 3. Resume at reduced dose (see literature) when: ANC ≥0.5×109/L, platelets ≥50×109/L, ECOG PS 0–1, and non-hematologic toxicity has completely resolved or improved to Grade 1. Children: <18yrs: not established. Contraindications: Anaphylaxis to peginterferon alfa-2b or interferon alfa-2b. Autoimmune hepatitis. Hepatic decompensation (Child-Pugh score >6 [Class B and C]). Warnings/Precautions: Increased risk of depression and other neuropsychiatric disorders.

Permanently discontinue for: persistent severe or worsening neuropsychiatric disorders (eg, depression, psychosis, encephalopathy); new onset ventricular arrhythmia or cardiovascular decompensation; new or worsening retinopathy; severe (Grade 3) hepatic injury or hepatic decompensation; hypothyroidism, hyperthyroidism, or diabetes mellitus that cannot be effectively managed; or if unable to tolerate a dose of 1mcg/kg/week. Monitor for signs/symptoms of depression/psychosis every 3 weeks during first 8 weeks, then every 6 months, continue for at least 6 months after last dose. Perform eye exam in patients with retinopathy and those with vision changes during therapy. Monitor hepatic function with serum bilirubin, ALT/AST, alkaline phosphate, and LDH at 2 and 8 weeks, and 2 and 3 months following initiation, then every 6 months. Obtain TSH levels within 4 weeks prior to initiation, at 3 and 6 months following initiation, then every 6 months. Moderate-to-severe renal impairment (monitor). Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Therapeutic effect of drugs metabolized by CYP2C9 or CYP2D6 may be altered. Adverse reactions: Fatigue, increased ALT/AST, pyrexia, headache, anorexia, myalgia, nausea, chills, inj site reactions; neuropsychiatric disorders. How supplied: Single-use vial–1, 4 (w. diluent)

TAFINLAR GlaxoSmithKline

℞

Kinase inhibitor. Dabrafenib 50mg, 75mg; caps. Indications: As monotherapy for the treatment of unresectable or metastatic melanoma with BRAF V600E mutation, as detected by an FDAapproved test. In combination with trametinib for the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations, as detected by an FDA-approved test. Limitation of use: not indicated for the treatment of wild-type BRAF melanoma. Adults: Confirm presence of BRAF V600E or V600K mutation prior to initiation. Swallow whole. Take at least 1hr before or 2hrs after a meal. Monotherapy or in combination with trametinib: 150mg twice daily (about 12hrs apart); continue until disease progression or unacceptable toxicity occurs. Dose modifications or reductions: see full labeling. Children: Not established. Warnings/Precautions: See full labeling for trametinib prior to starting combination therapy. Increased incidence of new primary cutaneous malignancies; perform skin evaluation prior to initiation, every 2 months during therapy, and up to 6 months after discontinuation. Withhold if fever ≥101.3°F or any serious febrile drug reaction occurs and evaluate for infection; prophylaxis with antipyretics may be needed when resuming. Pre-existing diabetes or hyperglycemia; monitor serum glucose levels. Monitor for visual signs/

symptoms of uveitis. Closely monitor patients with G6PD deficiency for signs of hemolytic anemia. Males (risk of infertility). Embryo-fetal toxicity. Females of reproductive potential should use highly effective non-hormonal contraception during and for 4 weeks after treatment. Pregnancy (Cat.D). Nursing mothers: not recommended. Interactions: Concomitant strong inhibitors (eg, ketoconazole, nefazodone, clarithromycin, gemfibrozil) or inducers (eg, rifampin, phenytoin, carbamazepine, phenobarbital, St John’s wort) of CYP3A4 or CYP2C8: not recommended; if unavoidable, monitor closely. Drugs that affect gastric pH (eg, PPIs, H2-blockers, antacids) may decrease dabrafenib exposure. May antagonize effects of CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19, UGT, transporters, or other substrates (eg, midazolam, warfarin, dexamethasone, hormonal contraceptives). Adverse reactions: Hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, palmar-plantar erythrodysesthesia syndrome; combination with trametinib: chills, fatigue, rash, nausea, vomiting, diarrhea, constipation, abdominal pain, peripheral edema, cough, night sweats, decreased appetite, myalgia; hemorrhage, thromboembolic events. How supplied: Caps–120

YERVOY Bristol-Myers Squibb

℞

Cytotoxic T-lymphocyte antigen 4 (CTLA-4)blocking antibody. Ipilimumab 5mg/mL; soln for IV infusion; preservative-free. Indications: Treatment of unresectable or metastatic melanoma. Adults: Give by IV infusion over 90 mins. 3mg/kg every 3 weeks for a total of 4 doses. Withhold dose for moderate immune-mediated reactions or symptomatic endocrinopathy. Complete/partial resolution of adverse reaction and receiving <7.5mg prednisone or equivalent per day: may resume treatment. Permanently discontinue and initiate systemic high-dose corticosteroids for severe adverse reactions. Children: Not established. Warnings/Precautions: Permanently discontinue if: persistent moderate adverse reactions or inability to reduce corticosteroid dose to 7.5mg prednisone or equivalent per day; failure to complete full treatment course within 16 weeks from first dose; severe or lifethreatening reactions, including: 1) colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency and incontinence, need for IV hydration for >24hrs, GI hemorrhage/ perforation; 2) AST or ALT >5X ULN or total bilirubin >3X ULN; 3) Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; 4) severe motor or sensory neuropathy, GuillainBarre syndrome, or myasthenia gravis; 5) severe immune-mediated reactions involving any organ

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SKIN CANCER squamous cell carcinoma (cuSCC): ≥65yrs, prior skin cancer, chronic sun exposure; if occurs, do excision and evaluate. Perform dermatologic evaluation before therapy, every 2 months during, and consider monitoring 6 months after discontinuation. Monitor for signs/symptoms of new non-cutaneous SCC and other malignancies. Long QT syndrome or QTc >500ms, uncorrectable electrolyte abnormalities, or concomitant drugs that prolong the QT interval: not recommended. Prior to and following initiation or after dose adjustment for QTc prolongation, evaluate ECG and electrolytes after 15 days, monthly during the 1st 3 months, then every 3 months thereafter, or more as clinically indicated. Severe hepatic or renal impairment. Monitor liver enzymes, bilirubin before initiating and monthly during treatment, or as needed. Monitor for ophthalmologic reactions routinely. Avoid sun exposure. Pregnancy (Cat.D); avoid. Use adequate contraception during therapy and for at least 2 months after discontinuation. Nursing mothers: not recommended. Interactions: Avoid concomitant strong CYP3A4 inhibitors (eg, azole antifungals, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir) or strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); consider alternatives. Concomitant CYP1A2 substrates with narrow therapeutic indices: not recommended; if unavoidable, consider dose

system; 6) immune-mediated ocular disease that is unresponsive to topical immunosuppressive therapy. Monitor for enterocolitis, dermatitis, neuropathy, endocrinopathy; perform LFTs and thyroid tests at baseline and before each dose. Moderate or severe hepatic impairment. Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Fatigue, diarrhea, pruritus, rash, colitis; immune-mediated adverse reactions (may be severe and fatal). How supplied: Single-use vial (50mg, 200mg)–1

ZELBORAF Genentech

℞

Kinase inhibitor. Vemurafenib 240mg; tabs. Indications: Treatment of unresectable or metastatic melanoma with BRAFV600E mutation as detected by an FDA-approved test. Limitation of use: not for treatment of wild-type BRAF melanoma. Adults: Swallow whole. ≥18yrs: 960mg every 12hrs; until disease progression or unacceptable toxicity occurs. Dose modifications for adverse reactions or QTc prolongation: see full labeling. Dose reductions <480mg twice daily: not recommended. Children: <18yrs: not established. Warnings/Precautions: Confirm BRAFV600E mutation-positive melanoma with FDA-approved test before initiating. Risk of cutaneous

reduction of substrates and monitor. Increased transaminase and bilirubin with concomitant ipilimumab. Adverse reactions: Arthralgia, rash, alopecia, fatigue, photosensitivity, nausea, pruritus, skin papilloma; severe hypersensitivity or dermatologic reactions (permanently discontinue if occurs), uveitis, blurry vision, photophobia, other malignancies. How supplied: Tabs–120

HYPERSENSITIVITY to

a drug or its class is assumed to be a contraindication in all product monographs, although not explicitly stated.

LIVER FUNCTION ASSESSMENT Child-Pugh Score is used to assess residual liver function and injury severity in cirrhosis patients.

CHILD-PUGH SCORES Criteria

1 point

2 points

3 points

Total serum bilirubin (mg/dL)

2–3

Serum albumin (g/dL)

>3.5

2.8–3.5

<2.8

INR

<1.70

1.71–2.20

>2.20

Ascites

No ascites

Ascites controlled

Ascites not controlled

Encephalopathy

No encephalopathy

Encephalopathy controlled

Encephalopathy not controlled

INTERPRETATION OF CHILD-PUGH SCORES Class A

Class B

Class C

Points

5–6

7–9

10–15

Life expectancy

15–20 years

Candidate for liver transplant

1–3 years

Perioperative mortality

10%

30%

82%

Take advantage of our free online medical calculators at CancerTherapyAdvisor.com/MedicalCalculators.

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Anemias

ANADROL-50 Meda

CIII

Androgen. Oxymetholone 50mg; scored tabs. Indications: Anemia caused by deficient red cell production. Acquired aplastic anemia, congenital anemia, myelofibrosis, and hypoplastic anemias due to myelotoxic drugs. Adults and Children: Individualized. 1–5mg/kg per day for at least 3–6 months; may attempt to lower dose or discontinue after remission. Congenital aplastic anemia: may need continued maintenance dose. Contraindications: Male breast or prostate carcinoma. Breast cancer in females with hypercalcemia. Nephrosis or the nephrotic phase of nephritis. Severe hepatic dysfunction. Pregnancy (Cat.X). Warnings/Precautions: Not a replacement for other supportive treatments (eg, transfusion; iron, folic acid, Vit. B12, Vit. B6 replacement). Discontinue if jaundice, abnormal liver function, hypercalcemia, or edema occurs. Cardiac, hepatic, or renal dysfunction. Monitor hepatic function, blood, and bone age. Elderly. Young children. Nursing mothers: not recommended. Interactions: May potentiate oral anticoagulants. May alter insulin needs. Adverse reactions: Peliosis hepatis, premature epiphyseal closure in adolescents, edema, hepatic carcinoma, prostatic hypertrophy or carcinoma, gynecomastia, priapism, oligospermia, nausea, jaundice, hirsutism, virilization, male pattern baldness, acne, polycythemia, headache, CNS excitation, insomnia, altered libido, fluid and electrolyte disturbances, suppression of clotting factors, increased serum cholesterol. How supplied: Tabs–100

ARANESP Amgen

℞

Erythropoiesis stimulating protein. Darbepoetin alfa 25mcg/mL, 40mcg/mL, 60mcg/mL, 100mcg/mL, 150mcg/0.75mL, 200mcg/mL, 300mcg/mL, 500mcg/mL; for IV or SC inj; preservative-free; contains albumin (human) or polysorbate 80. Also: ARANESP SINGLEJECT ℞ Darbepoetin alfa 25mcg/0.42mL, 40mcg/0.4mL, 60mcg/0.3mL, 100mcg/0.5mL, 150mcg/0.3mL, 200mcg/0.4mL, 300mcg/0.6mL, 500mcg/mL; per prefilled syringe; for IV or SC inj; preservativefree; contains albumin (human) or polysorbate 80. Indications: Anemia of chronic renal failure (CRF), including patients on and not on dialysis. Chemotherapy-induced anemia in patients with non-myeloid malignancies. Adults: CRF (not currently on epoetin alfa): initially 0.45mcg/kg SC or IV once weekly; alternatively for CRF (not on dialysis): 0.75mcg/kg SC once every 2 weeks. Cancer: initially 2.25mcg/kg SC once weekly or 500mcg SC once every 3 weeks. Discontinue after completion of chemotherapy course. Adjust dose to maintain hemoglobin level (target 10–12g/dL; max 12g/dL) sufficient to

avoid red blood cell transfusion; see literature. Converting from epoetin alfa, and for dose adjustment: see literature. Children: Not recommended. Contraindications: Uncontrolled hypertension. Do not use in patients with pure red cell aplasia due to erythropoietin antibodies. Warnings/Precautions: See literature. Evaluate serum iron, ferritin, transferrin saturation before and during therapy; most patients will need iron supplementation. Monitor hemoglobin weekly for 4 weeks after start and dose changes, until stabilized, then periodically; reduce dose if hemoglobin increases >1g/dL in any 2-week period; withhold dose if hemoglobin exceeds 12g/dL. Monitor BP (reduce or withhold dose if hypertension occurs), folate, Vit. B12, renal function, electrolytes, fluid balance, and for premonitory neurological symptoms. Seizure, cardiovascular, or hematologic disorders. Infection, inflammation, malignancy, occult blood loss, severe albumin toxicity, bone marrow fibrosis may reduce effectiveness; consider other etiologies in treatment failures. Adjust dialysis ℞ as needed. Latex allergy. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Infection, hyper- or hypotension, myalgia, headache, GI upset, dyspnea, edema, arthralgia, limb or back pain, arrhythmia/cardiac arrest, cough, fatigue, chest pain, dizziness, pruritus, clotted vascular access, CHF, flu-like symptoms, local reactions, asthenia, seizure, iron deficiency. Increased risk of death, cardiovascular or thrombotic events if hemoglobin >12g/dL. May stimulate tumor growth, shorten time to tumor progression or overall survival if hemoglobin ≥12g/dL. Cancer patients also: pneumonia, dehydration. How supplied: Single-dose vials (25, 40, 60, 100, 150mcg)–4; Single-dose vial (200, 300mcg)–1; Single-dose prefilled syringes (25, 40, 60, 100, 150mcg)–4; Single-dose prefilled syringes (200, 300, 500mcg)–1

ATGAM Pfizer

℞

Immune globulin. Lymphocyte immune globulin, anti-thymocyte globulin [equine] 50mg/mL; soln for IV infusion after dilution. Indications: Treatment of moderate to severe aplastic anemia in patients who are unsuitable for bone marrow transplantation. Adults: Perform intradermal test dose before initiating therapy (see literature). Do not dilute in dextrose injection or highly acidic infusion solutions. Give by IV infusion over >4hrs. 10–20mg/kg daily for 8–14 days. Additional alternate-day therapy up to a total of 21 doses can be administered. May need prophylactic platelet transfusions to maintain platelets. Children: Limited experience (see literature). Warnings/Precautions: To be administered by physicians with experience in immunosuppressive therapy and in facilities equipped with adequate lab and supportive medical resources. Discontinue if symptoms of anaphylaxis develop. Contains human

plasma; monitor for possible infection transmission. Monitor for leukopenia, thrombocytopenia, or infection esp. with concomitant corticosteroids and antimetabolites. Pregnancy (Cat.C): not recommended. Nursing mothers. Interactions: Previously masked reactions may occur when corticosteroids and other immunosuppressant doses are reduced. Adverse reactions: Fever, skin reactions, chills, arthralgia, headache, myalgia, GI upset, chest pain, phlebitis, diaphoresis, joint stiffness, edema, muscle ache, vomiting, agitation/lethargy, listlessness, lightheadedness, seizures, bradycardia, myocarditis, cardiac irregularity, hepatosplenomegaly, possible encephalitis or post viral encephalopathy, hypotension, CHF, hypertension, burning soles/ palms, foot sole pain, lymphadenopathy, postcervical lymphadenopathy, tender lymph nodes, bilateral pleural effusion, respiratory distress, anaphylactic reaction, proteinuria, abnormal LFTs and renal function, serum sickness. How supplied: Ampules (5mL)–5

BIFERA Meda

OTC

Iron (as polysaccharide iron complex [PIC] 22mg + heme iron polypeptide [HIP] as Proferrin bovine source 6mg) 28mg; gluten-free tabs. Indications: Iron supplement. Iron deficiency. Adults: 1 tab once daily. Children: Not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: May mask pernicious anemia. Monitor hemoglobin, hematocrit, ferritin levels periodically. Pregnancy. Nursing mothers. Adverse reactions: Allergic sensitization. How supplied: Tabs–30

BIFERARx Meda

℞

Iron (as polysaccharide iron complex [PIC] 22mg + heme iron polypeptide [HIP] as Proferrin bovine source 6mg) 28mg, folic acid 1mg, Vit. B12 25mcg; tabs. Indications: Iron supplement. Iron deficiency. Adults: 1 tab once daily. Children: Not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: May mask pernicious anemia. Monitor hemoglobin, hematocrit, ferritin levels periodically. Pregnancy. Nursing mothers. Adverse reactions: Allergic sensitization. How supplied: Tabs–90

Cyanocobalamin injection

℞

(various)

Vitamin. Cyanocobalamin 1000mcg/mL; soln for IM or SC inj; contains benzyl alcohol. Indications: Vit. B12 deficiencies due to malabsorption. Pernicious anemia. Vit. B12 absorption test (Schilling test). Adults: Give by IM or deep SC inj. Pernicious anemia: 100mcg daily for 6–7 days; then 100mcg

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ASSOCIATED HEMATOLOGICAL DISORDERS every other day for 7 doses; then every 3–4 days for 2–3 weeks; then 100mcg monthly for life. Deficiencies due to malabsorption: if severe, may need to treat like pernicious anemia; use oral preparations for chronic treatment. Schilling test: 1000mcg. Children: See literature. Contraindications: Sensitivity to cobalt. Warnings/Precautions: Hereditary optic nerve atrophy (Leber’s disease). Severe megaloblastic anemia (intense treatment may lead to hypokalemia and death). Monitor potassium for first 48 hours; replace if needed. Obtain hematocrit, reticulocyte count, Vit. B12, folate, and iron levels before and during treatment. Reevaluate periodically. Premature infants. Renal impairment (possible aluminum toxicity). Folic acid use may mask B12 deficiency. Pregnancy (Cat.C). Interactions: Antibiotics, methotrexate, pyrimethamine interfere with Vit. B12 diagnostic tests. Colchicine, para-aminosalicylic acid, heavy alcohol intake for >2 weeks may produce malabsorption of Vit. B12. Adverse reactions: Pulmonary edema, CHF, vascular thrombosis, polycythemia vera, transient diarrhea, itching, transitory exanthema; anaphylactic shock (may be fatal; do test dose if hypersensitivity suspected). How supplied: Contact supplier.

DEXFERRUM American Regent

℞

Hematinic. Iron (as dextran complex) 50mg/mL; soln for IV inj. Indications: Iron deficiency where oral therapy is unsatisfactory or impossible. Adults and Children: <4months: not recommended. Give by IV inj. Administer 0.5mL test dose first; if no signs/symptoms of anaphylactictype reactions, may give full therapeutic dose. ≥4months: Iron deficiency anemia: determine total dose based on hemoglobin and body weight (see literature). Iron replacement for blood loss: Replacement iron (in mg) = blood loss (in mL) × hematocrit. Max daily doses: <5kg: 0.5mL (25mg), <10kg: 1mL (50mg), ≥10kg: 2mL (100mg). Contraindications: Anemia not associated with iron deficiency. Warnings/Precautions: Monitor for signs/ symptoms of anaphylactic-type reactions, esp. in patients with history of allergies, asthma; have epinephrine available. Hepatic impairment. Avoid during acute phase of infectious kidney disease. Cardiovascular disease. Avoid large IV doses: higher incidence of adverse events. Iron overload more likely with hemoglobinopathies or refractory anemias. Rheumatoid arthritis. Neonates. Pregnancy (Cat.C). Nursing mothers.

Interactions: Concomitant ACE inhibitors may increase the risk for anaphylactic-type reactions. May falsely elevate serum bilirubin and decrease serum calcium. Adverse reactions: See literature. Anaphylactic reactions (may be fatal, even in patients who tolerated test dose), cardiovascular events, pruritus, GI upset, arthralgia, arthritis, inj site reactions, others. How supplied: Single-dose vials (1mL, 2mL)–10

DROXIA Bristol-Myers Squibb

℞

Substituted urea. Hydroxyurea 200mg, 300mg, 400mg; caps. Indications: To reduce the frequency of painful crises and to reduce the need for blood transfusions in adults with sickle cell anemia with recurrent moderate-to-severe painful crises. Adults: Base dose on ideal or actual weight, whichever is less. Initially 15mg/kg/day as a single dose. May increase dose by 5mg/kg/day every 12 weeks to maximum tolerated dose or 35mg/kg/day achieved; do not increase dose if blood counts are between acceptable range and toxic. If blood counts toxic, discontinue until hematologic recovery, see literature for dosage adjustments. Renal impairment (CrCl <60mL/min or ESRD): initially 7.5mg/kg per day; give dose following dialysis. Children: Not recommended. Warnings/Precautions: Markedly depressed bone marrow function: not recommended. Monitor hematologic, renal, and liver function before and during therapy. Renal dysfunction. Macrocytosis may mask folic acid deficiency; prophylactic folic acid is recommended. Myeloproliferative disorders; discontinue if cutaneous vasculitic ulcerations develop. Pregnancy (Cat.D); avoid use. Nursing mother: not recommended. Interactions: Avoid concomitant didanosine, with or without stavudine, or other antiretrovirals (may cause pancreatitis [monitor], fatal hepatotoxicity, peripheral neuropathy). May antagonize antigout agents. Increased risk of vasculitic toxicities with interferon therapy. May cause falsely elevated urease, uricase, lactate dehydrogenase. Adverse reactions: Neutropenia, thrombocytopenia, anemia, low reticulocyte count, hair loss, rash, fever, GI upset, weight gain, bleeding, parvovirus B-19 infection, melanonychia, erythema, CNS effects, temporary renal impairment, acute pulmonary reactions, secondary leukemias, skin cancer. Note: Wear disposable gloves when handling caps or bottle. How supplied: Caps–60

EPOGEN Amgen

℞

Erythropoietin (human, recombinant). Epoetin alfa 2000 Units, 3000 Units, 4000 Units, 10000 Units, 40000 Units; per mL; soln for IV or SC inj; contains albumin (human); preservative-free. ℞ Also: EPOGEN MULTIDOSE Epoetin alfa 10000 Units, 20000 Units; per mL; soln for IV or SC inj; contains albumin (human) and benzyl alcohol. Indications: Anemia in chronic renal failure (CRF). Anemia related to zidovudine in HIVinfected patients. Chemotherapy-induced anemia in patients with non-myeloid malignancies (serum erythropoietin ≤200 mUnits/mL). To reduce need for allogeneic blood transfusions in anemic (hemoglobin >10 to ≤13g/dL) patients scheduled for elective, noncardiac, nonvascular surgery. Adults: Individualize (see literature for titration). CRF: initially 50–100 Units/kg 3 times per week IV (dialysis or non dialysis) or SC (non dialysis); usual max (non dialysis) 150 Units/kg 3 times per week; (dialysis) 200 Units/kg 3 times per week; target hemoglobin 10–12g/dL. Zidovudinetreated HIV patients: if serum erythropoietin ≤500 mUnits/mL and zidovudine dose ≤4.2 g/wk: initially 100 Units/kg IV or SC 3 times per week for 8 weeks; usual max 300 Units/kg 3 times per week. Chemotherapy-induced: initially 150 Units/kg SC 3 times per week; may increase to 300 Units/kg 3 times per week after 8 weeks. Or, initially 40000 Units SC once weekly; may increase to 60000 Units once weekly after 4 weeks. Discontinue after completion of chemotherapy course. Surgery: If ≥21 days until surgery: 600 Units/kg once weekly SC at 21, 14 and 7 days before surgery, and a 4th dose on day of surgery. If <21 days until surgery: 300 Units/kg per day SC for 10 days before, on day of, and for 4 days after surgery. All: adjust dose to maintain the lowest hemoglobin level (target max 12g/dL) sufficient to avoid red blood cell transfusion; see literature. Children: Individualize (see literature for monitoring). CRF (dialysis): <1 month: not recommended. ≥1 month of age: initially 50 Units/kg three times per week IV or SC. Target hemoglobin: 10–12g/dL. Chemotherapy-induced: ≥5yrs: 600 Units/kg IV weekly (max 40,000 Units); may increase to 900 Units/kg IV weekly (max 60,000 Units) after 4 weeks. Discontinue after completion of chemotherapy course. Other uses: see literature. Contraindications: Uncontrolled hypertension. Warnings/Precautions: See literature. Evaluate serum iron, ferritin, transferrin saturation before therapy; all patients will need iron supplementation. Monitor hemoglobin (measure twice weekly for 2–6 weeks after any dosage adjustment;

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS reduce dose if hemoglobin increases >1g/dL in any 2-week period; withhold dose if hemoglobin exceeds 12g/dL), blood pressure, renal function, iron levels, clotting times, serum chemistry, CBC, and for premonitory neurological symptoms. Seizure disorders. Cardiovascular or hematologic disorders. Hypertension (esp. in renal failure). Porphyria. Concurrent infection, inflammation, increased zidovudine dose, or other factors may reduce effectiveness. Perisurgery: consider DVT prophylaxis. Consider other etiologies in treatment failures. Adjust anticoagulant dose in dialysis patients. Menses may resume. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Iron deficiency, hypertension, headache, arthralgia, GI disturbances, edema, local reaction, rash, paresthesia, dizziness, clotted vascular access (A-V shunt), pyrexia, respiratory congestion, seizures. Increased risk of death, cardiovascular or thrombotic events if hemoglobin >12g/dL. May stimulate tumor growth, shorten time to tumor progression or overall survival if hemoglobin ≥12g/dL. Children: also abdominal pain, upper respiratory infection, cough, pharyngitis, constipation. How supplied: Single-use 1mL vials (all)–10; Multidose 2mL vials (10000 Units/mL)–10; Multidose 1mL vials (20000 Units/mL)–10

FEOSOL Meda

OTC

Iron 65mg (as sulfate 200mg); tabs. Also: FEOSOL CAPLETS OTC Iron 50mg (as carbonyl). Also: FEOSOL ELIXIR OTC Iron 44mg/5mL (as sulfate 220mg/5mL); alcohol 5%. Indications: Iron deficiency and iron deficiency anemia. Adults: 1 tab or 1 caplet or 5mL daily. Children: Individualize. May mix with water or fruit juice. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools, tooth discoloration (elixir). How supplied: Tabs, caplets–30, 60; Elixir–16oz

FER-IN-SOL DROPS

OTC

Mead Johnson Nutrition

Iron 15mg/1mL (as sulfate 75mg/1mL); contains sulfites, alcohol; gluten-free. Indications: Iron deficiency and iron deficiency anemias. Adults and Children: May give directly into the mouth or mix with formula, fruit juice, cereal or other foods. <4yrs: 1mL daily. ≥4yrs: not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly.

Interactions: Inhibits tetracycline absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, masks occult bleeding, black stools, stains teeth and dentures. How supplied: Drops–50mL (w. calibrated dropper)

FERAHEME AMAG

℞

Hematinic. Elemental iron 30mg/mL (as ferumoxytol 510mg/17mL); colloidal iron for IV inj; contains mannitol 44mg/mL; preservative-free. Indications: Iron deficiency anemia in adult patients with chronic kidney disease. Adults: Give undiluted by IV injection at a rate up to 1mL/sec (30mg/sec). Initially 510mg, then an additional dose 3–8 days later. May repeat in persistent or recurrent iron deficiency anemia. Hemodialysis: give at least 1 hour after starting hemodialysis and after BP is stable. Children: Not recommended. Warnings/Precautions: Iron overload: do not administer. Monitor for severe hypotension, and for hypersensitivity for at least 30 minutes after each injection. Evaluate hemoglobin, ferritin, iron, transferrin saturation at least 1 month after 2nd injection. Have equipment/personnel available to treat hypersensitivity reactions. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: May reduce absorption of concomitantly administered oral iron preparations. May transiently (up to 3 months) affect diagnostic ability of MRI (see literature). Adverse reactions: Diarrhea, nausea, hypotension (may be significant), dizziness, constipation, peripheral edema; infusion reactions, anaphylactoid reactions (may be fatal), other hypersensitivity reactions (eg, rash, pruritus, urticaria, wheeze). How supplied: Single-use vials (17mL)–1, 10

FERGON Bayer Consumer

OTC

Iron 27mg (as gluconate 240mg); tabs. Indications: Iron deficiency anemias. Adults: 1 tab daily. Children: Not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools. How supplied: Tabs–100

FERRALET 90 Mission Iron (as carbonyl) 90mg, folic acid 1mg, Vit.B12 12mcg, Vit.C 120mg, docusate sodium 50mg; tabs; contains tartrazine. Indications: Iron deficiency anemia. Adults: Swallow whole. Take 2hrs after meals. 1 tab once daily. Children: Not recommended.

℞

Contraindications: Hemolytic anemia. Hemochromatosis. Hemosiderosis. Warnings/Precautions: May mask pernicious anemia. Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly. Interactions: Inhibits tetracycline, fluoroquinolone absorption. Aluminum- or magnesium-containing antacids inhibit iron absorption. Adverse reactions: GI upset or irritation, constipation, dark stools, allergic sensitization. How supplied: Tabs–90

FERRETTS Pharmics

OTC

Iron 106mg (as fumarate); scored tabs; phosphorus- and gluten-free. Indications: Iron deficiency and iron deficiency anemia. Adults: 1 tablet daily. Children: Not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: GI upset, abdominal discomfort, constipation, masks occult bleeding, black stools. How supplied: Tabs–60

FERRLECIT Sanofi Aventis

℞

Hematinic. Iron (as sodium ferric gluconate complex in sucrose) 12.5mg/mL; soln for IV inj or infusion; contains benzyl alcohol. Indications: Iron deficiency anemia in patients on chronic hemodialysis receiving epoetin therapy. Adults: Give by IV infusion (diluted) or slow IV inj (undiluted). 125mg infused over 1 hour or by slow IV inj (at a rate of up to 12.5mg/min). Minimum cumulative dose: 1g given over 8 sequential dialysis sessions; usual max: 125mg/dose. Children: <6 yrs: not recommended. Give by IV infusion (diluted) over 1 hour. ≥6yrs: 1.5mg/kg per dose at 8 sequential dialysis sessions; max: 125mg/dose. Contraindications: Anemias not caused by iron deficiency. Iron overload. Neonates. Warnings/Precautions: Hemoglobinopathies. Refractory anemias. Pregnancy (Cat.B). Nursing mothers. Interactions: May reduce absorption of concomitant oral iron preparations. Adverse reactions: Hypotension, hypertension, GI upset, chest pain, back pain, abdominal pain, pruritus, inj site reaction, headache, dizziness, syncope, fatigue, fever, cramps, dyspnea, tachycardia; rare: hypersensitivity reactions. How supplied: Ampules (5mL)–10

FERRO-SEQUELS IVC

OTC

Iron (as fumarate) 50mg; timed-rel caplets; contains docusate sodium. Indications: Iron deficiency and iron deficiency anemias.

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ASSOCIATED HEMATOLOGICAL DISORDERS Adults: 1 caplet daily or as needed. Children: Not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools. How supplied: Caplets–100

Folic acid (various)

℞

Hematinic. Folic acid 1mg; tabs. Also: Folic acid injection ℞ Folic acid 5mg/mL; soln for IV, IM or SC inj; contains benzyl alcohol and aluminum. Indications: Megaloblastic anemias of folic acid deficiency. Anemias of nutritional origin, pregnancy, infancy or childhood. Adults and Children: Usual dose: up to 1mg daily; may need higher dose if resistant disease. Maintenance: infants: 0.1mg/day; <4yrs: 0.3mg/day; ≥4yrs: 0.4mg/day. Pregnant or lactating: 0.8mg/day. Alcoholism, hemolytic anemia, anticonvulsant therapy or chronic infection: may require higher dose. Warnings/Precautions: Use injectable form if disease is severe or GI absorption impaired. Rule out or treat vitamin B12 deficiency prior to treatment. May obscure diagnosis of pernicious anemia. Pregnancy (Cat.A). Interactions: May antagonize phenytoin. False low serum and red cell folate levels may occur with antibiotics (eg, tetracycline). Adverse reactions: Allergic sensitization. How supplied: Contact supplier.

ICAR-C Hawthorn

OTC

Iron (as carbonyl) 100mg, Vit. C 250mg; tabs. Also: ICAR-C PLUS ℞ Iron (as carbonyl) 100mg, Vit. B12 25mcg, folic acid 1mg, Vit. C 250mg; tabs. Also: ICAR PEDIATRIC SUSP OTC Iron (as carbonyl) 15mg/1.25mL; grape flavor; sugar- and alcohol-free. Indications: Iron deficiency and iron deficiency anemia. Adults: 1 tab once daily. Children: Use Ped Susp. 15mg (of iron) once daily. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: Folic acid may mask pernicious anemia. Monitor hemoglobin, hematocrit, reticulocyte count periodically. Elderly. Interactions: Inhibits tetracycline absorption. Aluminum- or magnesium-containing antacids inhibit iron absorption.

Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools. How supplied: Tabs–100 Ped Susp–4oz (w. dosing syringe)

INFED Actavis

℞

Hematinic. Iron (as dextran complex) 50mg/mL; soln for IV or IM inj. Indications: Iron deficiency where oral therapy is unsatisfactory or impossible. Adults and Children: Give by IV or by deep IM (into upper outer quadrant of buttock only) inj. Administer 0.5mL test dose first; if no signs/ symptoms of anaphylactic-type reactions, may give full therapeutic dose. Iron deficiency anemia: determine total dose based on hemoglobin and body weight (see literature). Iron replacement for blood loss: Replacement iron (in mg) = blood loss (in mL) × hematocrit. Max daily doses: <5kg: 0.5mL (25mg), <10kg: 1mL (50mg), ≥10kg: 2mL (100mg). Contraindications: Anemias not associated with iron deficiency. Warnings/Precautions: Monitor for signs/ symptoms of anaphylactic-type reactions, esp. in patients with history of drug allergies, asthma; have epinephrine available. Avoid large IV doses: higher incidence of adverse events. Severe hepatic impairment. Avoid during acute phase of infectious kidney disease. Dialysis. Cardiovascular disease. May reactivate quiescent rheumatoid arthritis. Neonates (avoid during first 4 months). Pregnancy (Cat.C). Nursing mothers. Interactions: Concomitant ACE inhibitors may increase the risk for anaphylactic-type reactions. May falsely elevate serum bilirubin or decrease serum calcium levels. Adverse reactions: See literature. Anaphylactic reactions (may be fatal; even if test dose was tolerated), cardiovascular events, pruritus, GI upset, arthralgia, arthritis, inj site reactions, others; possible IM inj site tumors, sepsis in neonates. How supplied: Vials (2mL)–10

INJECTAFER American Regent

℞

Hematinic. Iron (as ferric carboxymaltose) 50mg/mL; soln for IV inj or infusion; preservativefree. Indications: Iron deficiency anemia in adults who have intolerance or insufficient response to oral iron; or have non-dialysis-dependent chronic kidney disease. Adults: Give by slow IV push (undiluted) at rate of approx. 100mg (2mL)/min; or by IV infusion (diluted) administered over at least 15 mins. When giving via IV infusion, dilute to concentration not less than 2mg iron/mL. Give in 2 doses separated

by ≥7 days. <50kg: 15mg/kg/dose. ≥50kg: 750mg/dose. Total cumulative dose per course: max 1500mg. May repeat treatment if condition reoccurs. Children: Not established. Warnings/Precautions: Have epinephrine inj (1:1000) available. Monitor for serious hypersensitivity reactions during and after administration for ≥30 mins and until clinically stable. Monitor for signs/symptoms of hypertension after each administration. Avoid extravasation. Pregnancy (Cat.C). Nursing mothers. Interactions: Lab assays may result in overestimating serum iron and transferrin bound iron within 24hrs after administration. Adverse reactions: Nausea, hypertension, flushing, hypophosphatemia, dizziness; rare: hypersensitivity reactions. How supplied: Single-use vial (15mL)–1, 2

Leucovorin Teva

℞

Folic acid derivative. Leucovorin calcium 100mg/vial, 350mg/vial; lyophilized pwd for IV or IM inj after reconstitution; preservative-free. Indications: Megalobastic anemia due to folic acid deficiency when oral therapy is not feasible. Adults: Up to 1mg daily. Children: See literature. Contraindications: Pernicious anemia and other megaloblastic anemias due to Vit. B12 deficiency. Warnings/Precautions: Do not administer intrathecally. CNS metastases. Monitor CBCs with differential, platelets, electrolytes, liver function tests prior to each treatment, then periodically. Elderly. Debilitated. Pregnancy (Cat.C). Nursing mothers. Interactions: Potentiates toxicity of 5-fluorouracil; use lower 5-fluorouracil dose. May antagonize phenobarbital, phenytoin, and primidone. Caution with trimethoprim-sulfamethoxazole. Adverse reactions: Leukopenia, thrombocytopenia, infection, GI upset, stomatitis, constipation, lethargy, malaise, fatigue, alopecia, dermatitis, anorexia; seizures, syncope. How supplied: Single-use vials–1

LUPRON DEPOT 3.75mg

℞

AbbVie

GnRH analogue. Leuprolide acetate 3.75mg; depot susp for IM inj; preservative-free. Indications: Presurgical treatment of patients with anemia due to uterine leiomyomata (fibroids), with iron therapy if iron therapy alone is inadequate. Adults: ≥18 years: 3.75mg IM once per month for up to 3 months. Children: <18 years: not applicable.

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Also: LUPRON DEPOT-3 MONTH 11.25mg ℞ Leuprolide acetate 11.25mg; depot susp for IM inj; preservative-free. Adults: ≥18 years: 11.25mg IM once every 3 months (1 injection). Do not split doses. Children: <18 years: not applicable. Contraindications: Undiagnosed abnormal vaginal bleeding. Pregnancy (Cat.X). Nursing mothers. Warnings/Precautions: Exclude pregnancy before starting; use nonhormonal contraception during therapy; discontinue if pregnancy occurs. Risk factors for decreased bone mineral density (eg, chronic alcohol, tobacco, anticonvulsants, corticosteroids). Missing successive doses may cause breakthrough bleeding or ovulation. Elderly. Adverse reactions: Hot flashes, headache, vaginitis, depression, emotional lability, pain, decreased libido, breast changes, amenorrhea, mastodynia, joint disorder, asthenia, GI upset, edema, bone density loss, local reactions, acne, memory disorders, others; rarely: anaphylaxis, asthma, increased serum transaminases or lipids. How supplied: Kit–1 (single-dose syringe w. diluent, supplies)

NASCOBAL Strativa

℞

Cyanocobalamin 500mcg/spray; soln for nasal spray; contains benzalkonium chloride. Indications: Maintenance of normal hematologic status in pernicious anemia patients who are in remission after intramuscular Vit. B12 therapy and who have no nervous system involvement. Supplementation for other Vit. B12 deficiencies. Adults: Hematological parameters must be within normal range before beginning therapy. Allow at least 1hr before or after hot foods or liquids. Initial dose: One spray (500mcg) in one nostril once weekly. Monitor response, may increase dose if serum B12 levels decline. Children: Not recommended. Warnings/Precautions: Confirm diagnosis. May need supplemental folate. Risk of hypokalemia or sudden death in severe megablastic anemia. Leber’s disease. Defer dose if nasal congestion, rhinitis, or upper respiratory infections occur. Reevaluate if low levels of Vit. B12 persist despite treatment. Do not use for Schilling Test. Infection, uremia, and iron or folic acid deficiency may reduce response. Increased risk of stomach carcinoma in those with pernicious anemia; perform tests when indicated. May unmask polycythemia vera. Monitor B12 blood levels 1 month after starting therapy, 1 month after any dose increase, and regularly at 3–6 month intervals. Monitor serum potassium, platelet counts. Pregnancy (Cat.C). Interactions: Antibiotics, methotrexate, pyrimethamine may interfere with lab tests. Colchicine, chronic heavy alcohol use may impair Vit. B12 absorption. Reduced response with bone marrow suppressants (eg, chloramphenicol). Adverse reactions: Headache, nausea, rhinitis. How supplied: Single-use nasal spray (0.125mL)–4

NULECIT Actavis

℞

Hematinic. Iron (as sodium ferric gluconate complex in sucrose) 12.5mg/mL; soln for IV inj or infusion; contains benzyl alcohol. Indications: Iron deficiency anemia in patients on chronic hemodialysis receiving epoetin therapy. Adults: Give by IV infusion (diluted) or slow IV inj (undiluted). 125mg infused over 1 hour or by slow IV inj (at a rate of up to 12.5mg/min). Minimum cumulative dose: 1g given over 8 sequential dialysis sessions; usual max: 125mg/dose. Children: <6yrs: not recommended. Give by IV infusion (diluted) over 1 hour. ≥6yrs: 1.5mg/kg per dose at 8 sequential dialysis sessions; max: 125mg/dose. Contraindications: Anemias not caused by iron deficiency. Iron overload. Warnings/Precautions: Hemoglobinopathies. Refractory anemias. Avoid in neonates. Pregnancy (Cat.B). Nursing mothers. Interactions: May reduce absorption of concomitant oral iron preparations. Adverse reactions: Hypotension, hypertension, GI upset, chest pain, back pain, abdominal pain, pruritus, inj site reaction, cramps, headache, dizziness, syncope, fatigue, fever, dyspnea, tachycardia; rare: hypersensitivity reactions. How supplied: Vials (5mL)–10

PROCRIT Janssen Biotech

℞

SC at 21, 14 and 7 days before surgery, and a 4th dose on day of surgery. If <21 days until surgery: 300 Units/kg per day SC for 10 days before, on day of, and for 4 days after surgery. All: adjust dose to maintain the lowest hemoglobin level (target max 12g/dL) sufficient to avoid red blood cell transfusion; see literature. Children: Individualize (see literature for monitoring). CRF (dialysis): <1 month: not recommended. ≥1 month of age: initially 50 Units/kg three times per week IV or SC. Target hemoglobin: 10–12g/dL. Chemotherapy-induced: ≥5yrs: 600 Units/kg IV weekly (max 40,000 Units); may increase to 900 Units/kg IV weekly (max 60,000 Units) after 4 weeks. Discontinue after completion of chemotherapy course. Other uses: see literature. Contraindications: Uncontrolled hypertension. Warnings/Precautions: See literature. Evaluate serum iron, ferritin, transferrin saturation before therapy; all patients will need iron supplementation. Monitor hemoglobin (measure twice weekly for 2–6 weeks after any dosage adjustment; reduce dose if hemoglobin increases >1g/dL in any 2-week period; withhold dose if hemoglobin exceeds 12g/dL), blood pressure, renal function, iron levels, clotting times, serum chemistry, CBC, and for premonitory neurological symptoms. Seizure disorders. Cardiovascular or hematologic disorders. Hypertension (esp. in renal failure). Porphyria. Concurrent infection, inflammation, increased zidovudine dose, or other factors may reduce effectiveness. Perisurgery: consider DVT prophylaxis. Consider other etiologies in treatment failures. Adjust anticoagulant dose in dialysis patients. Menses may resume. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Iron deficiency, hypertension, headache, arthralgia, GI disturbances, edema, local reaction, rash, paresthesia, dizziness, clotted vascular access (A-V shunt), pyrexia, respiratory congestion, seizures. Increased risk of death, cardiovascular or thrombotic events if hemoglobin >12g/dL. May stimulate tumor growth, shorten time to tumor progression or overall survival if hemoglobin ≥12g/dL. Children: also abdominal pain, upper respiratory infection, cough, pharyngitis, constipation. How supplied: Single-use 1mL vials (2000 Units/mL, 3000 Units/mL, 4000 Units/mL, 10000 Units/mL)–6, 25; Single-use 1mL vials (40000 Units/mL)–4; Multidose 2mL vials (10000 Units/mL)–4, 6; Multidose 1mL vials (20000 Units/mL)–4, 6

PROMACTA GlaxoSmithKline

℞

Thrombopoietin receptor agonist. Eltrombopag (as olamine) 12.5mg, 25mg, 50mg, 75mg; tabs. Indications: Severe aplastic anemia in adults who have had insufficient response to immunosuppressive therapy. Adults: Take on empty stomach. Initially 50mg once daily. Hepatic impairment or East Asian ancestry: initially 25mg once daily.

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ASSOCIATED HEMATOLOGICAL DISORDERS Titrate dose by 50mg every 2 weeks as needed to maintain platelet count ≥50×109/L; max 150mg daily. Monitoring, dose adjustment, and discontinuation: see full labeling. Children: Not established. Warnings/Precautions: Increased risk of hepatic decompensation in chronic hepatitis C, when concomitant with interferon and ribavirin; discontinue Promacta if antiviral therapy is discontinued. Monitor liver function prior to initiation, every 2 weeks during dose adjustments, and monthly after stabilized (see full labeling); discontinue if ALT ≥3×ULN and is progressive or persistent for ≥4 weeks, or if occurs with increased bilirubin, or evidence of hepatic injury/ decompensation; reinitiate therapy if benefit outweighs risk; if restarted, monitor carefully. Increased risk of thromboembolism; do not use to normalize platelet counts. Do baseline eye exam; monitor for cataracts. Renal impairment. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Do not take within 4hrs of food/ drugs containing polyvalent cations (eg, Fe+2, Ca+2, Al+3, Mg+2, Se+2, Zn+2). Potentiate substrates of OATP1B1 (eg, most statins, bosentan, ezetimibe, glyburide, olmesartan, valsartan, repaglinide, rifampin) or BCRP (eg, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, topotecan); monitor and consider reducing their doses. Antagonized by lopinavir/ ritonavir. Adverse reactions: Nausea, diarrhea, fatigue, cough, headache, pain, dyspnea, pyrexia, dizziness, febrile neutropenia, ecchymosis, muscle spasms, arthralgia, rhinorrhea; elevated hepatic enzymes, hepatotoxicity, hemorrhage, thrombotic complications from excessive increases in platelet counts, cataracts. How supplied: Tabs–30

REVLIMID Celgene

℞

Immunomodulator. Lenalidomide 2.5mg, 5mg, 10mg, 15mg, 20mg, 25mg; caps. Indications: Transfusion-dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality. Adults: Swallow whole with water. ≥18yrs: initially 10mg per day; adjust dose based on response. Renal impairment: Moderate (CrCL 30–60mL/min): 5mg per day. Severe (CrCL <30mL/min without dialysis): 2.5mg per day. ESRD (CrCL <30mL/min with dialysis): 2.5mg once daily; administer after dialysis (on dialysis days). Dose adjustments if thrombocytopenia or neutropenia develops: see full labeling. Children: <18yrs: not established.

Contraindications: Pregnancy (Cat.X). Women who may become pregnant. Warnings/Precautions: Must register patient in Revlimid REMS program; patient must understand toxicity with fetal exposure. Counsel patient on need for contraception; female: use 2 forms of contraception 1 month before, during, and 1 month after therapy; male: use condom during and 1 month after therapy; obtain 2 negative pregnancy tests (one within 10–14 days, and then another within 24hrs prior to starting therapy), repeat at least weekly for 1st month then every 4 weeks; get informed consent. Monitor for signs/symptoms of thromboembolic events. Obtain CBCs weekly for first 8 weeks, then monthly. Renal impairment (monitor). Monitor for tumor lysis syndrome in those with high tumor burden. Monitor liver enzymes; discontinue if elevation occurs. Maximum 1 month per ℞. Nursing mothers: not recommended. Interactions: Monitor digoxin. Concomitant warfarin; monitor PT, INR. May increase risk of thrombosis with dexamethasone, erythropoietic agents, or estrogen containing therapies. Adverse reactions: Birth defects, thrombocytopenia, neutropenia, anemia, leukopenia, constipation, diarrhea, nausea, vomiting, pruritus, rash, fatigue, arthralgia, pyrexia, back pain, cough, dizziness, headache, dyspnea, upper respiratory tract infection, tremor, blurred vision, muscle cramp, peripheral edema; thrombosis/embolism, allergic reactions (discontinue if occurs; do not resume), tumor flare reaction (monitor; esp. in treating MCL), hepatotoxicity. Note: Available only through Revlimid REMS program. Report any suspected fetal exposure to the FDA at (800) FDA-1088 and Celgene at (888) 423-5436. How supplied: Caps 2.5mg, 5mg, 10mg–28, 100; 15mg, 20mg, 25mg–21, 100

SLOW FE Novartis Consumer

OTC

Iron 50mg (as sulfate 160mg); sust-rel tabs. Indications: Iron deficiency and iron deficiency anemias. Adults: Swallow whole. 1–2 tabs daily; max 4 daily. Children: Swallow whole. <6 yrs: not recommended. ≥6 yrs: 1 tab daily. Also: SLOW FE PLUS FOLIC ACID OTC Iron, elemental 50mg (as ferrous sulfate 160mg), folic acid 0.4mg; sust-rel tabs. Adults: Swallow whole. 1–2 tabs daily. Children: Not recommended. Contraindications: Hemochromatosis. Hemosiderosis.

Warnings/Precautions: Hepatitis. Pancreatitis. Peptic ulcer or GI inflammation. Achlorhydria. Monitor hematocrit. Folic acid may mask pernicious anemia. Repeated blood transfusions. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools. How supplied: Slow Fe–30, 60, 90; Plus folic acid–20

SOLIRIS Alexion

℞

Complement inhibitor. Eculizumab 10mg/mL; soln for IV infusion after dilution; preservative-free. Indications: Treatment of paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. Treatment of atypical hemolytic uremic syndrome (aHUS) to inhibit complement-mediated thrombotic microangiopathy. Limitation of use: not for treating Shiga toxin E. coli-related HUS. Adults: Give by IV infusion over 35 mins; monitor for ≥1hr after completion. ≥18yrs: PNH: initially 600mg weekly for the first 4 weeks, followed by 900mg for the fifth dose 1 week later, then 900mg every 2 weeks thereafter. aHUS: initially 900mg weekly for the first 4 weeks, followed by 1200mg for the fifth dose 1 week later, then 1200mg every 2 weeks thereafter. Supplemental dosing after PE/PI: see full labeling. Children: <18yrs: PNH: not established. aHUS: Give by IV infusion over 1–4hrs via gravity feed, syringe-type pump, or infusion pump; monitor for ≥1hr after completion. 5–<10kg: induction: 300mg weekly for 1 dose; maintenance: 300mg at Week 2, then 300mg every 3 weeks; 10–<20kg: induction: 600mg weekly for 1 dose; maintenance: 300mg at Week 2, then 300mg every 2 weeks; 20–<30kg: induction: 600mg weekly for 2 doses; maintenance: 600mg at Week 3, then 600mg every 2 weeks; 30–<40kg: induction: 600mg weekly for 2 doses; maintenance: 900mg at Week 3, then 900mg every 2 weeks; ≥40kg: induction: 900mg weekly for 4 doses; maintenance: 1200mg at Week 5, then 1200mg every 2 weeks. Supplemental dosing after PE/PI: see full labeling. Contraindications: Unresolved serious Neisseria meningitidis infection. Individuals not vaccinated against Neisseria meningitidis. Warnings/Precautions: Increased risk of meningococcal infection. Give meningococcal vaccine at least 2 weeks prior to treatment. Monitor for early signs of meningococcal infection; evaluate and treat if an infection develops. Discontinue eculizumab if undergoing treatment for meningococcal infections. Administering eculizumab treatment with any other systemic infection (eg, S. pneumoniae, H. influenza). PNH: risk

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS of hemolysis after treatment discontinuation; monitor for at least 8 weeks. aHUS: risk of thrombotic microangiopathy (TMA) after treatment discontinuation; monitor for at least 12 weeks; if TMA occurs, consider reinitiating eculizumab, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/PI)], or appropriate organ-specific supportive measures. Monitor platelets, serum LDH, and creatinine during and after therapy. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Headache, nasopharyngitis, back pain, nausea, diarrhea, vomiting, abdominal pain, hypertension, upper respiratory tract infection, anemia, cough, peripheral edema, UTI, pyrexia; meningococcal infection (may be fatal), hypersensitivity reactions. How supplied: Single-use vials (30mL)–1

TRINSICON UCB

℞

Iron (as fumarate) 110mg, Vit. B12 15micrograms, folic acid 0.5mg, Vit. C 75mg, liver-stomach concentrate 240mg; caps. Indications: Megaloblastic anemias. Iron deficiency anemia. Adults: 1 cap twice daily. Children: <10yrs: not recommended. Contraindications: Hemochromatosis. Hemosiderosis. Warnings/Precautions: For pernicious anemia, parenteral cyanocobalamin is preferred. Resistance to exogenous intrinsic factor may develop. Folic acid may mask pernicious anemia. Monitor blood parameters. Hepatitis. Pancreatitis. Peptic ulcer or GI inflammation. Achlorhydria. Repeated blood transfusions. Pregnancy (Cat.C). Nursing mothers. Elderly. Interactions: Inhibits tetracycline absorption. Adverse reactions: Nausea, abdominal discomfort and pain, constipation, diarrhea, masks occult bleeding, black stools, rash. How supplied: Caps–60, 100

VENOFER American Regent

℞

Hematinic. Iron (as sucrose) 20mg/mL; soln for IV inj or infusion; preservative-free. Indications: Iron deficiency anemia in chronic kidney disease. Adults: Give by slow IV inj (undiluted) or infusion (diluted). Usual total cumulative dose: 1000mg. Hemodialysis dependent: 100mg slow IV inj over 2–5 mins or infuse 100mg over at least 15 mins per consecutive session. Non-dialysis dependent: 200mg slow IV inj over 2–5 mins on 5 different occasions within a 14-day period; limited experience with IV infusion (see full labeling). Peritoneal dialysis dependent: Two infusions of 300mg over 1.5hrs 14 days apart, then one 400mg infusion over 2.5hrs 14 days later. Children: Not recommended. Contraindications: Anemia not caused by iron deficiency. Iron overload. Warnings/Precautions: Withhold therapy if tissue iron overload suspected. Monitor hemoglobin, hematocrit, serum ferritin, transferrin

saturation; obtain serum iron values 48 hours after dosing. Pregnancy (Cat.B). Nursing mothers. Interactions: May reduce absorption of concomitant oral iron preparations. Adverse reactions: Hypotension (esp. by IV infusion), hypertension, muscle cramps, GI upset, headache, dizziness, chest pain, graft complications, dysgeusia, pruritus, edema, constipation; rare: hypersensitivity reactions (may be severe). How supplied: Single-dose vials (100mg/5mL)–1, 10, 25; 200mg/10mL–1, 5,10

Bleeding disorders

ADVATE Baxter

℞

Clotting factor. Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU, 1500 IU, 2000 IU, 3000 IU; per vial; pwd for IV inj after reconstitution; albumin- and preservative-free. Indications: In patients with Hemophilia A: to control and prevent hemorrhagic episodes, for perioperative management, and routine prophylaxis to prevent or reduce the frequency of hemorrhagic episodes. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Infuse over ≤5 minutes (max infusion rate 10mL/min); monitor pulse; if increased significantly, reduce infusion rate or hold. Hemorrhage: Mild: obtain 20–40% FVIII increase; give every 12–24hrs for 1–3 days until resolved. Moderate: obtain 30–60% FVIII increase; give every 12–24hrs for 3 days or until pain or disability resolved. Major: obtain 60–100% FVIII increase; give every 8–24hrs until resolved. Perioperative: Minor: obtain 60–100% FVIII increase; give single bolus infusion within 1 hour of surgery, then every 12–24hrs as needed to control bleeding; Major: pre- and Post-op: obtain 80–120% FVIII increase; give pre-op and maintenance bolus infusion, then repeat every 8–24hrs based on healing. Routine prophylaxis: give 20–40 IU/kg every other day (3–4 times weekly). Or, alternatively, an every 3rd day dosing regimen may be followed. Adjust based on response. Contraindications: Mouse or hamster protein sensitivity. Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Monitor for development of Factor VIII inhibitors. Labor & delivery. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Headache, arthralgia, pyrexia, cough, nasopharyngitis, pharyngolaryngeal pain; antibody formation, hypersensitivity reactions. How supplied: Single-dose vial–1 (w. diluent, Baxject II needleless transfer device)

ALPHANATE Grifols Biologicals

℞

Clotting factor. Antihemophilic Factor VIII/von Willebrand Factor Complex (human) 250 IU, 500 IU, 1000 IU, 1500 IU; per vial; lyophilized pwd for IV inj after reconstitution; contains albumin.

Indications: Prevention and control of bleeding in Hemophilia A or acquired Factor VIII deficiency. Surgical and/or invasive procedures in von Willebrand disease (VWD) when desmopressin is ineffective or contraindicated. Adults: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Give by IV inj; max infusion rate ≤10mL/min. Hemorrhage: Minor: 15 FVIII IU/kg twice daily for 1–2 days. Moderate: 25 FVIII IU/kg twice daily for 2–7 days. Severe: 40–50 FVIII IU/kg twice daily for at least 3–5 days, then 25 FVIII IU/kg twice daily until healed (up to 10 days). Surgery: 40–50 FVIII IU/kg prior to surgery then 25–50 FVIII IU/kg twice daily for 7–10 days or until healed. Von Willebrand: pre-op dose: 60 VWF:RCof IU/kg, then 40–60 VWF:RCof IU/kg every 8–12hrs if needed; may reduce dose after 3rd post-op day; treat until healed. Others: see literature. Children: Give by IV inj; max infusion rate ≤10mL/min. Von Willebrand: initially 75 VWF:RCof IU/kg, then 50–75 VWF:RCof IU/kg every 8–12hrs if needed; may reduce dose after 3rd post-op day; treat until healed. Warnings/Precautions: Not for those with severe VWD undergoing major surgery. Contains human plasma; monitor for possible infection transmission. Blood groups A, B or AB; large and/or frequent dosing may result in hemolytic anemia. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Adverse reactions: Urticaria, fever, chills, GI upset, headache, somnolence, lethargy, inj site reactions, pruritus, pharyngitis, paresthesia, facial edema, rash; antibody formation, infection, thromboembolic events (in VWD patients), hemolytic anemia (rare). Note: Report all infections suspected to be transmitted by Alphanate to (888) GRIFOLS. How supplied: Single-dose vial–1 (w. diluent, supplies)

ALPHANINE SD Grifols Biologicals ℞ Clotting factor. Coagulation Factor IX (human) 250 IU, 500 IU, 1000 IU, 1500 IU; per vial; lyophilized concentrate for IV infusion after reconstitution; contains non-therapeutic Factor II, Factor VII, Factor X. Indications: Prevention and control of bleeding in Hemophilia B. Adults: Dosage Required (IU) = Body Weight (kg) × Desired Factor IX increase × 1 IU/kg. Individualize. Max infusion rate: 10mL/min. Mild hemorrhage: increase FIX 20–30% (20–30 IU/kg twice daily) for 1–2 days or until resolved. Moderate hemorrhage: increase FIX 25–50% (25–50 IU/kg twice daily) for 2–7 days. Major hemorrhage: increase FIX 50% (30–50 IU/kg twice daily) for 3–5 days then maintain at 20% (20 IU/kg twice daily) for up to 10 days. Surgery: Pre-op: increase FIX 50–100% (50–100 IU/kg twice daily), then maintain at 50–100% for 7–10 days or until healed. Children: See literature. Warnings/Precautions: Not for treating Factor II, VII, or X deficiencies; Hemophilia A with Factor

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ASSOCIATED HEMATOLOGICAL DISORDERS VIII inhibitors, or reversal of coumarin-induced hemorrhage. Contains human plasma; monitor for transmission of infectious diseases. Previously untreated patients: closely monitor for signs of anaphylaxis between days 10 and 20 of exposure. Immune tolerance induction. Major deletion mutations in Factor IX gene. Liver disease. Surgery. Pregnancy (Cat.C). Adverse reactions: Chills, nausea, inj site reactions; hypersensitivity reactions, thrombosis, disseminated intravascular coagulation. Note: Report all infections suspected to be transmitted by AlphaNine SD to (888) 675-2762. How supplied: Single-use vials–1 (w. diluent, supplies)

AMICAR TABLETS Clover

℞

Hemostatic (plasmin and plasminogen activator inhibitor). Aminocaproic acid 500mg, 1000mg; scored tabs. ℞ Also: AMICAR ORAL SOLUTION Aminocaproic acid 250mg/mL; raspberry-flavor. Indications: Bleeding associated with fibrinolysis. Adults: Initially 5g during 1st hour, then 1g/hour for 8 hours or until bleeding is controlled. Children: Not recommended. Also: Aminocaproic Acid Injection (various) ℞ Aminocaproic acid 250mg/mL; soln for IV infusion after dilution; contains benzyl alcohol. Adults: 4–5g (in 250mL of diluent) by IV infusion during the 1st hour, then 1g/hour (in 50mL of diluent) for 8 hours or until bleeding is controlled. Children: Not recommended. Contraindications: Active intravascular clotting process. Disseminated intravascular coagulation without concomitant heparin. Warnings/Precautions: Upper urinary tract bleeding: not recommended. Cardiac, hepatic or renal disease. Risk of myopathy with long-term use; monitor creatine phosphokinase (CPK); discontinue if CPK rises. Avoid rapid IV administration. Neonates. Pregnancy (Cat.C). Nursing mothers. Interactions: Avoid concomitant Factor IX complex or Anti-inhibitor Coagulant concentrates; may increase thrombosis risk. Adverse reactions: Inj site reactions, bradycardia, hypotension, GI upset, edema, headache, malaise, CNS effects, thrombosis, others; rare: myopathy. How supplied: Tabs–100; Oral soln–473mL; Inj–contact supplier

BEBULIN VH Baxter

℞

Clotting factor. Coagulation Factor IX Complex (human) 500–700 IU; per vial; freeze-dried concentrate for IV infusion after reconstitution; contains Factors II, VII, X and heparin.

Indications: Prevention and control of bleeding in Hemophilia B. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired Factor IX increase × 1.2 IU/kg. Max infusion rate: 2mL/min. Bleeding: minor: 20% increase (25–35 IU/kg) for 1 dose. Moderate: 40% increase (40–55 IU/kg) once, give 2nd dose after 24hrs (continue until resolved). Major: ≥60% increase (60–70 IU/kg) once daily for 2–3 days or until healed. Surgery: Give loading dose 1hr prior to surgery. May repeat dose every 12hrs initially then every 24hrs in late post-op period. Minor: Initially 40–60% (50–60 IU/kg), then 20–40% (25–55 IU/kg) for 1–2 weeks. Major: Initially ≥60% increase (70–95 IU/kg) then 20–60% (35–75 IU/kg) for 1–2 weeks, then 20% (25–35 IU/kg) until healed. Prophylaxis: 20–30 IU/kg 1–2 times weekly. Warnings/Precautions: Not for treating factor deficiencies other than Factor IX deficiency. Contains human plasma; monitor for possible infection transmission. Thromboembolic disorders; risk increased during post-op period; avoid FIX increases >60%; monitor for thrombosis, disseminated intravascular coagulation (DIC). Surgery. Pregnancy (Cat.C). Adverse reactions: Hypersensitivity reactions, thrombosis, DIC. Note: Report all infections suspected to be transmitted by Bebulin VH to (800) 423-2862. How supplied: Single-use vials–1 (w. diluent, needles)

BENEFIX Pfizer

℞

Clotting factor. Coagulation Factor IX (recombinant) 250 IU, 500 IU, 1000 IU, 2000 IU; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free. Indications: Prevention and control of bleeding in hemophilia B. Peri-operative management in patients with hemophilia B. Adults: Dosage Required (IU) = Body Weight (kg) × Desired Factor IX increase × 1.3 IU/kg. Give by IV infusion over several minutes. If inhibitor present or low Factor IX recovery, may need higher doses. Minor hemorrhage: 20–30% increase every 12–24hrs for 1–2 days. Moderate: 25–50% increase every 12–24hrs for 2–7 days until resolved. Major: 50–100% increase every 12–24 hrs for 7–10 days. Children: <15yrs: See literature. Dose (IU) = body weight (kg) × % FIX increase × 1.4 IU/kg. Contraindications: Hamster protein hypersensitivity. Warnings/Precautions: Not for Hemophilia A with FVIII inhibitors or other factor deficiencies, reversal of coumarin-induced anticoagulation or for low levels of liver-dependant coagulation factors. Fibrinolysis, disseminated intravascular

coagulation (DIC), liver disease, neonates, or during post-op period; increased risk of thromboembolic events. Monitor for Factor IX inhibitors and deletion mutations of Factor IX gene; increased risk of anaphylaxis. Immune tolerance induction. Latex allergy. Pregnancy (Cat.C). Adverse reactions: Headache, fever, chills, flushing, GI upset, lethargy, taste perversion, hypoxia, inj site reactions, dizziness, allergic rhinitis; hypersensitivity reactions, inhibitor development, thrombosis. How supplied: Single-use vials–1 (w. diluent, supplies)

CARIMUNE NF CSL Behring

℞

Immune globulin. Immune globulin (human) 3g, 6g, 12g; per vial; pwd for IV infusion after reconstitution; contains sucrose and NaCl; preservative-free. Indications: Immune thrombocytopenic purpura (ITP). Adults and Children: Induction: give by IV infusion at a rate of 0.5mg/kg/min for first 30mins, if tolerated may increase to 1mg/kg/min up to max 3mg/kg/min in a stepwise manner. 0.4g/kg on 2–5 consecutive days. Use of 6% immunoglobulin solution is recommended. Acute childhood ITP: discontinue therapy after second day of 5 day course if platelet count response to first two doses is 30–50000/μL. Maintenance: If platelet count falls to <30000/μL and/or clinically significant bleed: give 0.4g/kg as a single infusion, may increase to 0.8–1g/kg as single infusion if inadequate response. Risk of renal dysfunction/failure or thrombosis: max infusion rate <2mg/kg/min. Contraindications: IgA-deficiency with antibodies against IgA. Previous severe reaction to human immune globulin. Warnings/Precautions: Advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, cardiovascular risk factors: increased risk of thrombosis. Monitor for signs/symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Pre-existing renal insufficiency, diabetes, >65yrs, hypovolemia, sepsis, paraproteinemia: increased risk of renal dysfunction or acute renal failure. Correct volume depletion; assess renal function, BUN, serum creatinine, urine output before and during therapy; discontinue if renal function deteriorates. Monitor for aseptic meningitis, hemolysis and delayed hemolytic anemia. Monitor for pulmonary dysfunction; perform test for anti-neutrophil antibodies if transfusionrelated acute lung injury (TRALI) suspected.

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS Contains human plasma; monitor for possible infection transmission. Have epinephrine inj available. Elderly. Pregnancy (Cat.C). Interactions: Concomitant nephrotoxic drugs: increased risk of renal toxicity. May affect response to live virus vaccines. Adverse reactions: Headache, arthralgia, myalgia, transient skin reactions, infusion reactions (eg, flushing, chills, fever), renal toxicities; aseptic meningitis syndrome (esp. high dose 2g/kg), TRALI, thrombosis. How supplied: Single-use vial–1

CORIFACT CSL Behring

℞

Clotting factor. Factor XIII concentrate (human); 1000–1600 units; per vial; powder for IV injection after reconstitution; preservative-free. Indications: Routine prophylactic treatment and peri-operative management of surgical bleeding in patients with congenital Factor XIII (FXIII) deficiency. Adults and Children: Give by slow IV injection at a rate of ≤4mL/min. Initially 40units/kg. Adjust ±5units/kg to maintain 5–20% trough FXIII activity levels using Berichrom Activity Assay: One trough level of <5%: increase by 5units/kg; trough level of 5–20%: no change; two trough levels of >20%: decrease by 5units/kg; one trough level of >25%: decrease by 5units/kg. Routine prophylaxis: give every 28 days. Peri-operative management: individualized based on patient’s FXIII activity level, surgery type, and clinical response; dose adjustment: see full labeling. Warnings/Precautions: Contains human plasma; monitor for possible infection transmission. Longterm therapy: consider appropriate vaccination (hepatitis A and B virus). Monitor FXIII activity levels during and after surgery. Monitor for development of inhibitory antibodies, thromboembolic events. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Joint inflammation, hypersensitivity, rash, pruritus, erythema, hematoma, arthralgia, headache, elevated thrombin-antithrombin levels, increased blood lactate dehydrogenase; acute ischemia, neutralizing antibodies. How supplied: Single-use vial–1

CYKLOKAPRON Pfizer

℞

Plasminogen activation inhibitor. Tranexamic acid 100mg/mL; soln for IV inj. Indications: Short-term use in hemophilia to reduce or prevent hemorrhage, and reduce the need for replacement therapy during and following tooth extraction. Adults and Children: Give by IV inj. Max injection rate: 1mL/min. Pre-extraction: 10mg/kg; Post-op: 10mg/kg 3–4 times daily for 2–8 days. Renal impairment: serum creatinine 1.36–2.83mg/dL: 10mg/kg twice daily; 2.83–5.66mg/dL: 10mg/kg once daily; >5.66mg/dL: 10mg/kg every 48hrs or 5mg/kg every 24 hours. Contraindications: Acquired defective color vision. Subarachnoid hemorrhage. Active intravascular clotting.

Warnings/Precautions: Therapy longer than several days: do ophthalmologic exam (before and during); discontinue if visual changes occur. Renal insufficiency; reduce dose. History of thromboembolic disease. Disseminated intravascular coagulation. Upper urinary tract bleeding. Pregnancy (Cat.B). Nursing mothers. Interactions: Avoid concomitant Factor IX complex concentrates or Anti-inhibitor Coagulant concentrates; increased risk of thrombosis. Do not mix with solutions containing penicillin. Adverse reactions: GI upset, giddiness, hypotension, visual abnormalities; rare: thromboembolic events. How supplied: Amps (10mL)–10

DDAVP INJECTION Ferring

℞

Antidiuretic hormone. Desmopressin acetate 4mcg/mL; soln for inj or IV infusion after dilution. Indications: To maintain hemostasis or to stop bleeding in Hemophilia A and mild-to-moderate Type 1 von Willebrand’s disease (VWD), each with >5% Factor VIII activity. Adults and Children: <3 months: not recommended. ≥3 months: 0.3micrograms/kg IV over 15–30 minutes. Pre-op: give 30 minutes before scheduled procedure. May repeat dose based on clinical response. Repeated administration before 48hrs associated with tachyphylaxis. Contraindications: Moderate to severe renal impairment (CrCl <50mL/min). Hyponatremia, or history of. Warnings/Precautions: Not for treating Hemophilia A with Factor VIII coagulant activity levels ≤5%, Hemophilia B, in patients with FVIII antibodies, or for Type IIB VWD, or severe Type 1 VWD and evidence of abnormal molecular form of FVIII antigen. Monitor fluid intake, urine volume plasma osmolality. Fluid/electrolyte imbalance (eg, cystic fibrosis). Adjust fluid intake downward (esp in children and elderly) to decrease risk of water intoxication, hyponatremia. Habitual or psychogenic polydipsia. Coronary artery insufficiency. Hypertension. Predisposition to thrombosis. Pregnancy (Cat.B). Nursing mothers. Interactions: Caution with other pressor agents, drugs that may increase the risk of water intoxication with hyponatremia (eg, tricyclic antidepressants, SSRIs, chlorpromazine, opiates, NSAIDs, lamotrigine, carbamazepine). Possible convulsions with oxybutynin, imipramine. Adverse reactions: Headache, nausea, flushing, abdominal cramps, vulval pain, inj site reaction, water intoxication, hyponatremia, rare: changes in BP, severe allergic reactions, thrombotic events (inj). How supplied: Amp (1mL)–10; Multi-dose vial (10mL)–1

ETHAMOLIN QOL Medical

℞

Sclerosing agent. Ethanolamine oleate 50mg/mL; soln for IV inj; contains benzyl alcohol 2%. Indications: For the treatment of esophageal varices that have recently bled, to prevent rebleeding.

Adults: Usual IV dose: 1.5–5mL per varix. Max dose per treatment session: 20mL. Child Class C or concomitant cardiopulmonary disease: give less than the recommended max dose. To obliterate the varix, may give injections at the time of the acute bleeding episode and then after one week, six weeks, three months, and six months as indicated. Children: Not recommended. Warnings/Precautions: Should be performed by physician familiar with technique. Submucosal inj: not recommended. Cardiorespiratory disease; monitor. Child Class C (more likely to develop esophageal ulceration). Elderly, critically ill (increased risk of fatal aspiration pneumonia). Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Pleural effusion/infiltration, esophageal ulcer, pyrexia, retrosternal pain, esophageal stricture, pneumonia, rare: anaphylactic reaction (may be fatal), acute renal failure. How supplied: Ampules (2mL)–10

FEIBA Baxter

℞

Clotting factor. Anti-inhibitor Coagulant Complex (AICC) 500 units, 1000 units, 2500 units; per vial; lyophilized pwd for IV infusion after reconstitution; contains Factors II, IX, X (non-activated); Factor VII (activated); Factor VIII inhibitor bypassing activity; Prothrombin Complex Factors; heparin-free. Indications: To control and prevent bleeding episodes, perioperative management, or as routine prophylaxis to prevent or reduce the frequency of bleeding episodes in Hemophilia A and B with inhibitors (see full labeling). Not for treating bleeding episodes due to coagulation factor deficiencies in the absence of inhibitors to factor VIII or IX. Adults and Children: Infusion rate: ≤2units/kg/ min. Joint hemorrhage: 50–100units/kg every 12hrs until improved. Mucous membrane bleeding: 50–100units/kg every 6hrs for at least 1 day or until resolved. Soft tissue hemorrhage: 100units/kg every 12hrs until resolved. Other severe hemorrhage (eg, CNS bleeds): 100units/kg every 6–12hrs until resolved. Preoperative: 50–100units/kg once immediately prior to surgery. Postoperative: 50–100units/kg every 6–12hrs until resolved and healed. Routine prophylaxis: 85units/kg every other day. All: Max 200units/kg per day (100units/kg per dose). Contraindications: Hypersensitivity to factors of the kinin generating system. Disseminated intravascular coagulation (DIC). Acute thrombosis or embolism (including myocardial infarction). Warnings/Precautions: Increased risk of thromboembolic events esp. after high-doses (>200units/kg/day) and/or in patients with thrombotic risk factors (eg, DIC, atherosclerosis, crush injury, septicemia, concomitant recombinant factor VIIa). Monitor patients receiving doses >100units/kg for DIC development, acute coronary ischemia, and signs/symptoms of other thromboembolic events; discontinue if occurs and treat. Discontinue if hypersensitivity reactions occur. Contains human plasma; monitor

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ASSOCIATED HEMATOLOGICAL DISORDERS for possible infection transmission. Elderly. Neonates. Pregnancy (Cat.C). Nursing mothers. Interactions: Separate systemic antifibrinolytics by 12hrs. Adverse reactions: Anemia, diarrhea, hemarthrosis, hep B surface antibody positive, nausea, vomiting; hypersensitivity, thromboembolic events (eg, stroke, DVT, PE). Note: Report all infections suspected to be transmitted by Feiba to (800) 423-2862. How supplied: Single-dose vials–1 (w. diluent, transfer device)

GAMUNEX-C Grifols Biologicals

increased risk of acute renal failure. May cause false positive direct or indirect Coombs’ test. Adverse reactions: Headache, vomiting, fever, nausea, back pain, rash; renal dysfunction (may be fatal), hypersensitivity reactions; rare: hemolytic anemia, aseptic meningitis syndrome (esp. high dose of 2g/kg and/or rapid infusion), TRALI, thrombosis, hyperproteinemia. Note: Report all infections suspected to be transmitted by Gamunex-C to (800) 520-2807. How supplied: Vials–1

HELIXATE FS CSL Behring ℞

Immune globulin. Immune Globulin (human) 1g/10mL, 2.5g/25mL, 5g/50mL, 10g/100mL, 20g/200mL; soln for IV or SC infusion; preservative- and sucrose-free. Indications: Idiopathic thrombocytopenic purpura (ITP). Adults and Children: Give by IV infusion at a rate of 1mg/kg/min for first 30mins, if tolerated may increase to max 8mg/kg/min. 1g/kg once daily given on 2 consecutive days or 0.4g/kg once daily given on 5 consecutive days. If adequate response after first 1g/kg dose, may withhold second dose. Risk of renal dysfunction or thrombosis: give at minimum practicable infusion rate (<8mg/kg/min). Expanded fluid volumes: high dose regimen not recommended. Contraindications: IgA deficiency with antibodies against IgA. Previous severe reaction to human immune globulin. Warnings/Precautions: Advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, cardiovascular risk factors: increased risk of thrombosis. Monitor for signs/symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Pre-existing renal insufficiency, diabetes, >65yrs, hypovolemia, sepsis, paraproteinemia: increased risk of renal dysfunction or acute renal failure. Correct volume depletion; assess renal function, BUN, serum creatinine, urine output before and during therapy; discontinue if renal function deteriorates. Monitor for aseptic meningitis, hemolysis, hemolytic anemia. Monitor for pulmonary dysfunction; perform test for antineutrophil antibodies if transfusion-related acute lung injury (TRALI) suspected. Contains human plasma; monitor for possible infection transmission. Have epinephrine inj available. Pregnancy (Cat.C). Nursing mothers: not evaluated. Interactions: May affect response to live virus vaccines. Concomitant nephrotoxic drugs:

℞

Clotting factor. Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU; per bottle; dried concentrate for IV infusion after reconstitution; contains sucrose; preservative-free. Indications: Prevention and control of hemorrhagic episodes or in order to perform emergency or elective surgery in Hemophilia A patients. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infuse over 5–10minutes if tolerated. Minor hemorrhage: 10–20 IU/kg; may repeat dose if needed. Moderate/major hemorrhage or minor surgery: 15–30 IU/kg; may repeat 1 dose at 12–24hrs if needed. Major/ life-threatening hemorrhage, fractures or head trauma: initially 40–50 IU/kg, then 20–25 IU/kg every 8–12hrs. Major surgery: pre-op dose: 50 IU/kg (verify ∼100% activity prior to surgery); may repeat after 6–12hrs initially, and for 10–14 days until completely healed. Contraindications: Mouse or hamster protein sensitivity. Warnings/Precautions: Not for treating von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Inj site reactions, dizziness, rash, dysgeusia, increased BP, pruritus, depersonalization, GI upset, rhinitis; antibody formation, hypersensitivity reactions. How supplied: Single-use bottle–1 (w. diluent)

HEMOFIL M Baxter

℞

Clotting factor. Antihemophilic Factor VIII (human) 220–400 IU, 401–800 IU, 801–1700 IU, 1701–2000 IU; per bottle; dried concentrate for IV infusion after reconstitution; contains albumin. Indications: Prevention and control of hemorrhagic episodes in Hemophilia A. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII

Increase × 0.5. Individualize. Infuse at rate of up to 10mL/min. Monitor pulse rate; if increased significantly, reduce infusion rate or hold. Hemorrhage: Mild: obtain 20–40% FVIII increase; give every 12–24hrs for 1–3 days until resolved. Moderate: obtain 30–60% FVIII increase; give every 12–24hrs for 3 days or until pain or disability resolved. Life-threatening: obtain 60–100% FVIII increase; give every 8–24hrs until resolved. Surgery: Minor: obtain 60–80% FVIII increase; give single infusion plus oral antifibrinolytic therapy within 1 hour; Major: pre- and Post-op: obtain 80–100% FVIII increase; repeat every 8–24hrs based on healing. Contraindications: Mouse protein sensitivity. Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Contains human plasma; monitor for possible infection transmission. Monitor for development of Factor VIII inhibitors. Latex allergy. Pregnancy (Cat.C). Adverse reactions: Allergic reactions, nausea, fever, chills, urticaria, antibody formation. Note: Report all infections suspected to be transmitted by Hemofil M to (800) 423-2862. How supplied: Single-dose bottle–1 (w. diluent, needles)

HUMATE-P CSL Behring

℞

Clotting factors. Antihemophilic Factor VIII/Von Willebrand Factor Complex (human) 250 IU FVIII + 600 IU VWF, 500 IU FVIII + 1200 IU VWF, 1000 IU FVIII + 2400 IU VWF; per vial; lyophilized pwd for IV infusion after reconstitution; contains albumin. Indications: Treatment and prevention of bleeding in adults with Hemophilia A. Treatment of spontaneous and trauma-induced bleeding, and prevention of excessive bleeding during and after surgery in adults and children with von Willebrand disease (VWD). Adults: Max injection rate: 4mL/min. Hemophilia A: Minor bleed: 15 IU FVIII/kg (obtain 30% FVIII increase) once; if needed, may give ½ dose once or twice daily for 1–2 days. Moderate bleed: initially 25 IU FVIII/kg (obtain 50% FVIII increase), then 15 IU FVIII/kg (maintain 30% FVIII increase) every 8–12hrs for 1–2 days, then repeat dose for 1–2 times daily for a total of 7 days or until healed. Severe bleed: initially 40–50 IU FVIII/kg, then 20–25 IU FVIII/kg every 8hrs (maintain 80–100% FVIII increase) for 7 days, then repeat dose for 1–2 times daily for additional 7 days (maintain 30–50% FVIII increase). VWD: Type 1 (Mild): major bleed: initially 40–60 IU/kg, then 40–50 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Type 1 (Moderate or severe): minor bleed: 40–50 IU/kg for 1–2 doses;

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ASSOCIATED HEMATOLOGICAL DISORDERS major bleed: initially 50–75 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Types 2 and 3: minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 60–80 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. For dosing in surgery: see literature. Children: Max injection rate: 4mL/min. VWD: Type 1 (Mild): major bleed: initially 40–60 IU/kg, then 40–50 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Type 1 (Moderate or severe): minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 50–75 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. Types 2 and 3: minor bleed: 40–50 IU/kg for 1–2 doses; major bleed: initially 60–80 IU/kg, then 40–60 IU/kg every 8–12hrs for 3 days, then once daily for a total of 7 days. For dosing in surgery: see literature. Contraindications: Previous anaphylactic or severe systemic response to antihemophilic factor or von Willebrand factor preparations. Warnings/Precautions: Confirm Factor VIII or von Willebrand factor deficiency prior to treatment. Increased risk of thromboembolic events in VWD. Contains human plasma; monitor for possible infection transmission. Large or frequent doses: monitor hematocrit for signs of hemolytic anemia. Monitor for development of inhibitors. Pregnancy (Cat.C). Adverse reactions: Allergic reaction, GI upset, inj site reactions, mild vasodilation, pruritus, paresthesia, peripheral edema, antibody formation; anaphylaxis, thrombosis. Note: Report all infections suspected to be transmitted by Humate-P to (800) 504–5434. How supplied: Single-use vials–1 (w. diluent, supplies)

KCENTRA CSL Behring

℞

Clotting factor. Prothrombin complex concentrate (human) 500 units, 1000 units; per vial; lyophilized pwd for IV infusion after reconstitution; contains non-activated coagulation Factors II, VII, IX, X, antithrombotic Proteins C and S; also, heparin, human albumin, antithrombin III; preservative-free; latex-free. Indications: Urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA) therapy in adults with acute major bleeding or need for an urgent surgery/ invasive procedure. Adults: See full labeling. Administer concomitant Vitamin K. Individualize dosing based on patient’s baseline INR and weight. Potency (units) is defined by Factor IX content. Give by IV Infusion at a rate of 0.12mL/kg/min (∼3 units/kg/min); max rate of 8.4mL/min (∼210 units/min). ≤100kg: Pre-treatment INR: (2–<4): 25 units of Factor IX/kg; max 2500 units; (4–6): 35 units of Factor IX/kg; max 3500 units; (>6): 50 units of Factor IX/kg; max 5000 units. >100kg: do not exceed max dose. Repeat dosing: not recommended. Children: Not established.

Contraindications: Severe hypersensitivity to heparin, Factors II, VII, IX, X, Proteins C and S, antithrombin III, human albumin. Disseminated intravascular coagulation (DIC). Known heparininduced thrombocytopenia (HIT). Warnings/Precautions: Risk of arterial and venous thromboembolic complications (may be fatal). History of thromboembolic events within the previous 3 months. Monitor for signs/symptoms of thromboembolic events during and after infusion. Discontinue immediately if hypersensitivity reactions occur. Measure INR before, during, and after each treatment. Contains human plasma; monitor for possible infection transmission. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Headache, nausea, vomiting, hypotension, anemia; hypersensitivity, thromboembolic events (eg, stroke, PE, DVT). Note: Report all infections suspected to be transmitted by Kcentra to (866) 915-6958. How supplied: Kit (500 units, 1000 units)–1 (single-use vial + diluent, supplies)

KOATE-DVI Grifols Biologicals

℞

Clotting factor. Antihemophilic Factor VIII (human) 250 IU, 500 IU, 1000 IU; per bottle; dried concentrate for IV infusion after reconstitution; contains albumin. Indications: Prevention and control of hemorrhagic episodes or in order to perform emergency or elective surgery in Hemophilia A patients. Adults: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infuse over 5–10 minutes if tolerated. Use filter needle. Hemorrhage: Mild: 10 IU/kg as single dose. Moderate: 15–25 IU/kg, then 10–15 IU/kg every 8–12hrs if needed. Severe: initially 40–50 IU/kg, then 20–25 IU/kg every 8–12hrs. Major surgery: pre-op dose: 50 IU/kg, then verify Factor VIII level achieved prior to surgery; may repeat every 6–12hrs initially and for 10–14 days until healing complete. Children: Not recommended. Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Contains human plasma; monitor for possible infection transmission. Large or frequent doses: monitor hematocrit for signs of progressive anemia. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Adverse reactions: Allergic reactions, tingling sensations, blurred vision, headache, GI upset, jittery feeling, antibody formation. How supplied: Single-dose bottle–1 (w. diluent)

KOGENATE FS Bayer

℞

Clotting factor. Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU; per vial; lyophilized pwd for IV infusion after reconstitution; contains sucrose; preservative-free. Indications: Prevention and control of hemorrhagic episodes in Hemophilia A. Surgical prophylaxis in Hemophilia A. Routine prophylaxis

to reduce frequency of hemorrhagic episodes and joint damage in children with Hemophilia A with no pre-existing joint damage. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infuse over 1–15mins if tolerated. Minor hemorrhage: 10–20 IU/kg; may repeat dose if needed. Moderate hemorrhage or minor surgery: 15–30 IU/kg; may repeat dose every 12–24hrs until resolved. Major hemorrhage, fractures or head trauma: initially 40–50 IU/kg, then 20–25 IU/kg every 8–12hrs until resolved. Major surgery: Pre-op: 50 IU/kg (verify 100% activity prior to surgery); repeat if needed after 6–12hrs initially, and for 10–14 days until completely healed. Routine prophylaxis in children: 25 IU/kg every other day. Contraindications: Mouse or hamster protein sensitivity. Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Monitor for development of Factor VIII inhibitors. Labor & delivery. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Inj site reactions, dizziness, rash, BP increase, pruritus, hypersensitivity reactions, antibody formation, central venous line-associated infections. How supplied: Kit–1 (vial w. diluent and BIO-SET system)

MONOCLATE-P CSL Behring

℞

Clotting factor. Antihemophilic Factor VIII:C (human) 250 IU, 500IU, 1000 IU, 1500 IU; per vial; lyophilized concentrate for IV infusion after reconstitution; contains albumin. Indications: Treatment and surgical prophylaxis for Hemophilia A. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infusion rate: 2mL/min if tolerated. Mild hemorrhages: single infusion to attain 30% FVIII increase. Moderate hemorrhage or minor surgery: initially 15–25 IU/kg, then 10–15 IU/kg every 8–12hrs if needed. Severe hemorrhage: initially 40–50 IU/kg, then 20–25 IU/kg every 8–12hrs. Major surgery: give first dose 1 hour pre-op to attain 80–100% FVIII increase, then give a ½ dose 5 hours after first dose; maintain daily at ≥30% FVIII increase for 10–14 days post-op. Contraindications: Mouse protein sensitivity. Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Contains human plasma; monitor for possible infection transmission. Large or frequent dosing: monitor hematocrit for signs of progressive anemia. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Adverse reactions: Allergic reactions, chills, GI upset, inj site reactions, antibody formation. Note: Report any infections suspected to be transmitted by Monoclate-P to (800) 504-5434. How supplied: Single-dose vial–1 (w. diluent, supplies)

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ASSOCIATED HEMATOLOGICAL DISORDERS MONONINE CSL Behring

℞

Clotting factor. Coagulation Factor IX (human) 500 IU, 1000 IU; per vial; lyophilized pwd for IV infusion after reconstitution. Indications: Prevention and control of bleeding in Hemophilia B. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired Factor IX increase × 1 IU/kg. Individualize. Infuse at a rate of 2mL/min. Minor spontaneous hemorrhage, prophylaxis: increase FIX 15–25%; give up to 20–30 IU/kg once; may repeat in 24hrs if needed. Major trauma, surgery: increase FIX 25–50%; give up to 75 IU/kg every 18–30hrs for up to 10 days; adjust based on FIX levels. FIX inhibitors: may use higher doses. Contraindications: Mouse protein sensitivity. Warnings/Precautions: Not for Hemophilia A or other factor deficiencies, reversal of coumarin-induced anticoagulation or for bleeding due to low levels of liver-dependant coagulation factors. Fibrinolysis, disseminated intravascular coagulation (DIC), liver disease, neonates, or during post-op period; increased risk of thromboembolic events. Immune tolerance induction. Contains human plasma; monitor for possible infection transmission. Monitor for Factor IX inhibitors and deletion mutations of Factor IX gene; increased risk of hypersensitivity reactions. Pregnancy (Cat.C). Adverse reactions: Headache, fever, chills, flushing, GI upset, tingling, lethargy, inj site reaction, elevated ALT, inhibitor development; hypersensitivity reactions, thrombosis. Note: Report all infections suspected to be transmitted by Mononine to (800) 504-5434. How supplied: Single-dose vial–1 (w. diluent, supplies)

NEUMEGA Pfizer

℞

Thrombopoietic growth factor (Interleukin-11). Oprelvekin 5mg/vial; lyophilized pwd for SC inj after reconstitution; preservative-free. Indications: Prevention of severe thrombocytopenia. To reduce platelet transfusions following myelosuppressive chemotherapy in adults with non-myeloid malignancies who are at high risk of severe thrombocytopenia. Adults: Initiate 6–24hrs after chemotherapy completion. Give by SC inj into abdomen, thigh, or hip; also upper arm if not self-injecting. 50micrograms/kg once daily until post-nadir platelet count is ≥50,000/microliter; max 21 days. Discontinue ≥2days prior to next chemotherapy cycle. Severe renal impairment: CrCl <30mL/min:

25micrograms/kg. May give for ≤6 cycles following chemotherapy. Children: Not recommended. Warnings/Precautions: Not for use after myeloablative chemotherapy. Monitor fluid balance and electrolytes; increased risk of serious fluid retention with CHF, renal impairment, chronic diuretic or aggressive hydration therapy. Consider draining pre-existing fluid collections (eg, pericardial effusion, ascites). Obtain CBCs before and during therapy; monitor platelet counts. Pre-existing papilledema or tumors involving the CNS. History of stroke, transient ischemic attack, or atrial arrhythmias. Effectiveness unknown with chemotherapy regimens >5 days duration or with regimens associated with delayed myelosuppression (eg, nitrosoureas, mitomycin-C). Pregnancy (Cat.C). Nursing mothers: not recommended. Adverse reactions: Edema, dyspnea, tachycardia, conjunctival injection, palpitations, atrial arrhythmias, pleural effusions, neutropenic fever, syncope, atrial fibrillation, fever, pneumonia, CHF, pulmonary edema, dilutional anemia, blurred vision, paresthesia, dehydration, skin discoloration, exfoliative dermatitis, eye hemorrhage, stroke, papilledema, hypersensitivity reactions (permanently discontinue if occur). How supplied: Single-use vials–7 (w. diluent)

NITROPRESS Hospira

℞

Vasodilator. Sodium nitroprusside 25mg/mL; soln for IV infusion after dilution. Indications: To produce controlled hypotension to reduce surgical bleeding. Adults and Children: Use infusion pump only. Monitor BP closely. Initially 0.3microgram/kg/ min; may increase infusion rate every few minutes until desired effect; max 10microgram/kg/min and no more than 10 minutes. Titrate infusion rate (see literature). Contraindications: Compensatory hypertension due to aortic coarctation or arteriovenous shunting. Inadequate cerebral circulation or moribund patients requiring emergency surgery. Congenital (Lebers) optic atrophy. Tobacco amblyopia. Acute CHF associated with reduced peripheral vascular resistance. Warnings/Precautions: Use only when available equipment and personnel allow BP to be continuously monitored. Cyanide toxicity possible (esp. at infusion rates >2micrograms/kg/min); monitor acid-base disturbances and venous oxygen concentration. Elevated intracranial pressure. Correct pre-existing anemia and hypovolemia, esp. during anesthesia. Poor surigical

risk. Hepatic impairment. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Hypotensive effect potentiated by ganglionic blocking agents, negative inotropic agents, and inhaled anesthetics. Adverse reactions: Excessive hypotension, cyanide toxicity, methemoglobinemia, abdominal pain, apprehension, diaphoresis, dizziness, headache, muscle twitch, nausea, palpitations, restlessness, rash, hypothyroidism, ileus, flushing, infusion site reactions. How supplied: Single-dose vials (2mL)–100

NOVOSEVEN RT Novo Nordisk

℞

Clotting factors. Recombinant Coagulation Factor VIIa (rFVIIa) Room Temperature Stable 1mg, 2mg, 5mg, 8mg; per vial; lyophilized pwd for IV inj after reconstitution; preservative-free. Indications: Treatment of bleeding and perioperative management in adults and children with Hemophilia A and B with inhibitors, congenital Factor VII deficiency, and Glanzmann’s thrombasthenia refractory to platelet transfusions, with or without antibodies to platelets. Treatment of bleeding and peri-operative management in adults with acquired hemophilia. Adults and Children: See full labeling. Give by IV bolus only. Individualize; base treatment schedule modification on hemostasis evaluation. Hemophilia A or B with inhibitors: Bleeding: 90mcg/kg every 2hrs, adjust until hemostasis is achieved; post-hemostatic dosing: continue at 3–6hrs intervals for severe bleeds. Peri-operative: initially 90mcg/kg prior to surgery, repeat at 2hr intervals during surgery; minor (post-surgical dosing): every 2hrs for 48hrs, then every 2–6hrs until healed; major (post-surgical dosing): every 2hrs for 5 days, then every 4hrs until healed. Congenital Factor VII deficiency: Bleeding: 15–30mcg/kg every 4–6hrs until hemostasis is achieved; Peri-operative: 15–30mcg/kg prior to surgery, repeat every 4–6hrs during surgery and until hemostasis is achieved. Glanzmann’s thrombasthenia: Bleeding: 90mcg/kg every 2–6hrs until hemostasis is achieved; Perioperative: initially 90mcg/kg prior to surgery, repeat every 2hrs during surgery, then every 2–6hrs post-surgical. Acquired hemophilia: Bleeding: 70–90mcg/kg every 2–3hrs until hemostasis is achieved; Peri-operative: 70–90mcg/kg prior to surgery, repeat every 2–3hrs during surgery and until hemostasis is achieved. Warnings/Precautions: Risk of serious arterial and venous thromboembolic events. Disseminated intravascular coagulation (DIC), advanced atherosclerotic disease, crush injury, septicemia,

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ASSOCIATED HEMATOLOGICAL DISORDERS uncontrolled post-partum hemorrhage, history of coronary heart disease, hepatic disease, post-op immobilization, elderly, neonates; increased risk of developing thrombotic events. Monitor for signs/ symptoms of coagulation activation or thrombosis; discontinue or reduce dose if occur. Monitor prothrombin time and FVII coagulant activity before and after dosing in FVII deficiency. Perform analysis for antibodies if factor VIIa activity fails to reach expected level. Mouse, hamster, or bovine protein hypersensitivity. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Avoid concomitant activated or non-activated prothrombin complex concentrates; may increase risk of thrombotic events. Do not mix with infusion solutions. Concomitant Coagulation Factor XIII may cause thrombosis. Adverse reactions: Thrombotic events, fever, fibrinogen plasma decreased, hypertension, headache, nausea, dyspnea; pain, thrombophlebitis, pulmonary embolism, decreased therapeutic response, cerebrovascular disorder, angina pectoris, abnormal hepatic function, DIC, hypersensitivity reactions (discontinue and treat if occur). How supplied: Single-use vial–1 (w. diluent); MixPro–1 (single-use vial + pre-filled diluent syringe + vial adapter)

NPLATE Amgen

℞

Thrombopoietin receptor agonist. Romiplostim (recombinant) 250mcg, 500mcg; per vial; lyophilized pwd for SC inj after reconstitution; contains sucrose and mannitol; preservative-free. Indications: Thrombocytopenia in patients with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Adults: Give by SC inj. To reduce risk of bleeding: use lowest effective dose to achieve and maintain platelets ≥50×109/L. ≥18yrs: initially: 1mcg/kg weekly; may increase by 1mcg/kg if platelets <50×109/L; max: 10mcg/kg weekly. May reduce by 1mcg/kg if platelets >200×109/L for 2 consecutive weeks. Do not dose if platelets >400×109/L; resume Nplate at a dose reduced by 1mcg/kg when platelets fall to <200×109/L. Discontinue if platelets have not increased after 4 weeks at max dose. Children: <18yrs: not recommended. Warnings/Precautions: Not for normalization of platelet counts or to treat thrombocytopenia due to MDS or any cause of thrombocytopenia other than chronic ITP. Risk of bone marrow fibrosis with cytopenias. Worsened thrombocytopenia after discontinuation. Monitor CBCs, platelets, and peripheral blood smears before and weekly during dose adjustments then monthly after achieving stable dose; and weekly for 2 weeks after discontinuation of therapy. Monitor after initial response for formation of neutralizing antibodies. Risk of hematologic malignancies (esp. myelodysplastic syndrome).

Renal or hepatic impairment. Elderly. Pregnancy (Cat.C). Nursing mothers. Interactions: May increase bleeding risk with anticoagulants or antiplatelet agents. Adverse reactions: Arthralgia, dizziness, insomnia, myalgia, pain in extremity, abdominal pain, shoulder pain, dyspepsia, paresthesia, headaches; bone marrow reticulin deposition, worsening thrombocytopenia, risk of bleeding, thrombotic/thromboembolic complications, antibody formation. How supplied: Single-use vial–1

PRIVIGEN CSL Behring

℞

Immune globulin. Immune globulin (human) 0.1g/mL; soln for IV infusion; contains L-proline; sucrose-, preservative-, and latex-free. Indications: Chronic immune thrombocytopenic purpura (ITP). Adults and Children: <15yrs: not established. ≥15yrs: Give by IV infusion at an initial rate of 0.5mg/kg/min, if tolerated may increase to 4mg/kg/min. Renal dysfunction, thrombosis risk: give at the minimum infusion rate practicable. Usual dose: 1g/kg once daily for 2 consecutive days for a total dose of 2g/kg. Increased risk of thrombosis, hemolysis, acute renal injury, or volume overload: consider carefully the relative risks and benefits before prescribing high dose regimen (2g/kg). Contraindications: IgA-deficiency with antibodies against IgA and history of hypersensitivity. Hyperprolinemia. Previous severe reaction to human immune globulin. Warnings/Precautions: Advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, cardiovascular risk factors: increased risk of thrombosis. Monitor for signs/symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. Pre-existing renal insufficiency, diabetes, >65yrs, obese, hypovolemia: increased risk of renal dysfunction and acute renal failure. Correct volume depletion; assess renal function, BUN, serum creatinine, urine output before and during therapy; discontinue if renal function deteriorates. Monitor for aseptic meningitis, hemolysis, delayed hemolytic anemia, transfusionrelated acute lung injury (eg, respiratory distress, pulmonary edema, hypoxemia). Antibody formation. Risk of transmission of viral diseases. Have epinephrine inj available. Elderly. Pregnancy (Cat.C). Nursing mothers. Interactions: Concomitant nephrotoxic drugs: increased risk of renal toxicity. May affect response to live virus vaccines. May interfere with serological test interpretation. Adverse reactions: Headache, elevated body temperature, positive direct antiglobulin test, anemia, nausea, epistaxis, vomiting, hematocrit decreased, increase in blood bilirubin, blood total bilirubin and blood lactate dehydrogenase;

hyperproteinemia, increased serum viscosity, hyponatremia; rare: aseptic meningitis syndrome (esp. high dose of 2g/kg), hemolysis, TRALI, thrombosis. How supplied: Single-use vial (50mL, 100mL, 200mL, 400mL)–1

PROFILNINE SD Grifols Biologicals ℞ Clotting factor. Coagulation Factor IX complex (human) 500 IU, 1000 IU, 1500 IU; per vial; lyophilized concentrate for IV infusion after reconstitution; contains Factor X, Factor II, Factor VII; preservative-free. Indications: Prevention and control of bleeding in Hemophilia B. Adults: Dosage Required (IU) = Body Weight (kg) × Desired Factor IX increase × 1 IU/kg. Individualize. Max infusion rate: 10mL/min. Mild to moderate hemorrhage: give single dose to increase Factor IX 20–30%. Serious hemorrhage: give daily infusions to increase Factor IX 30–50%. Surgery: increase Factor IX by 30–50% for at least 1 week Post-op. Dental extraction: increase Factor IX to 50% immediately prior to procedure; may give additional doses if bleeding recurs. Children: See literature. Warnings/Precautions: Not for treating Factor VII deficiency. Contains human plasma; monitor for possible infection transmission. Liver disease, prolonged treatment duration or if undergoing surgery: increased risk of disseminated intravascular coagulation (DIC) and thrombosis. Pregnancy (Cat.C). Adverse reactions: Urticaria, fever, chills, GI upset, headache, somnolence, lethargy, flushing, tingling; hypersensitivity reactions, thrombosis, DIC. Note: Report all infections suspected to be transmitted by Profilnine SD to (888) 675-2762. How supplied: Single-use vials–1 (w. diluent, supplies)

PROMACTA GlaxoSmithKline

℞

Thrombopoietin receptor agonist. Eltrombopag (as olamine) 12.5mg, 25mg, 50mg, 75mg; tabs. Indications: Thrombocytopenia in adults with chronic immune (idiopathic) thrombocytopenic purpura (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. Thrombocytopenia in adults with chronic hepatitis C to allow initiation and maintenance of interferon-based therapy. Limitations of use: should be used only in ITP whose degree of thrombocytopenia and clinical condition increase the risk of bleeding; or, in chronic hepatitis C whose degree of thrombocytopenia prevents starting or limiting ability to maintain interferon-based therapy. Safety and efficacy not established in combination with direct-acting antiviral agents without interferon for chronic hepatitis C infection. Adults: Take on empty stomach. ITP: initially 50mg once daily. Hepatic impairment or East

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ASSOCIATED HEMATOLOGICAL DISORDERS Asian ancestry: initially 25mg once daily. East Asian ancestry with hepatic impairment: consider initiating at 12.5mg once daily. Titrate to maintain platelet count ≥50×109/L; max 75mg once daily. Chronic hepatitis C-associated thrombocytopenia: initially 25mg once daily. Titrate dose by 25mg every 2 weeks as needed to achieve target platelet counts; max 100mg/day. Monitoring, dose adjustment, and discontinuation: see full labeling. Children: Not established. Warnings/Precautions: Increased risk of hepatic decompensation in chronic hepatitis C, when concomitant with interferon and ribavirin; discontinue Promacta if antiviral therapy is discontinued. Monitor liver function prior to initiation, every 2 weeks during dose adjustments, and monthly after stabilized (see full labeling); discontinue if ALT ≥3×ULN and is progressive or persistent for ≥4 weeks, or if occurs with increased bilirubin, or evidence of hepatic injury/ decompensation; reinitiate therapy if benefit outweighs risk; if restarted, monitor carefully. Increased risk of thromboembolism; do not use to normalize platelet counts. Do baseline eye exam; monitor for cataracts. Renal impairment. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Do not take within 4hrs of food/ drugs containing polyvalent cations (eg, Fe+2, Ca+2, Al+3, Mg+2, Se+2, Zn+2). Potentiate substrates of OATP1B1 (eg, most statins, bosentan, ezetimibe, glyburide, olmesartan, valsartan, repaglinide, rifampin) or BCRP (eg, imatinib, irinotecan, lapatinib, methotrexate, mitoxantrone, sulfasalazine, topotecan); monitor and consider reducing their doses. Antagonized by lopinavir/ ritonavir. Adverse reactions: Nausea, diarrhea, vomiting, infections, increased ALT/AST, myalgia, pain, pharyngitis, paresthesia, rash, anemia, pyrexia, fatigue, headache, decreased appetite, asthenia, insomnia, cough, pruritus, chills, alopecia, peripheral edema; hepatotoxicity, hemorrhage, thrombotic complications from excessive increases in platelet counts, cataracts. How supplied: Tabs–30

RECOMBINATE Baxter

℞

Clotting factor. Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU; per bottle; lyophilized pwd for IV infusion after reconstitution; contains albumin; preservative-free. Indications: Prevention and control of hemorrhagic episodes and perioperative management in Hemophilia A. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase

× 0.5. Infuse at rate of up to 10mL/min. Monitor pulse rate; if increased significantly, reduce infusion rate or hold. Hemorrhage: Mild: obtain 20–40% FVIII increase; give every 12–24hrs for 1–3 days until resolved. Moderate: obtain 30–60% FVIII increase; give every 12–24hrs for 3 days or until pain or disability resolved. Life-threatening: obtain 60–100% FVIII increase; give every 8–24hrs until resolved. Surgery: Minor: obtain 60–80% FVIII increase; give single infusion plus oral antifibrinolytic therapy within 1 hour; Major: pre- and Post-op: obtain 80–100% FVIII increase; repeat every 8–24hrs based on healing. Contraindications: Mouse, hamster, or bovine protein sensitivity. Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Monitor for development of Factor VIII inhibitors. Latex allergy. Pregnancy (Cat.C). Adverse reactions: Allergic reactions, nausea, fever, chills, urticaria, antibody formation. How supplied: Single-dose bottle–1 (w. diluent)

RECOTHROM ZymoGenetics

℞

Topical hemostatic. Thrombin [recombinant] 5000 IU, 20000 IU; per vial; pwd for topical use after reconstitution; preservative-free. Indications: Aid to hemostasis for minor bleeding/ oozing from capillaries and venules when standard surgical techniques are inadequate or ineffective. May use with absorbable gelatin sponge. Adults: Apply directly to bleeding area, or soak into absorbable gelatin sponge and apply in a single layer. Children: Not recommended. Contraindications: Not for direct injection into circulatory system. Not for treatment of massive or brisk arterial bleeding. Hypersensitivity to hamster proteins. Warnings/Precautions: Avoid systemic absorption (thrombosis may occur). Hypersensitivity to snake proteins. Pregnancy (Cat.C). Adverse reactions: Incision site complication, infection, pain, bleeding, nausea/vomiting, cardiac events, thromboembolic events. How supplied: Single-use vial (5000 IU, 20000 IU)–1 (w. diluent, supplies) 20000 IU Recothrom kit (co-packaged with ZymoGenetics Spray Applicator Kit)–1

REFACTO Pfizer

℞

Clotting factor. Antihemophilic Factor VIII (recombinant) 250 IU, 500 IU, 1000 IU, 2000 IU; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free.

Indications: Prevention and control of hemorrhagic episodes and for surgical prophylaxis in Hemophilia A. Short-term routine prophylaxis to reduce frequency of spontaneous bleeding episodes. Adults and Children: Dosage Required (IU) = Body Weight (kg) × Desired % Factor VIII Increase × 0.5. Individualize. Infuse at rate comfortable to patient. Minor hemorrhage: obtain 20–40% FVIII increase; give every 12–24hrs for at least 1 day until resolved. Moderate hemorrhage and tooth extraction: obtain 30–60% FVIII increase; give every 12–24hrs for 3–4 days until adequate hemostasis; for tooth extraction: a single infusion plus oral antifibrinolytic therapy within 1hr may be sufficient. Major hemorrhage: obtain 60–100% FVIII increase; give every 8–24hrs until resolved; or, for surgery, until local hemostasis achieved. Prophylaxis: give ≥2 times weekly; children may need shorter dosage intervals or higher doses. Contraindications: Mouse or hamster protein sensitivity. Warnings/Precautions: Not for von Willebrand’s disease. Confirm Factor VIII deficiency prior to treatment. Monitor for development of Factor VIII inhibitors. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Allergic reactions, headache, fever, chills, flushing, nausea, vomiting, lethargy, pruritus, antibody formation. How supplied: Single-use vial–1 (w. diluent, supplies)

RHOPHYLAC CSL Behring

℞

Rho (D) immune globulin human 1500 IU (300mcg)/2mL; syringe; for IV or IM inj; preservative- and latex-free; contains albumin (human); solvent/detergent treated. Indications: Raising platelet counts in Rho (D) positive non-splenectomized patients with chronic immune thrombocytopenic purpura (ITP). Adults: See full labeling. 250 IU (50mcg) per kg by IV only at rate of 2mL per 15–60 secs. Children: Not recommended. Contraindications: Rho (D) positive patients. IgA deficiency. Warnings/Precautions: Monitor patients 20 mins after administration. Pregnancy (Cat.C). Interactions: Do not give live vaccines within 3 months. Adverse reactions: Local or infusion reactions, fever, chills, headache; see full labeling. How supplied: Single-dose prefilled syringes–1, 10

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ASSOCIATED HEMATOLOGICAL DISORDERS RIASTAP CSL Behring

℞

Hemostatic. Fibrinogen concentrate (human) 900–1300mg; per vial; lyophilized pwd for IV inj after reconstitution; contains albumin; preservative-free. Indications: Acute bleeding episodes in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia. Adults and Children: See literature. Give by slow IV inj at rate not exceeding 5mL/min. Individualize. Calculate dose when baseline fibrinogen level is known: Dose (mg/kg body wt) = [Target level (mg/dL)–measured level (mg/dL)]/1.7 (mg/dL per mg/kg body wt). When baseline fibrinogen level is not known: 70mg/kg. Monitor fibrinogen level during therapy. Maintain target fibrinogen level of 100mg/dL until hemostatis is obtained. Warnings/Precautions: Not for use in dysfibrinogenemia. Monitor for allergic or hypersensitivity reactions; discontinue if occur. Risk of thrombosis (monitor). Contains human plasma; monitor for possible infection transmission. Labor & delivery. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Fever, headache, chills, nausea, vomiting; thrombotic episodes (eg, pulmonary embolism, MI, DVT), anaphylactic reactions. How supplied: Single-use vial–1

RIXUBIS Baxter

℞

Clotting factor. Coagulation Factor IX (recombinant) 250 IU, 500 IU, 1000 IU, 2000 IU, 3000 IU; per vial; lyophilized pwd for IV infusion after reconstitution; preservative-free. Indications: Control and prevention of bleeding episodes, perioperative management, and routine prophylaxis in hemophilia B. Adults: Empirical finding: 1 IU/kg increases circulating activity of FIX by 0.9 IU/dL. Initial dose = body weight (kg) × desired FIX increase (% or IU/dL) × reciprocal of observed recovery (IU/dL per IU/kg). Incremental recovery in previously treated patients (PTPs): Dose (IU) = body weight (kg) × desired FIX increase (% or IU/dL) × 1.1 dL/kg. Individualize. Give by IV bolus infusion only. Max infusion rate 10mL/min. Control/ prevention of bleeding: Minor: 20–30% required every 12–24hrs for at least 1 day until healing achieved. Moderate: 25–50% required every 12–24hrs for 2–7 days until bleeding stops and healing achieved. Major: 50–100% required every 12–24hrs for 7–10 days until bleeding stops and healing achieved. Peri-op management: Minor surgery: 30–60% required every 24hrs for at least 1 day until healing achieved. Major surgery: 80–100% required every 8–24hrs for 7–10 days until bleeding stops and healing achieved. Routine prophylaxis in PTPs: 40–60 IU/kg twice weekly; titration may be necessary based on patient’s age, bleeding pattern, physical activity. Children: Empirical finding: 1 IU/kg increases circulating activity of FIX by 0.7 IU/dL. Initial dose = body weight (kg) × desired FIX increase (% or

IU/dL) × reciprocal of observed recovery (IU/dL per IU/kg). Incremental recovery in previously treated patients (PTPs): Dose (IU) = body weight (kg) × desired FIX increase (% or IU/dL) × 1.4 dL/kg. Individualize. Give by IV bolus infusion only. Max infusion rate 10mL/min. Control/ prevention of bleeding: Minor: 20–30% required every 12–24hrs for at least 1 day until healing achieved. Moderate: 25–50% required every 12–24hrs for 2–7 days until bleeding stops and healing achieved. Major: 50–100% required every 12–24hrs for 7–10 days until bleeding stops and healing achieved. Peri-op management: Minor surgery: 30–60% required every 24hrs for at least 1 day until healing achieved. Major surgery: 80–100% required every 8–24hrs for 7–10 days until bleeding stops and healing achieved. Routine prophylaxis in PTPs: 60–80 IU/kg twice weekly; titration may be necessary based on patient’s age, bleeding pattern, physical activity. Contraindications: Hamster protein hypersensitivity. Disseminated intravascular coagulation (DIC). Signs of fibrinolysis. Warnings/Precautions: Not for induction of immune tolerance in patients with hemophilia B; risk of nephrotic syndrome. Evaluate regularly for development of Factor IX inhibitors; measure Factor IX inhibitor concentration if expected activity plasma levels are not attained, or if bleeding is not controlled with an expected dose. Potential risk for thromboembolic complications; monitor for signs of thrombotic and consumptive coagulopathy, in patients with liver disease, signs of fibrinolysis, peri- and post-operatively, or at risk for thrombotic events or DIC. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Dysgeusia, extremity pain, positive test for furin antibody; hypersensitivity reactions (discontinue if occur). How supplied: Single-use vials–1 (w. diluent, supplies)

STIMATE CSL Behring

℞

Antidiuretic hormone. Desmopressin acetate 150mcg/spray; soln for nasal spray. Indications: To maintain hemostasis or to stop bleeding in Hemophilia A and mild-to-moderate Type I von Willebrand Disease (VWD), each with Factor VIII levels >5%. Adults and Children: <11months: not recommended. Give test dose prior to initiating therapy. >11months: <50kg: 1 spray in one nostril (150mcg). ≥50kg: 1 spray per nostril (300mcg). May repeat dose based on clinical response. Pre-op: give 2hrs prior to procedure. Repeated administration before 48 hrs associated with tachyphylaxis. Warnings/Precautions: Not for treating Type IIb VWD, or severe VWD with abnormal molecular form of Factor VIII antigen. Adjust fluid intake downward (esp in children and elderly) to reduce risk of water intoxication, hyponatremia. Monitor fluid intake, plasma osmolality. Fluid and electrolyte imbalances (eg, cystic fibrosis). Coronary artery disease. Hypertension. Predisposition to thrombosis. Unreliable absorption if altered nasal

mucosa (eg, scarring, edema); discontinue until resolved. Pregnancy (Cat.B). Nursing mothers. Interactions: Caution with other pressor agents (monitor). Adverse reactions: Headache, nausea, abdominal cramps, vulval pain, facial flushing, local reactions, sore throat, water intoxication, hyponatremia; rare: BP changes, severe allergic reactions, thrombotic events. How supplied: Spray Pump–2.5mL (25 sprays)

THROMBIN-JMI Pfizer

℞

Topical hemostatic. Thrombin [bovine origin] 5000 IU, 20000 IU; per vial; pwd for topical use after reconstitution; preservative-free. Indications: Aid to hemostasis for oozing blood and minor bleeding from accessible capillaries and small venules. Adjunct for surgical hemostasis with absorbable gelatin sponge. Adults: For topical use only. See literature. Profuse bleeding (eg, abraided surfaces of liver or spleen): 1000IU/mL. General use (eg, plastic surgery, dental extractions, skin grafting): 100IU/mL. May dilute to prepare intermediate strengths, if needed. Oozing surfaces: may use dry form. Children: Not recommended. Warnings/Precautions: Not for injection or use in large blood vessels. Antibody formation: do not re-expose, abnormalities in hemostasis (eg, severe bleeding or thrombosis) more likely with repeated use. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Hypersensitivity reactions, antibody formation. How supplied: Vials–1 (w. diluent) Pump Spray Kit (20000 IU)–1 (w. diluent) Syringe Spray Kit (20000 IU)–1 (w. diluent) Epistaxis Kit (5000 IU)–1 (w. diluent)

WILATE Octapharma

℞

Coagulation factor complex. Von Willebrand Factor/Factor VIII Complex (human); 450 IU VWF:RCo and 450 IU FVIII activities per 5mL; 900 IU VWF:RCo and 900 IU FVIII activities per 10mL; pwd; for IV injection after reconstitution; preservative-free; solvent-detergent treated. Indications: Bleeding episodes (spontaneous and trauma induced) in patients with severe von Willebrand disease, and patients with mild to moderate von Willebrand disease for whom desmopressin is ineffective or contraindicated. Adults and Children: <5yrs: contact manufacturer. Give by IV injection at 2–4mL/min. ≥5yrs: Minor bleed: 20–40 IU/kg once, then 20–30 IU/kg every 12–24 hours. Major bleed: 40–60 IU/kg once, then 20–40 IU/kg every 12–24 hours. Monitor and adjust according to VWF:RCo and FVIII activity, and location of bleed; usual treatment duration is 3 days (minor hemorrhage) and 5–7 days (major hemorrhage). See literature for activity level goals. Warnings/Precautions: Not for prophylaxis of spontaneous bleeding, prevention of surgical bleeding, or hemophilia A. Treatment should be supervised by physician trained in coagulopathies.

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ASSOCIATED HEMATOLOGICAL DISORDERS Risk of thrombotic events with sustained excessive FVIII levels; monitor. Ineffectiveness may indicate antibody formation; discontinue if confirmed. Risk of transmission of blood-borne diseases; consider vaccination against hepatitis A and B. Monitor pulse during injection; slow or stop infusion if marked increase in heart rate occurs. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Urticaria, dizziness, hypersensitivity reactions, antibody formation. How supplied: Kit–1 (w. diluent, supplies)

WINRHO SDF Emergent BioSolutions ℞ Rho(D) immune globulin intravenous human 600IU (120mcg), 1500IU (300mcg), 2500IU (500mcg), 5000IU (1000mcg), 15000IU (3000mcg); per vial; lyophilized pwd or soln; for IV or IM inj after reconstitution; preservative-free. Indications: Treatment of non-splenectomized, Rho(D) positive children with acute immune thrombocytopenic purpura (ITP); adults and children with chronic ITP and ITP secondary to HIV infection; in clinical situations requiring an increase in platelet count to prevent excessive hemorrhage. Adults and Children: Give by IV inj only. Confirm Rho(D) positive prior to treatment. Initially: 250 IU/kg as single dose or 2 divided doses on separate days; if Hgb <10g/dL, reduce to 125–200 IU/kg. Maintenance: 125–300 IU/kg; Hbg >10g/dL: 250–300 IU/kg; Hgb 8–10g/dL: 125–200 IU/kg; Hgb <8g/dL: use with caution. Base frequency and dose on clinical response. Contraindications: IgA deficiency. Allergy to blood products. Treatment of immune globulin deficiency syndromes. Warnings/Precautions: Not for use in Rho(D) negative or splenectomized patients; monitor for intravascular hemolysis, anemia, renal insufficiency; hemoglobin <10g/dL decrease dose, if <8g/dL use extreme caution. Pregnancy (Cat.C). Interactions: Do not give live vaccines within 3 months. Adverse reactions: Headache, chills, fever, local or infusion reactions; see literature. Note: Report all infections suspected to be transmitted by WinRho SDF to (800) 423-2090. How supplied: Single-dose vials (pwd) 600IU, 1500IU, 5000IU–1 (w. diluent); Single-dose vials (soln) 600IU, 1500IU, 2500IU, 5000IU, 15000IU–1

XYNTHA Pfizer

℞

Clotting factor. Antihemophilic Factor (recombinant): nominally 250 IU, 500 IU, 1000 IU, or 2000 IU per vial; pwd for IV infusion after reconstitution; plasma/albumin-free; preservative-free; contains polysorbate 80. Actual factor VIII activity noted on each vial.

Indications: In Hemophilia A: to control bleeding episodes, and for surgical prophylaxis. Adults: Individualize and titrate. Give by IV infusion over several minutes. One IU of factor VIII per kg raises the plasma factor VIII activity by about 2 IU/dL. Minor bleeds: factor VIII level required is 20–40 IU/dL or % of normal, repeat infusion every 12–24 hours as needed for at least 1 day, until resolution. Moderate bleeds: 30–60 IU/dL or % of normal; repeat infusion every 12–24 hours for 3–4 days or until hemostasis. Major bleeds: 60–100 IU/dL or % of normal, repeat infusion every 8–24 hours until resolution. Minor surgical procedures: 30–60 IU/dL or % of normal, repeat infusion every 12–24 hours for 3–4 days or until hemostasis. Major surgery: 60–100 IU/dL or % of normal; repeat infusion every 8–24 hours until hemostasis and wound healing occurs. Children: Consult manufacturer (limited pharmacokinetic data available; studies are ongoing). Warnings/Precautions: Monitor for development of Factor VIII inhibitors; may need dose adjustment. Pregnancy (Cat.C). Labor & delivery. Nursing mothers. Adverse reactions: Hypersensitivity reactions/ anaphylaxis, pyrexia, headache, GI upset, asthenia. How supplied: Kit–1 (w. diluent, supplies)

Immune-mediated blood disorders

BAYRHO-D FULL DOSE Bayer ℞ Rho(D) immune globulin human 300mcg; for IM inj; solvent/detergent treated. Indications: Preventing Rho(D) sensitization in nonsensitized Rho(D) negative or Du negative patients to the Rho(D) factor, following pregnancy or accidental transfusion. Adults: Each vial or syringe (approx. 300mcg) prevents sensitization to a volume of up to 15mL of Rh positive red blood cells. Administer IM at 28 weeks of gestation, within 72 hours of an Rh incompatible delivery, miscarriage, abortion, or transfusion accident. Children: Not recommended. Also: BAYRHO-D MINI-DOSE ℞ Rho(D) immune globulin human 50mcg; for IM inj. Indications: Prevention of Rho(D) sensitization following termination of pregnancies up to 12 weeks gestation. Adults: Each syringe (approx. 50mcg) prevents sensitization to 2.5mL of Rh positive red blood cells. Give IM up to 12 weeks’ gestation, within 3 hours of an Rh incompatible delivery, miscarriage, or abortion. Children: Not recommended.

Contraindications: Rho(D) positive patients. Pregnancy (Cat.C). Warnings/Precautions: Live vaccines. Have epinephrine available. Adverse reactions: Local reactions. How supplied: Full Dose (single-dose syringes and vials)–1, 10; Mini-Dose (single-dose syringes)–10

HYPERRHO S/D FULL DOSE ℞

Grifols Biologicals

Immune globulin. Rho(D) immune globulin human 1500 IU; per syringe; soln for IM inj; preservativefree; latex-free. Indications: Prevention of isoimmunization in non-sensitized Rho(D) negative women during pregnancy and in appropriate obstetrical conditions, unless the fetus or father is known to be Rho(D) negative. Prevention of isoimmunization in Rho(D) negative individuals transfused with Rho(D) positive blood products. Adults: See literature. Give IM only. Pregnancy (28 weeks gestation), postpartum prophylaxis (within 72 hours), obstetric complications, invasive procedures during pregnancy: 1500IU. Incompatible transfusions (within 72 hours): volume of red blood cells transfused divided by 15mL provides the number of syringes to be administered; if the dose is a fraction, round to next higher whole number of syringes. Children: Not recommended. Also: HYPERRHO S/D MINI-DOSE ℞ Rho(D) immune globulin human; 250 IU; per syringe; soln for IM inj.; preservative-free; latexfree. Indications: Prevention of isoimmunization of Rho(D) negative women during spontaneous or induced abortion of ≤12 weeks’ gestation when mother is not sensitized to Rho(D) antigen and father is not known to be Rho(D) negative. Adults: Postabortion or miscarriage of up to 12 weeks gestation: 1 syringe IM within 3hrs of spontaneous or induced abortion or within 72hrs following termination of pregnancy. Children: Not recommended. Contraindications: Neonates. Warnings/Precautions: Contains human plasma; monitor for possible infection transmission. IgA deficiency. Pregnancy (Cat.C). Interactions: Avoid live vaccines within 3 months. Adverse reactions: Local or infusion reactions. Note: Report all infections suspected to be transmitted by HyperRHO S/D to (800) 520-2807. How supplied: Full dose (Single-dose prefilled syringe)–1; Mini dose (Single-dose prefilled syringe)–10

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS RHOGAM Kedrion

℞

Rho(D) immune globulin human 300mcg; for IM inj. Indications: Preventing Rho(D) sensitization in nonsensitized Rho(D) negative or Du negative patients to the Rho(D) factor, following pregnancy or accidental transfusion. Adults: Each vial or syringe (approx. 300mcg) prevents sensitization to a volume of up to 15mL of Rh positive red blood cells. Administer IM at 28 weeks of gestation, within 72 hours of an Rh incompatible delivery, miscarriage, abortion, or transfusion accident. Children: See literature. Contraindications: Rho(D) positive patients. Warnings/Precautions: Pregnancy (Cat.C). Adverse reactions: Local reactions. How supplied: Single-dose syringes–5, 25

RHOPHYLAC CSL Behring

℞

Rho (D) immune globulin human 1500 IU (300mcg)/2mL; syringe; for IV or IM inj; preservative- and latex-free; contains albumin (human); solvent/detergent treated. Indications: Suppression of Rh isoimmunization in non-sensitized Rho (D) negative women during pregnancy and in appropriate obstetrical conditions, unless the fetus or father is known to be Rho (D) negative. Suppression of Rh isoimmunization in Rho (D) negative individuals transfused with Rho (D) positive blood products. Adults: See full labeling. Pregnancy (28–30 weeks gestation), postpartum prevention (within 72hrs), obstetric complications, invasive procedures during pregnancy: 1500 IU (300mcg). Incompatible transfusions (within 72hrs): 100 IU (20mcg) per 2mL transfused blood or per 1mL erythrocyte concentrate. Children: Not recommended. Contraindications: Rho (D) positive patients. IgA deficiency. Warnings/Precautions: Monitor patients 20 mins after administration. Pregnancy (Cat.C). Interactions: Do not give live vaccines within 3 months. Adverse reactions: Local or infusion reactions, fever, chills, headache; see full labeling. How supplied: Single-dose prefilled syringes–1, 10

WINRHO SDF

℞

Emergent BioSolutions

Rho(D) immune globulin intravenous human 600IU (120mcg), 1500IU (300mcg), 2500IU (500mcg), 5000IU (1000mcg), 15000IU (3000mcg); per vial; lyophilized pwd or soln; for IV or IM inj after reconstitution; preservative-free. Indications: Suppression of Rh isoimmunization in nonsensitized Rho(D) negative women in appropriate obstetrical conditions, unless the fetus or father is known to be Rho(D) negative. Suppression of Rh isoimmunization in Rho(D)

negative females after accidental transfusion of Rho(D) positive blood products. Adults: Pregnancy: 1500IU at 28 weeks gestation; if given early in pregnancy, repeat every 12 weeks. Post-delivery: 600IU as soon as possible (preferably within 72 hrs, up to 28 days) of an Rh incompatible delivery. Amniocentesis or other manipulation late in pregnancy (after 34 weeks gestation), abortion: 600IU as soon as possible (within 72 hrs). Chorionic villus sampling, amniocentesis (before 34 weeks gestation), threatened abortion: 1500IU as soon as possible, repeat every 12 weeks during pregnancy. Transfusion: IV route: 3000IU (600micrograms) every 8 hours; or IM route: 6000IU (1200micrograms) every 12 hours; for both: total dose based on exposure (see literature); give within 72 hours. Children: See literature. Do not give to infant for maternal Rh incompatability. Contraindications: Rho(D) positive patients. IgA deficiency. Allergy to blood products. Treatment of immune globulin deficiency syndromes. Warnings/Precautions: Rho(D) negative patients who are Rh immunized. Thrombocytopenia. Pregnancy (Cat.C). Interactions: Do not give live vaccines within 3 months. Adverse reactions: Local or infusion reactions, fever; see literature. Note: Report all infections suspected to be transmitted by WinRho SDF to (800) 423-2090. How supplied: Single-dose vials (pwd) 600IU, 1500IU, 5000IU–1 (w. diluent); Single-dose vials (soln) 600IU, 1500IU, 2500IU, 5000IU, 15000IU–1

White blood cell disorders

GRANIX Teva

℞

Granulocyte colony stimulating factor. Tbo-filgrastim 300mcg/0.5mL, 480mcg/0.8mL; soln for SC inj; preservative-free. Indications: To reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Adults: Administer the 1st dose no earlier than 24hrs following myelosuppressive chemotherapy. Do not administer within 24hrs prior to chemotherapy. Inject 5mcg/kg SC once daily until expected neutrophil nadir is passed and neutrophil count has recovered to normal range. Monitor CBC prior to chemotherapy and twice per week until recovery. Recommended inj sites: the abdomen (except for the 2-inch area around navel), the front of the middle thighs, the upper outer area of the buttocks, or the upper back portion of the upper arms; rotate inj site daily. Avoid injecting into an area that is tender, red, bruised or hard, or that has scars or stretch marks. Children: <18yrs: not established. Warnings/Precautions: Risk of splenic rupture; discontinue and evaluate if symptoms of enlarged

spleen or rupture occur. Evaluate for acute respiratory distress syndrome if fever and lung infiltrates or respiratory distress develop after treatment; discontinue if acute respiratory distress syndrome is diagnosed. Permanently discontinue if serious allergic reactions occur. Sickle cell disease: consider potential risks and benefits prior to treatment and discontinue if sickle cell crisis develops. Hepatic or moderate-to-severe renal impairment. Pregnancy (Cat.C). Nursing mothers. Interactions: Caution with drugs that may potentiate release of neutrophils (eg, lithium). May cause transient positive changes in boneimaging test results. Adverse reactions: Bone pain; splenic rupture (may be fatal), acute respiratory distress syndrome, serious allergic reactions, sickle cell crisis, potential for tumor growth stimulatory effects on malignant cells. How supplied: Single-use prefilled syringe (0.5mL, 0.8mL)–1, 10 (w. safety needle guard)

LEUKINE Genzyme

℞

Granulocyte-macrophage colony stimulating factor (recombinant). Sargramostim (recombinant human granulocyte-macrophage colony stimulating factor, or rhu GM-CSF) 250mcg; per vial; pwd for SC inj or IV infusion after reconstitution; preservative-free. Indications: To speed neutrophil recovery and reduce infections after induction chemotherapy in treatment of acute myelogenous leukemia (AML) in patients >55 years of age. To mobilize hematopoietic progenitor cells into peripheral blood for collection by leukapheresis. To speed myeloid recovery in non-Hodgkin’s lymphoma, acute lymphoblastic leukemia (ALL), and Hodgkin’s disease in autologous bone marrow transplantation (BMT). To speed myeloid recovery in allogeneic BMT. Patients with BMT failure or engraftment delay. Adults: See literature for timing and duration of dosing, and for repeat courses of therapy. Individualize. Neutrophil recovery: 250mcg/m2 per day IV over 4 hrs. Mobilization or post peripheral blood progenitor cell transplantation: 250mcg/m2 per day IV over 24 hrs or SC once daily. Myeloid recovery after BMT: 250mcg/m2 per day IV over 2 hrs. BMT failure or engraftment delay: 250mcg/m2 per day IV over 2 hrs for 14 days. Children: See literature. Contraindications: Excessive leukemic myeloid blasts in bone marrow or peripheral blood (≥10%). Allergy to GM-CMF or yeastderived products. Concomitant (within 24 hrs) chemotherapy or radiotherapy. Warnings/Precautions: Fluid retention, pleural or pericardial effusions. Pulmonary infiltrates. Respiratory disease or symptoms. Hypoxia. Reduce infusion rate by ½ if dyspnea occurs; discontinue if dyspnea worsens. Cardiac disease. CHF. Renal or hepatic dysfunction (monitor before and every other week during therapy). Monitor

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ASSOCIATED HEMATOLOGICAL DISORDERS CBC and differential twice weekly. Reduce dose by ½ or discontinue if absolute neutrophil count exceeds 20,000cells/mm3 or if platelet count exceeds 500,000cells/mm3. Myeloid malignancies. Monitor body weight and hydration. Pregnancy (Cat.C). Nursing mothers. Interactions: Caution with lithium, corticosteroids, others that may enhance myeloproliferative effects. May be antagonized by radiotherapy, myelotoxic drugs. Adverse reactions: Flu-like symptoms, GI disturbances, edema, dyspnea, pharyngitis, rash, joint or bone or chest pain, eye hemorrhage, hypomagnesemia, anxiety, headache, pleural +/or pericardial effusion, arthralgia, myalgia, others. How supplied: Vials–5

NEULASTA Amgen

℞

Granulocyte colony stimulating factor. Pegfilgrastim (polyethylene glycol/filgrastim conjugate) 6mg/0.6mL soln; SC inj; preservative-free. Indications: To decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with clinically significant incidence of febrile neutropenia. Adults: Do not give between 14 days before and 24 hours after chemotherapy. Adolescents <45 kg: not recommended. ≥45 kg: 6mg SC once per chemotherapy cycle. Children: Not recommended. Contraindications: Do not use for peripheral blood progenitor cell (PBPC) mobilization. Hypersensitivity to E. coli-derived products. Warnings/Precautions: Monitor CBC and platelets before and during therapy. Monitor for splenomegaly/splenic rupture and for adult respiratory distress syndrome (ARDS); suspend until ARDS resolves if fever or lung infiltrates occur. Sickle cell disease (may cause sickle cell crisis). Myeloid malignancies. Myelodysplasia. Pregnancy (Cat.C). Nursing mothers. Interactions: Caution with drugs that cause delayed myelosuppression (eg, nitrosoureas, mitomycin C), or increase release of neutrophils (eg, lithium), antimetabolites (eg, 5-FU), and radiation therapy. Adverse reactions: Bone pain, anaphylaxis, ARDS; splenic rupture (rare). How supplied: Prefilled syringe–1

NEUPOGEN Amgen

℞

Granulocyte colony stimulating factor. Filgrastim 600mcg/mL prefilled syringe; for SC or IV infusion; preservative-free.

℞ Also: NEUPOGEN VIALS Filgrastim 300mcg/mL; for SC or IV infusion; preservative-free. Indications: See full labeling. To decrease incidence of infection in patients with nonmyeloid malignancies receiving certain myelosuppressive anti-cancer drugs. To reduce time to neutrophil recovery and fever duration after induction and consolidation chemotherapy treatment of adults with AML. To reduce duration of neutropenia and related sequelae in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bonemarrow transplantation (BMT). To mobilize hematopoietic progenitor cells (PBPC) into peripheral blood for collection by leukapheresis. To reduce the incidence and duration of neutropenia sequelae in severe chronic neutropenia (SCN). Adults: See full labeling. Do not give for at least 24hrs before or after cytotoxic chemotherapy dose. BMT: Give 1st dose at least 24hrs after bone marrow infusion. SCN: Give on a daily basis. Children: See full labeling. Contraindications: Hypersensitivity to E. coliderived products. Warnings/Precautions: Monitor blood, including CBC and differential and platelets, before and during therapy (myelosuppressive chemotherapy: monitor twice weekly; BMT: at least 3 times weekly; SCN: twice per week during initial 4 weeks of therapy and during 2 weeks after dose adjustment). Discontinue if post nadir absolute neutrophil count (ANC) reaches 10,000/mm3 for patients receiving myelosuppressive chemotherapy; other indications: see full labeling. Monitor for splenomegaly/splenic rupture and for adult respiratory distress syndrome (ARDS); suspend until ARDS resolves if fever or lung infiltrates occur. Confirm diagnosis and do appropriate pretreatment hematological workup in SCN. Preexisting cardiac or hyperplastic skin conditions. Sickle cell disease (may cause sickle cell crisis). Avoid simultaneous chemo- and radiation therapy. Pregnancy (Cat.C). Nursing mothers. Interactions: Caution with mitomycin C, and with concomitant (same day) drugs that decrease platelets, or increase release of neutrophils (eg, lithium), or cause delayed myelosuppression, or with myelosuppressive doses of antimetabolites (eg, nitrosoureas, 5-FU). Adverse reactions: Bone pain, cutaneous vasculitis, splenomegaly, others (see literature). How supplied: Prefilled syringes (0.5mL, 0.8mL)–10; Vials (1mL, 1.6mL)–10

Miscellaneous hematological agents

CINRYZE ViroPharma

℞

C1 inhibitor. C1 inhibitor (human) 500 Units/vial; lyophilized pwd for IV infusion after reconstitution; preservative-free. Indications: Routine prophylaxis against angioedema attacks in adolescent and adult patients with hereditary angioedema. Adults: Give by IV infusion at a rate of 1mL/min (10mins). 1000 Units every 3–4 days. Children: Not recommended. Warnings/Precautions: Contains human plasma; monitor for possible infection transmission. Have epinephrine available to treat hypersensitivity reactions. Monitor patients with known risk factors for thrombotic events. Labor & delivery. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Upper respiratory tract infection, sinusitis, rash, headache; thrombotic events, hypersensitivity reactions (may be severe); discontinue if occurs. Note: To report infections that may have been transmitted by Cinryze, call CinryzeSolutions at (877) 945-1000. How supplied: Single-use vial–1

EXJADE Novartis

℞

Iron chelating agent. Deferasirox 125mg, 250mg, 500mg; tabs for oral susp. Indications: Chronic iron overload due to blood transfusions in patients ≥2yrs of age. Chronic iron overload in patients ≥10yrs of age with nontransfusion dependent thalassemia syndromes and with a liver iron concentration (LIC) of at least 5mg Fe per gram of dry weight and a serum ferritin >300 mcg/L. Adults and Children: Calculate dose to nearest whole tab. Take on empty stomach at least 30 mins before food. Do not chew or swallow tabs; disperse completely in water, orange juice or apple juice; drink immediately; resuspend remainder and drink. Transfusional iron overload: <2yrs: not established. ≥2yrs: initially 20mg/kg once daily; may adjust dose by 5 or 10mg/kg every 3–6 months based on serum ferritin levels or response. If inadequate control at 30mg/kg, may consider increasing up to max 40mg/kg. Adjust dose if severe skin rashes occur; consider suspending therapy if serum ferritin <500mcg/L. Non-transfusion dependent thalassemia syndromes: <10yrs: not established. ≥10yrs: 10mg/kg once daily; if baseline LIC>15mg Fe/g dw, consider increasing dose to 20mg/kg after 4 weeks. Suspend therapy if serum ferritin

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DRUG MONOGRAPHS

ASSOCIATED HEMATOLOGICAL DISORDERS <300mcg/L and obtain LIC to determine whether it has fallen to <3mg Fe/g dw. After 6 months, if LIC remains >7mg Fe/g dw, increase dose to max 20mg/kg/day. If after 6 months, LIC is 3–7mg Fe/g dw, continue with max 10mg/kg/day. When LIC is <3mg Fe/g dw, interrupt treatment and continue to monitor LIC. Restart when LIC rises again to >5mg Fe/g dw. Adjustments based on serum creatinine: see full labeling. Hepatic impairment: moderate: reduce dose by 50%; severe: avoid. Contraindications: CrCl <40mL/min or serum creatinine >2x age-appropriate ULN. Poor performance status. High risk myelodysplastic syndromes. Advanced malignancies. Platelets <50×109/L. Warnings/Precautions: May cause renal or hepatic failure, GI hemorrhage; may be fatal. Hepatic or renal impairment. Advanced disease or co-morbid conditions. Obtain baseline serum ferritin level, monitor monthly and adjust dose accordingly. Measure serum creatinine and CrCl in duplicate before starting therapy; monitor weekly during 1st month then at least monthly thereafter; more frequently if creatinine levels increase. Monitor for proteinuria monthly. Measure serum transaminases, bilirubin before initiating therapy then every 2 weeks during 1st month, then monthly. Monitor blood counts; interrupt therapy if cytopenias develop. For non-transfusion dependent thalassemia syndromes: obtain LIC by liver biopsy prior to starting therapy, monitor LIC every 6 months. Do baseline auditory and ocular exams, then every 12 months; if disturbances occur, adjust dose or suspend therapy. Elderly. Pregnancy (Cat.C). Nursing mothers: not recommended. Interactions: Avoid aluminum-containing antacids, bile acid sequestrants (eg, cholestyramine, colesevelam, colestipol), or UGT inducers (eg, rifampicin, phenytoin, phenobarbital, ritonavir); if concomitant administration necessary consider increasing initial Exjade dose by 50% and monitor serum ferritin levels and clinical responses. Caution with drugs that have ulcerogenic or hemorrhagic potential (eg, NSAIDs, corticosteroids, oral bisphosphonates, anticoagulants) or drugs metabolized by CYP3A4 (eg, cyclosporine, simvastatin, hormonal contraceptives). Potentiates repaglinide (consider reducing repaglinide dose); monitor blood glucose levels. Caution with other CYP2C8 substrates (eg, paclitaxel). Avoid concomitant theophylline or other CYP1A2 substrates with narrow therapeutic index. Other concomitant iron chelation therapy: not recommended. Adverse reactions: GI upset, abdominal pain, elevated serum creatinine, rash; renal or hepatic impairment/failure (may be fatal), GI hemorrhage, cytopenias (eg, agranulocytosis, neutropenia, thrombocytopenia, anemia), hypersensitivity reactions, severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme); discontinue if occurs. How supplied: Tabs–30

FERRIPROX ApoPharma

℞

Iron chelating agent. Deferiprone 500mg; scored tablets. Indications: Treatment of transfusional iron overload due to thalassemia syndromes when current chelation therapy is inadequate. Adults: Individualize. Initially 25mg/kg three times daily (total dose 75mg/kg/day). Max: 33mg/kg three times daily (total dose 99mg/kg/day). Round dose to the nearest 250mg (half-tablet). Adjust dose to individual response and therapeutic goals. Consider temporary dose interruption if serum ferritin falls consistently <500mcg/L. Children: Not recommended. Warnings/Precautions: Not established for use in treating other chronic anemias. Risk of neutropenia or fatal agranulocytosis. Measure ANC before starting therapy and monitor weekly during. Interrupt therapy if infection or neutropenia develops (ANC <1.5×109/L). If neutropenia occurs, obtain CBCs, WBCs, ANC, and platelets daily until recovery (ANC ≥1.5×109/L). History of QT prolongation (eg, those with CHF, bradycardia, diuretic use, cardiac hypertrophy, hypokalemia, hypomagnesemia). Monitor serum ALT monthly; consider interruption if persistent increase in transaminase levels. Monitor serum ferritin every 2–3 months. Monitor plasma zinc, supplement if deficient. Pregnancy (Cat.D); avoid use. Nursing mothers: not recommended. Interactions: Avoid concomitant use with other drugs associated with neutropenia or agranulocytosis. Allow at least 4-hour interval with antacids or mineral supplements containing polyvalent cations (eg, iron, aluminum, zinc). Concomitant UGT 1A6 inhibitors: closely monitor and may need dose adjustments or interruptions. Adverse reactions: Chromaturia, GI upset, abdominal pain, increased ALT, arthralgia, neutropenia; agranulocytosis, possible Torsades de Pointes. Note: This product is available from Centric Health Resources (CHR). CHR is a specialty pharmacy specializing in orphan drugs and is the sole distributor of Ferriprox in the U.S. For more information, contact Ferriprox Total Care at (866) 758-7071. How supplied: Tabs–100

FIRAZYR Shire

℞

Bradykinin B2 receptor antagonist. Icatibant 10mg/mL; soln for SC inj; preservative-free. Indications: Treatment of acute attacks of hereditary angioedema. Adults: ≥18yrs: 30mg SC in abdominal area; may give additional doses at intervals of at least 6 hours if response inadequate or symptoms recur. Max 3 doses/24hrs. Children: <18yrs: not recommended. Warnings/Precautions: Advise patients to seek medical attention after treating laryngeal attack given the potential for airway obstruction. Elderly.

Labor & delivery. Pregnancy (Cat.C). Nursing mothers. Interactions: May attenuate the antihypertensive effect of ACE inhibitors. Adverse reactions: Inj site reactions, pyrexia, transaminase increase, dizziness, rash. How supplied: Single-use prefilled syringe (3mL)–1, 3

KALBITOR Dyax

℞

Plasma kallikrein inhibitor. Ecallantide 10mg/mL; soln for SC inj; preservative-free. Indications: Treatment of acute attacks of hereditary angioedema. Adults: Give 30mg SC in three 10mg (1mL) inj into abdomen, thigh, or upper arm. May give additional 30mg within 24hrs if attack persists. Children: <12yrs: not established. Warnings/Precautions: Have medical support available to manage anaphylaxis and hereditary angioedema. Monitor closely for hypersensitivity reactions. Labor & delivery. Pregnancy (Cat.C). Nursing mothers. Adverse reactions: Headache, nausea, diarrhea, pyrexia, inj site reactions, nasopharyngitis, fatigue, upper respiratory tract infection, pruritus, upper abdominal pain; anaphylaxis, antibody formation. How supplied: Single-use vials–3

MOZOBIL Genzyme

℞

Hematopoietic stem cell mobilizer. Plerixafor 20mg/mL; soln for SC inj; preservative-free. Indications: In combination with granulocyte colony stimulating factor (G-CSF): To mobilize hematopoietic stem cells to the peripheral blood for collection and autologous transplantation in patients with non-Hodgkin’s lymphoma or multiple myeloma. Adults: Start after 4 days’ treatment with G-CSF. Give approximately 11hrs before starting apheresis. Repeat up to 4 consecutive days. Base dose on actual body weight. 0.24mg/kg SC; max 40mg/day. Renal impairment (CrCl≤50mL/min): 0.16mg/kg; max 27mg/day. Children: Not established. Warnings/Precautions: Not for use in leukemia. May cause mobilization of tumor cells. Monitor blood and platelet counts (esp. neutrophils). Monitor for splenic rupture (eg, left upper quadrant/scapular or shoulder pain). Monitor for signs/symptoms of hypersensitivity during and after administration for at least 30mins. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended. Interactions: May be potentiated by drugs that reduce renal function or compete for active tubular secretion. Adverse reactions: Diarrhea, nausea, fatigue, injection site reactions, headache, arthralgia, dizziness, vomiting; anaphylactic shock, hypersensitivity reactions (may be serious), tumor cell mobilization, increased circulating neutrophils, decreased platelet counts, enlarged spleen, vasovagal reaction may occur. How supplied: Single-use vials (1.2mL)–1

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ASSOCIATED HEMATOLOGICAL DISORDERS HEMATOLOGICAL REFERENCE VALUES Reference value Analyte

Conventional units

SI units

Antithrombin III • Antigenic • Functional

22–39mg/dL 80–130%

220–390mg/L 0.8–1.30 U/L

Bleeding time

2.0–9.5min

Erythrocyte count • Male • Female

4.50–5.90 × 106/mm3 4.00–5.20 × 106/mm3

4.50–5.90 × 1012/L 4.00–5.20 × 1012/L

Erythrocyte sedimentation rate • Male • Female

0–17mm/hr 1–25mm/hr

Ferritin • Male • Female

30–300ng/mL 10–200ng/mL

30–300μg/L 10–200μg/L

Fibrinogen

150–400mg/dL

1.50–4.00g/L

Folate (folic acid) • Normal • Borderline deficient • Deficient • Excess

3.1–17.5ng/mL 2.2–3.0ng/mL <2.2ng/mL >17.5ng/mL

7.0–39.7nmol/L 5.0–6.8nmol/L <5.0nmol/L >39.7nmol/L

Folic acid

150–450ng/mL/cells

340–1020nmol/L/cells

Hematocrit • Male • Female

41.0–53.0% 36.0–46.0%

0.41–0.53 0.36–0.46

Hemoglobin • Plasma • Whole blood, male • Whole blood, female

1–5mg/dL 13.5–17.5g/dL 12.0–16.0g/dL

0.01–0.05g/L 8.4–10.9mmol/L 7.4–9.9mmol/L

Hemoglobin electrophoresis • Hemoglobin A • Hemoglobin A1c • Hemoglobin A2 • Hemoglobin F • Hemoglobins other than A, A2, or F

95–98% 3.8–6.4% 1.5–3.5% 0–2.0% Absent

0.95–0.98 0.038–0.064Hg fraction 0.015–0.035 0–0.02 Absent

Iron (hematology and coagulation values)

30–160μg/dL

5.4–28.7μmol/L

Iron-binding capacity (hematology and coagulation values)

228–428μg/dL

40.8–76.7μmol/L

Iron (clinical chemistry values)

50–150μg/dL

9–27μmol/L

Iron-binding capacity (clinical chemistry values)

250–370μg/dL

45–66μmol/L

Leukocyte count (WBC)

4.5–11.0 × 103/mm3

4.5–11 × 109/L

Mean corpuscular hemoglobin (MCH)

26.0–34.0pg/cell

Mean corpuscular hemoglobin concentration (MCHC)

31.0–37.0g/dL

310–370g/L

Mean corpuscular volume (MCV)

80–100μm3

80–100fl

Partial-thromboplastin time (activated)

22.1–35.1sec

Platelet count

150–350 × 103/mm3

150–350 × 109/L

Prothrombin time

11.1–13.1sec

Reticulocyte count

0.5–2.5% red cells

0.005–0.025 red cells

Transferrin

230–390mg/dL

2.3–3.9g/L

Vitamin B12 • Normal • Borderline • Deficient

>250pg/mL 125–250pg/mL <125pg/mL

>185pmol/L 92–185pmol/L <92pmol/L

References National Institutes of Health. Third report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). September 2002. Available at: www.nhlbi.nih.gov/guidelines/cholesterol/index.htm. (Rev. 8/2012) Accessed August 2012.

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ALPHABETICAL INDEX A Abiraterone Zytiga Abraxane (inj) cancer, breast cancer, pancreatic non-small cell lung cancer Actinic keratoses Adcetris (inj) Ado-trastuzumab Kadcyla Advate (inj) Afatinib Gilotrif Afinitor cancer, breast cancer, pancreatic cancer, renal progressive neuroendocrine tumors of pancreatic origin (pNET) subependymal giant cell astrocytoma (SEGA) Aldesleukin Proleukin (inj) Alemtuzumab Campath (inj) Alimta (inj) Alitretinoin Panretin (ext) Alkeran cancer, ovarian multiple myeloma Alphanate (inj) AlphaNine SD (inj) Altretamine Hexalen Amicar Aminocaproic acid Amicar Anadrol-50 Anaplastic astrocytoma Anastrozole Arimidex Anemia Angioedema, hereditary Anti-inhibitor Coagulant Complex Feiba (inj) Anti-thymocyte globulin Atgam (inj)* Antihemophilic Factor VIII Advate (inj) Alphanate (inj)* Helixate FS (inj) Hemofil M (inj) Humate-P (inj)* Koate-DVI (inj)

Brand name–bold type Generic name–light type

Kogenate FS (inj) Monoclate-P (inj) Recombinate (inj) ReFacto (inj) Xyntha (inj)

94 94 97 97 99

5 17 73 80 51

Aplastic anemia

Aranesp (inj)

Arranon

8 90

Arsenic trioxide Trisenox (inj)

Arzerra (inj)

Asparaginase Erwinia chrysanthemi Erwinaze (inj)

Atgam (inj)

Atypical hemolytic uremic syndrome

3, 5, 17, 29 3, 5, 17, 29 3, 5, 17, 29 3, 5, 17, 29 3, 5, 17, 29 33, 81 53 73 79 39, 51 39, 51 90 90 39 91 91 84 3 5 84–90 101–102

Arimidex

Aromasin

Avastin (inj) cancer, cervical 3, 24, 29, 39, 73 cancer, colorectal 3, 24, 29, 39, 73 cancer, fallopian tube 3, 24, 29, 39, 73 cancer, ovarian 3, 24, 29, 39, 73 cancer, peritoneal 3, 24, 29, 39, 73 cancer, renal 3, 24, 29, 39, 73 glioblastoma 3, 24, 29, 39, 73 non-small cell lung cancer 3, 24, 29, 39, 73 Axitinib Inlyta

Azacitidine Vidaza (inj)

B Barrett’s esophagus

26, 75

Basal cell carcinoma

BayRho-D (inj)

BCG, live TheraCys (inj) Tice BCG (inj)

34 34

Bebulin VH (inj)

Beleodaq (inj)

Belinostat Beleodaq (inj)

Bendamustine Treanda (inj)

BeneFIX (inj)

Bevacizumab Avastin (inj)

Bexarotene Targretin Targretin (ext)

63 64

Bexxar

90 90 93 93 93 94

3, 24, 29, 39, 73

Bicalutamide Casodex

Bifera

Medical condition–red type

BiferaRx Bleeding Blinatumomab Blincyto (inj) Blincyto (inj) Bone metastases Bortezomib Velcade (inj) Bosulif Bosutinib Bosulif Brentuximab vedotin Adcetris (inj) Busulfan Busulfex (inj) Myleran Busulfex (inj)

84 91–92, 94, 97–98 52 52 1, 72 70 53 53 51 53 60 53

C C1 inhibitor Cinryze (inj) Cabazitaxel Jevtana (inj) Cabozantinib Cometriq Campath (inj) Cancer, adrenal cortex Cancer, bladder Cancer, breast

101 31

18 53 18 34–35 1, 3, 5–18, 25–26, 28–30, 40, 42, 65, 76 3, 24, 29, 39–40, 73–74

Cancer, cervical Cancer, colorectal 3, 6, 16, 18, 20–29, 39, 42, 73 Cancer, endometrial 8, 40 Cancer, esophageal 26, 75 Cancer, fallopian tube 3, 24, 29, 39, 73 Cancer, GI 7, 24, 26 Cancer, head and neck 1, 15, 24, 40, 42, 57, 65, 76, 80 Cancer, liver 26, 32 Cancer, lung 1, 15, 40, 42, 60, 65, 73–74, 76 Cancer, ovarian 3, 24, 29, 39–40, 42, 51, 55, 57, 73–74, 79–80 Cancer, pancreatic 3, 5–6, 17–19, 25, 27, 29, 33, 75 Cancer, peritoneal 3, 24, 29, 39, 73 Cancer, prostate 6, 29–33, 35–36 Cancer, renal 3, 5, 17, 19, 24, 26–27, 29, 31–35, 39, 73, 81 Cancer, sarcoma 1 Cancer, stomach 6, 18, 25 Cancer, testicular 30 Cancer, thyroid 17–19, 26, 32

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Brand name–bold type Generic name–light type

Capecitabine Xeloda 16, 28 Caprelsa 17 Carfilzomib Kyprolis (inj) 59 Carimune NF (inj) 91 Casodex 29 Ceritinib Zykadia 76 Cerubidine (inj) 53 Cetuximab Erbitux (inj) 24, 42 Chlorambucil Leukeran 59 Chorioadenoma destruens 1, 15, 40, 42, 65, 76 Choriocarcinoma, gestational 1, 15, 40, 42, 65, 76 Chronic kidney disease 87 Cinryze (inj) 101 Cladribine (inj) 54 Clofarabine Clolar (inj) 54 Clolar (inj) 54 Coagulation Factor IX AlphaNine SD (inj) 90 BeneFIX (inj) 91 Mononine (inj) 95 Rixubis (inj) 98 Coagulation Factor IX complex Bebulin VH (inj) 91 Profilnine SD (inj) 96 Coagulation Factor VIIa NovoSeven RT (inj) 95 Colorectal cancer 25 Cometriq 18 Congenital Factor VII deficiency 95 Congenital Factor VIII deficiency 90, 97 Congenital Factor XIII deficiency 92 Congenital fibrinogen deficiency 98 Corifact (inj) 92 Crizotinib Xalkori 76 Cyanocobalamin Cyanocobalamin (inj) 84 Nascobal (nasal) 88 Cyklokapron (inj) 92 Cyramza (inj) cancer, GI 24 cancer, lung 73

Medical condition–red type

Cytarabine Cytarabine DepoCyt (inj)

ALPHABETICAL INDEX 54 54

E Ecallantide Kalbitor (inj)

102

D

Eculizumab Soliris (inj)

Dabrafenib Tafinlar

Efudex (ext)

Eligard

Eloxatin (inj)

Eltrombopag Promacta

88, 96

Dacarbazine DTIC-Dome (inj)

Dacogen (inj)

Darbepoetin alfa Aranesp (inj)

Dasatinib Sprycel

Daunorubicin Cerubidine (inj)

DDAVP

Decitabine Dacogen (inj)

Deferasirox Exjade

101

Deferiprone Ferriprox

102

Degarelix Firmagon (inj)

Delestrogen (inj)

Denileukin diftitox Ontak (inj)

Denosumab Xgeva (inj)

DepoCyt (inj)

Dermatofibrosarcoma protuberans 25, 56, 80 Desmopressin DDAVP Stimate (nasal)

92 98

DexFerrum (inj) Docusate sodium Ferralet 90* Ferro-Sequels*

Emcyt

Enzalutamide Xtandi

Epoetin alfa Epogen (inj) Procrit (inj)

85 88

Epogen (inj)

Erbitux (inj) cancer, colorectal cancer, head and neck Eribulin Halaven Erivedge Erlotinib Tarceva

24, 42 24, 42 6 80 19, 75

Erwinaze (inj)

Erythema nodosum leprosum

Esophageal varices

Estrace cancer, breast cancer, prostate

6, 30 6, 30

Estradiol Estrace

6, 30

Estradiol valerate Delestrogen (inj)

Estramustine Emcyt

86 86

Estrogens, conjugated Premarin

Doxil (inj) cancer, ovarian Kaposi’s sarcoma multiple myeloma

39, 55, 79 39, 55, 79 39, 55, 79

Doxorubicin, liposomal Doxil (inj)

39, 55, 79

Droxia

DTIC-Dome (inj)

8, 32

Estrogens, esterified Menest

Ethamolin (inj)

Ethanolamine Ethamolin (inj)

Etoposide

Everolimus Afinitor Evista

3, 5, 17, 29 6

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ALPHABETICAL INDEX Exemestane Aromasin Exjade

5 101

F Factor VIII complex Wilate (inj)* Factor XIII Corifact (inj) Faslodex (inj) Feiba (inj) Femara Feosol Fer-In-Sol Feraheme (inj) Fergon Ferralet 90 Ferretts Ferric carboxymaltose Injectafer Ferriprox Ferrlecit (inj) Ferro-Sequels Fibrinogen RiaSTAP (inj) Filgrastim Neupogen (inj) Firazyr (inj) Firmagon (inj) Fludara (inj) Fludarabine Fludara (inj) Fluorouracil cancer, breast cancer, colorectal cancer, pancreatic cancer, stomach Fluorouracil Efudex (ext) Fluorouracil Flutamide Folic acid BiferaRx* Ferralet 90* Folic acid Trinsicon* Folotyn (inj) Fulvestrant Faslodex (inj) Fusilev (inj)

98 92 6 92 6 86 86 86 86 86 86 87 102 86 86 98 101 102 30 55 55 6, 18, 25 6, 18, 25 6, 18, 25 6, 18, 25 80 6, 18, 25 30 84 86 87 90 56 6 25

G Gamunex-C (inj) Gazyva (inj)

Brand name–bold type Generic name–light type

GI stromal tumors 19, 25, 27, 33, 56, 80 Gilotrif 74 Glanzmann’s thrombasthenia 95 Gleevec dermatofibrosarcoma protuberans 25, 56, 80 GI stromal tumors 25, 56, 80 hypereosinophilic syndrome 25, 56, 80 leukemia, acute myeloid 25, 56, 80 leukemia, chronic eosinophilic 25, 56, 80 leukemia, chronic myelogenous 25, 56, 80 mastocytosis 25, 56, 80 myelodysplastic syndromes 25, 56, 80 Glioblastoma Granix (inj)

3, 24, 29, 39, 73 100

H Halaven 6 Helixate FS (inj) 93 Hematopoietic stem cell mobilizer 102 Hemofil M (inj) 93 Hemophilia 92 Hemophilia A 90, 92–95, 97–99 Hemophilia B 90–91, 95–96, 98 Herceptin (inj) cancer, breast 7, 26 cancer, GI 7, 26 Hexalen 39 Histrelin Vantas 35 Hodgkin lymphoma 48–51 Hodgkin’s disease 55, 59–60, 74 Humate-P (inj) 93 Hycamtin cancer, cervical 40, 74 cancer, ovarian 40, 74 small cell lung cancer 40, 74 Hydatidiform mole 1, 15, 40, 42, 65, 76 Hydrea cancer, head and neck 40, 42, 57, 80 cancer, ovarian 40, 42, 57, 80 leukemia, chronic myelocytic 40, 42, 57, 80 melanoma 40, 42, 57, 80 Hydroxyurea Droxia 85 Hydrea 40, 42, 57, 80 Hypercalcemia 72 Hypereosinophilic syndrome 25, 56, 80 HyperRHO S/D Full Dose (inj) 99

93 56

Medical condition–red type

I Ibritumomab Zevalin (inj)

Ibrutinib Imbruvica

ICAR-C

Icatibant Firazyr (inj)

102

Iclusig

Idamycin (inj)

Idarubicin Idamycin (inj)

Idelalisib Zydelig

Idiopathic thrombocytopenic purpura 91, 93, 96–97, 99 Ifex (inj)

Ifosfamide Ifex (inj)

Imatinib Gleevec

25, 56, 80

Imbruvica

Immune globulin Carimune NF (inj) Gamunex-C (inj) Privigen (inj)

91 93 96

Immunomodulators

99–101

INFeD (inj)

Injectafer

Inlyta

Interferon alfa-2b Intron A (inj)

58, 79, 80

Intron A (inj) Kaposi’s sarcoma leukemia, hairy cell lymphoma, follicular melanoma

58, 79, 80 58, 79, 80 58, 79, 80 58, 79, 80

Iodine I 131 Tositumomab Bexxar*

Ipilimumab Yervoy (inj)

Iron ICAR-C

Iron deficiency anemia

Iron fumarate Ferretts Ferro-Sequels* Trinsicon*

86 86 90

Iron gluconate Fergon Ferrlecit (inj) Nulecit (inj)

86 86 88

Iron sulfate Feosol Fer-In-Sol Slow Fe

86 86 89

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BE ONE OF THE FIRST 75 REGISTRANTS and receive a FREE copy of ONS’s newly published Oncology Nurse Navigation book (a $91.00 value). It’s edited by Karyl Blaseg, RN, MSN, OCN, Interim Director at the Billings Clinic Cancer Center and ONA Navigation Summit Advisory Board Member and Speaker.

2/23/15 11:34 AM

ALPHABETICAL INDEX Iron (as carbonyl) Ferralet 90* Iron (as dextran complex) DexFerrum (inj) INFeD (inj) Iron (as ferumoxytol) Feraheme (inj) Iron (as polysaccharide iron complex + heme iron polypeptide) Bifera BiferaRx* Iron (as sucrose) Venofer (inj) Istodax Ixabepilone Ixempra (inj) Ixempra (inj)

86 85 87 86

84 84 90 58 7 7

J Jakafi Jevtana (inj)

58 31

K Kadcyla Kalbitor (inj) Kaposi’s sarcoma KCentra (inj) Keytruda (inj) Koate-DVI (inj) Kogenate FS (inj) Kyprolis (inj)

8 102 39, 55, 58, 79–80 94 81 94 94 59

L Lapatinib Tykerb 16 Lenalidomide Revlimid 62, 89 Letrozole Femara 6 Leucovorin anemia 87 cancer, colorectal 26 Leukemia 59–60, 74 Leukemia, acute lymphoblastic 52, 54–55, 57, 59–62, 71 Leukemia, acute lymphocytic 53–54, 61 Leukemia, acute myeloid 25, 56–57, 80 Leukemia, acute nonlymphocytic 53–54, 60, 63 Leukemia, acute promyelocytic 70–71 Leukemia, B-cell chronic lymphocytic 53, 55

Brand name–bold type Generic name–light type

Leukemia, chronic eosinophilic 25, 56, 80 Leukemia, chronic lymphocytic 51, 56–57, 62, 65, 72 Leukemia, chronic myelocytic 40, 42, 54, 57, 80 Leukemia, chronic myelogenous 25, 53, 56, 60, 62–64, 80 Leukemia, chronic myeloid 57 Leukemia, hairy cell 54, 58, 79–80 Leukemia, meningeal 54 Leukemia, T-cell acute lymphoblastic 51 Leukeran 59 Leukine (inj) 100 Leuprolide Eligard 30 Leuprolide acetate (inj) 31 Lupron Depot 3.75mg (inj) 87 Lupron Depot 7.5mg (inj) 32 Leuprolide acetate (inj) 31 Levoleucovorin Fusilev (inj) 25 Lupron Depot 3.75mg (inj) 87 Lupron Depot 7.5mg (inj) 32 Lymphocyte immune globulin Atgam (inj)* 84 Lymphoma, cutaneous T-cell 58, 60, 63–64, 70, 72 Lymphoma, follicular 58, 72, 79–80 Lymphoma, malignant 59 Lymphoma, mantle cell 57, 70 Lymphoma, peripheral T-cell 52, 58 Lymphoma, small lymphocytic 72 Lymphoma, T-cell 56 Lymphoma, T-cell lymphoblastic 51 Lymphomatous meningitis 54 Lymphosarcoma 60, 74 Lynparza 40 Lysodren 18

M Malignant pleural mesothelioma 73 Mantle cell lymphoma 62 Marqibo (inj) 59 Mastocytosis 25, 56, 80 Matulane 59 Mechlorethamine Mustargen (inj) 60, 74 Valchlor (ext) 70 Megestrol acetate cancer, breast 8, 40 cancer, endometrial 8, 40 Mekinist 81 Melanoma 40, 42, 55, 57–58, 79–83

Medical condition–red type

Melanoma, metastatic 33, 81 Melphalan Alkeran 39, 51 Menest 32 Mercaptopurine Purinethol 61 Purixan 61 Methotrexate Trexall 1, 15, 40, 42, 65, 76 Methoxsalen Uvadex 70 Mitotane Lysodren 18 Mitoxantrone HCl (inj) cancer, prostate 32 leukemia, acute nonlymphocytic 60 Monoclate-P (inj) 94 Mononine (inj) 95 Mozobil (inj) 102 Multiple myeloma 39, 51, 55, 59, 61–62, 64, 70, 72, 79 Mustargen (inj) cancer, lung 60, 74 Hodgkin’s disease 60, 74 leukemia 60, 74 lymphosarcoma 60, 74 mycosis fungoides 60, 74 polycythemia vera 60, 74 Mycosis fungoides 1, 15, 40, 42, 60, 65, 74, 76 Mycosis fungoides-type cutaneous T-cell lymphoma 70 Myelodysplastic syndromes 25, 54, 56, 71, 80 Myelofibrosis 58 Myleran 60

N Nascobal (nasal) Navelbine (inj) Nelarabine Arranon Neoplasms Neulasta (inj) Neumega (inj) Neupogen (inj) Neuroendocrine tumors Neutropenia Nexavar cancer, liver cancer, renal cancer, thyroid Nilandron Nilotinib Tasigna

88 75 51 30, 32, 34–35 101 95 101 19, 27, 33 100–101 26, 32 26, 32 18, 26, 32 32 64

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Brand name–bold type Generic name–light type

Nilutamide Nilandron 32 Nitropress (inj) 95 Non-Hodgkin’s lymphoma 1, 15, 40, 42, 48–50, 52, 62, 65, 71, 76 Non-small cell lung cancer 3, 19, 24, 26, 29, 39, 73–76 NovoSeven RT (inj) 95 Nplate (inj) 96 Nulecit (inj) 88

O Obinutuzumab Gazyva (inj) Ofatumumab Arzerra (inj) Olaparib Lynparza Omacetaxine mepesuccinate Synribo (inj) Oncaspar (inj) Ontak (inj) Oprelvekin Neumega (inj) Oxaliplatin Eloxatin (inj) Oxymetholone Anadrol-50

56 51 40 63 60 60 95 24 84

P Paclitaxel, protein-bound Abraxane (inj) 5, 17, 73 Panitumumab Vectibix (inj) 27 Panretin (ext) 79 Paroxysmal nocturnal hemoglobinuria 89 Pazopanib Votrient 1, 35 Pegaspargase Oncaspar (inj) 60 Pegfilgrastim Neulasta (inj) 101 Peginterferon alfa-2b Sylatron (inj) 82 Pembrolizumab Keytruda (inj) 81 Pemetrexed Alimta (inj) 73

Medical condition–red type

ALPHABETICAL INDEX

Perjeta (inj) 8 Pertuzumab Perjeta (inj) 8 Photofrin (inj) barrett’s esophagus 26, 75 cancer, esophageal 26, 75 non-small cell lung cancer 26, 75 Plerixafor Mozobil (inj) 102 Poisoning/overdose 101–102 Polycythemia vera 60, 74 Pomalidomide Pomalyst 61 Pomalyst 61 Ponatinib Iclusig 57 Porfimer Photofrin (inj) 26, 75 Pralatrexate Folotyn (inj) 56 Premarin cancer, breast 8 cancer, prostate 32 Privigen (inj) 96 Procarbazine Matulane 59 Procrit (inj) 88 Profilnine SD (inj) 96 Progressive neuroendocrine tumors of pancreatic origin (pNET) 3, 5, 17, 29 Proleukin (inj) cancer, renal 33, 81 melanoma, metastatic 33, 81 Promacta anemia 88 thrombocytopenia 96 Prothrombin complex concentrate (human) KCentra (inj) 94 Provenge (inj) 33 Purinethol 61 Purixan 61

R Radium Ra 223 dichloride Xofigo (inj) Raloxifene Evista Ramucirumab Cyramza (inj)

36 6 24, 73

Recombinate (inj) Recothrom ReFacto (inj) Regorafenib Stivarga Revlimid anemia mantle cell lymphoma multiple myeloma Rh Isoimmunization RhoGam (inj) Rhophylac (inj) idiopathic thrombocytopenic purpura Rh Isoimmunization Rho(D) immune globulin BayRho-D (inj) HyperRHO S/D Full Dose (inj) RhoGam (inj) Rhophylac (inj) WinRho SDF (inj) RiaSTAP (inj) Rituxan (inj) Rituximab Rituxan (inj) Rixubis (inj) Romidepsin Istodax Romiplostim Nplate (inj) Ruxolitinib Jakafi

97 97 97 27 89 62 62 99–100 100

97 100 99 99 100 97, 100 99, 100 98 62 62 98 58 96 58

S Sargramostim Leukine (inj) Sickle cell anemia Sipuleucel-T Provenge (inj) Skeletal-related events Slow Fe Small cell lung cancer Sodium nitroprusside Nitropress (inj) Soliris (inj) Soltamox Sorafenib Nexavar Sprycel

100 85 33 1 89 40, 74 95 89 15 18, 26, 32 62

Access Cancer Therapy Advisor treatment regimens in a user-friendly format. CancerTherapyAdvisor.com/TreatmentRegimens.

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ALPHABETICAL INDEX Stimate (nasal)

Stivarga

Subependymal giant cell astrocytoma (SEGA) 3, 5, 17, 29 Sunitinib Sutent

19, 27, 33

Superficial basal cell carcinoma

Surgical bleed

Sutent cancer, pancreatic cancer, renal GI stromal tumors neuroendocrine tumors

19, 27, 33 19, 27, 33 19, 27, 33 19, 27, 33

Sylatron (inj)

Synribo (inj)

Systemic anaplastic large cell lymphoma

T Tabloid

Tafinlar

Tamoxifen Soltamox Tamoxifen

15 15

Tarceva cancer, pancreatic non-small cell lung cancer

19, 75 19, 75

Targretin

Targretin (ext)

Tasigna

Tbo-filgrastim Granix (inj) Temodar

100 3

Medical condition–red type

Topotecan Hycamtin

40, 74

Torisel (inj)

Tositumomab Bexxar*

Vismodegib Erivedge

VKA reversal

Trametinib Mekinist

Tranexamic acid Cyklokapron (inj)

Trastuzumab Herceptin (inj)

7, 26

Treanda (inj)

Trelstar (inj)

Tretinoin Vesanoid

Trexall cancer, breast cancer, head and neck cancer, lung chorioadenoma destruens choriocarcinoma, gestational hydatidiform mole mycosis fungoides non-Hodgkin’s lymphoma

Vinorelbine Navelbine (inj)

Von Willebrand disease

90, 92–93, 98

Von Willebrand Factor Alphanate (inj)* Humate-P (inj)* Wilate (inj)*

90 93 98

Vorinostat Zolinza

Votrient cancer, renal cancer, sarcoma

35 1

Vumon (inj)

1, 15, 40, 42, 65, 76 1, 15, 40, 42, 65, 76 1, 15, 40, 42, 65, 76 1, 15, 40, 42, 65, 76 1, 15, 40, 42, 65, 76 1, 15, 40, 42, 65, 76 1, 15, 40, 42, 65, 76 1, 15, 40, 42, 65, 76

Trinsicon

W Wilate (inj) WinRho SDF (inj) idiopathic thrombocytopenic purpura Rh Isoimmunization

99 100

X Xalkori

Triptorelin Trelstar (inj)

Trisenox (inj)

Xeloda cancer, breast cancer, colorectal

Tykerb

Xgeva (inj)

Xofigo (inj)

U

Temozolomide Temodar

Temsirolimus Torisel (inj)

Teniposide Vumon (inj)

V

Valchlor (ext)

Thalidomide Thalomid

Thalomid

TheraCys (inj)

Thioguanine Tabloid

Vandetanib Caprelsa

Vantas

Thrombin Recothrom Thrombin-JMI

97 98

Thrombin-JMI Thrombocytopenia

Brand name–bold type Generic name–light type

Uvadex

16, 28 16, 28

Xtandi

Xyntha (inj)

Y 70

Valrubicin Valstar

Valstar

Yervoy (inj)

Z Zaltrap (inj)

Zelboraf

Zevalin (inj)

Vectibix (inj)

Velcade (inj)

Ziv-aflibercept Zaltrap (inj)

Vemurafenib Zelboraf

95–96

Venofer (inj)

Vesanoid

Vidaza (inj) Vincristine sulfate liposome Marqibo (inj)

Thyrogen (inj)

Thyrotropin alfa Thyrogen (inj)

Tice BCG (inj)

Zoledronic acid Zometa

Zolinza

Zometa

Zydelig

Zykadia

Zytiga

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MANUFACTURERS INDEX AbbVie (800) 633-9110 Actavis (800) 432-8534; (732) 465-3600 Actelion Pharmaceuticals (866) 228-3546 Alexion Pharmaceuticals, Inc. (203) 272-2596 Allos Therapeutics (888) 255-6788 AMAG Pharmaceuticals (617) 498-3300 American Regent, Inc. (800) 645-1706; (631) 924-4000 Amgen, Inc. (800) 772-6436; (805) 447-1000 ApoPharma USA Inc. (877) 427-6839 ARIAD Pharmaceuticals, Inc. (855) 552-7423 Astellas Pharma US, Inc. (800) 727-7003; (800) 888-7704 AstraZeneca Pharmaceuticals (800) 237-8898; (800) 236-9933 Baxter (800) 422-9837 Bayer Healthcare Pharmaceuticals Inc. (800) 288-8371; (800) 468-0894 Bayer Corp, Consumer Care Div. (800) 331-4536; (973) 254-5000 Bayer and Onyx (866) 639-2827 Bedford Laboratories (800) 521-5169; (800) 562-4797 Boehringer Ingelheim Pharmaceuticals (800) 542-6257; (800) 236-4248 Bristol-Myers Squibb (800) 321-1335 Celgene Corp (908) 673-9000 Clover Pharmaceuticals Corp. (770) 499-8100 Covis Pharmaceuticals, Inc. (919) 535-3049 CSL Behring, LLC (800) 504-5434; (800) 683-1288 DARA BioSciences, Inc. (919) 872-5578 Dendreon (877) 256-4545 Dyax Corp. (888) 452-5248 Eisai Pharmaceuticals (888) 422-4743; (201) 692-1100

Emergent BioSolutions Inc. (800) 768-2304 Endo Pharmaceuticals (800) 462-3636; (610) 558-9800 Exelixis, Inc. (650) 837-7000 Ferring Pharmaceuticals, Inc. (888) 337-7464 Genentech, Inc. (800) 821-8590; (650) 225-1000 Genzyme Corporation (800) 745-4447; (617) 252-7500 Gilead Sciences, Inc. (800) 445-3235; (650) 574-3000 GlaxoSmithKline (888) 825-5249 Grifols Biologicals, Inc. (888) 474-3657 Hawthorn Pharmaceuticals (888) 455-5253 Hospira (800) 615-0187 International Vitamin Corporation (888) 698-5032 Incyte Corporation (855) 463-3463 Janssen Biotech, Inc. (800) 526-7736 Jazz Pharmaceuticals plc (650) 496-3777 JHP Pharmaceuticals (866) 923-2547 Kedrion Biopharma (855) 353-7466 Lilly, Eli and Company (800) 545-5979; (317) 276-2000 Mead Johnson Nutrition (812) 429-5000; (812) 429-6399 Meda Pharmaceuticals (888) 455-8383 Merck & Co., Inc. (800) 672-6372; (800) 609-4618 Millennium Pharmaceuticals, Inc. (866) 835-2233 Mission Pharmacal Company (210) 696-8400; (800) 292-7364 Novartis Pharmaceuticals Corp (800) 693-9993; (973) 503-8300 Novartis Consumer Health (800) 452-0051 Novo Nordisk (800) 727-6500; (609) 987-5800 Octapharma (888) 429-4535

Onyx Pharmaceuticals (650) 266-0000 Otsuka America Pharmaceutical, Inc. (800) 441-6763; (301) 990-0030 Pfizer Inc. (800) 438-1985; (212) 573-2323 Pharmacyclics and Janssen Biotech (877) 877-3536 Pharmics Inc. (800) 456-4138; (801) 966-4138 Pierre Fabre Pharmaceuticals, Inc. (973) 355-8000 Pinnacle Biologics (847) 283-7690 Prometheus Labs, Inc. (888) 423-5227 QOL Medical, LLC (866) 469-3773 Rare Disease Therapeutics, Inc. (615) 399-0700 Recordati Rare Diseases, Inc. (908) 236-0888 Regeneron and Sanofi Aventis (800) 981-2491 Roche Laboratories (800) 526-6367; (973) 235-5000 Sanofi Aventis (800) 446-6267; (800) 633-1610 Sanofi Pasteur, Inc. (800) 822-2463 Seattle Genetics, Inc. (855) 473-2436 Shire US, Inc. (800) 536-7878; (859) 282-2100 Sigma-Tau Pharmaceuticals, Inc. (800) 447- 0169 Spectrum Pharmaceuticals, Inc. (877) 387-4538 Strativa Pharmaceuticals (201) 802-4000 Teva Pharmaceuticals (215) 591-3000 Therakos, Inc. (877) 865-6850; (610) 280-1000 UCB Inc. (800) 234-5535; (585) 475-9000 Valeant Pharmaceuticals, Inc (877) 361-2719 ViroPharma (610) 458-7300 Warner Chilcott Laboratories (800) 521-8813; (973) 442-3200 ZymoGenetics, Inc. (800) 775-6686; (206) 442-6600

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