The July 2012 Digital Edition of Pharmacy Practice News by McMahon Group

R’

The Pharmacist’s News Source

pharmacypracticenews.com

in this issue Time To Progression Front Longer in Myeloma Pts Up Capsules Taking Lenalidomide Compounding pharmacy linked to multistate ocular infections.

Operations & Mgmt

enalidomide maintenance therapy after initial treatment significantly prolonged progression-free survival (PFS) among patients with newly diagnosed multiple myeloma during three new randomized Phase III clinical trials. But that benefit came at the price of an increased rate of secondary cancers. Experts consider the findings a significant advance in melanoma treatment, but they acknowledge that many questions remain about what represents optimal therapy. The three studies, which were published in the May 10, 2012 online edition of The New England Journal of Medicine, are “setting the stage

•

see LENALIDOMIDE, page 10

Highlighting the Good, The Bad and the Ugly Of Rx Drug Misuse Progress cited, but poor medication disposal, ‘pill mills’ still causing harm

ith one brief anecdote about a toddler dying after exposure to a discarded fentanyl patch while visiting his grandmother in a nursing home, FDA Commissioner Margaret Hamburg, MD, crystallized the sometimes tragic consequences that can occur when safe drug disposal methods fall short. “Nobody noticed that he had stuck the patch on himself; he suffered an overdose and passed away two days later,” related Dr. Hamburg during an April press telebriefing with representatives from the Centers for Disease Control and Prevention (CDC), Drug Enforcement Administration (DEA) and Office of National Drug Control Policy (ONDCP). “As a physician, stories like this have both a professional and personal impact on me. Fentanyl patches have

•

see DRUG MISUSE, page 40

40th ANNIVERSARY YEAR 1972–2012

Printer-friendly versions available online

Three trials show benefit, but secondary cancer risk triggers concern

Volu ume 39 • Number 7 • July 2012

ASHP Late-Breaker Antibiotic stewardship program emphasizes care, not cost.

Clinical

Practice Pearls Pisa Syndrome triggered by psychoactive drugs.

Managing cardiotoxicity from metoclopramide.

Hem/Onc Pharmacy Same-day pegfilgrastim and cabazitaxel urged. Metronomic chemotherapy scores in breast cancer.

26 26

Critical Care Keeping an eye on colistin at both ends of the dosing spectrum.

Infectious Disease Switch to extended piperacillin/tazobactam infusion cuts cost.

ixty years ago, Henry Knowles Beecher, MD, and Donald Todd, MD, published a provocative study in the Annals of Surgery. The study showed that patients given neuromuscular blocking agents were six times as likely to die in recovery as those who did not receive the drugs. Most of that excess mortality resulted from respiratory events. Six decades later, shockingly little has changed. As many as 100,000 patients suffer respiratory complications and other adverse events after surgery each year in the United States because they experience residual paralysis from neuromuscular blocking agents (NMBAs), experts warn. The lack of clinical standards for monitoring post-surgery weakness means the situation is unlikely to improve anytime soon, according to Sorin Brull, MD, a professor of anesthesiology at Mayo Clinic in Jacksonville, Fla. Pharmacists who specialize in critical care and anesthesiology share Dr. Brull’s concern that the guidance gap may place patients at risk.

•

Journal Scan Pharmacists’ impact on diabetes, plus a call for more autism education.

Post-Op Paralysis and NMBAs Still a Threat to Patient Safety S

Educational Review

Emerging Therapies in the Systemic Treatment of Metastatic Melanoma See page 16

see NEUROMUSCULAR, page 31

Adding Boceprevir to Hepatitis C Therapy Deemed Practice-Changer

oceprevir, used in combination with peginterferon and ribavirin, achieved high rates of sustained virologic response in patients with hepatitis C who failed prior treatment with peginterferon and ribavirin alone, a new study has found. The results, documented in both partial and null responders, are potentially practice-changing, according to Janet Nguyen, PharmD, BCPS, vice president

Continuing Education The unSUMMIT for Bedside Barcoding introduces online CE for BPOC. See page 44.

of network strategy, at A-Med Health Care, Huntington Beach, Calif., who was not associated with the study. “This is the first time boceprevir has shown efficacy in null responders,” Dr. Nguyen said. Such patients, she noted, “are usually unlikely to respond to retreatment with an interferon-based therapy.” The results were based on an interim analysis from PROVIDE, an ongoing,

•

see HEPATITIS C, page 34

New Product Pfizer Injectables introduces cytarabine injection. See page 44.

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Up Front 3

Pharmacy Practice News • July 2012

Capsules

surf

Compounding Pharmacy Linked To Multistate Eye Disease Outbreak

JULY 2012

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. Med Errors and C. difficile Infections Pose Big Risks in ICUs 2. Vancomycin Plus Piperacillin-Tazo May Trigger Acute Kidney Injury 3. Rivaroxaban Edges Standard Therapy for Pulmonary Embolism 4. Changes Are Coming for Stress Ulcer Prevention Therapy 5. Overweight Patients Often Dosed Inaccurately in EDs Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here

‘Our goal is not to be the antibiotic police; rather, we round and partner

first

with the ID physicians and

ealth officials have tied contaminated drugs from a compounding pharmacy in Florida to an outbreak of fungal eye infections in nearly three dozen patients who underwent invasive ophthalmic procedures. The Centers for Disease Control and Prevention (CDC) and the FDA said the cases, which occurred in at least seven states, resulted from the use of unsterile eye medications provided by Franck’s Compounding Lab, in Ocala. Of the 33 known cases of fungal endophthalmitis, 70% involved some degree of vision loss; half of the patients required repeat ophthalmic surgery, officials said. The investigation began in March by the Los Angeles County Department of Public Health. Nine cases of fungal endophthalmitis were linked to using a dye called Brilliant Blue-G (BBG) from Franck’s. In every case, patients had undergone a vitrectomy with peeling of the epiretinal membrane, according to the investigation report. The investigation expanded to involve intravitreal injection of triamcinolone, which also came from Franck’s. As of April 30, health officials had confirmed 18 of the reported cases. Tests revealed the presence of Fusarium incarnatum-equisetii and Bipolaris hawaiiensis, two mold species present in air, soil and water. Post-procedural endophthalmitis occurs in 0.04% of patients who receive intravitreal injections or undergo pars plana vitrectomy, a surgery that involves removal of vitreous gel from the eye. Most cases of the complication involve bacteria rather than fungus, health officials said. The CDC is warning clinicians that Franck’s has not recalled or halted production of its other sterile compounded products and recommends that clinicians and patients avoid using any compounded products labeled as sterile from Franck’s until the root cause and extent of contamination are identified. —Gabrielle N. Rosen

make clinical interventions that are focused on

The Book Page

Fundamentals of Pharmacognosy and Phytotherapy, Second Edition

improving patient care.’

Michael Heinrich

—Kristie Zappas, PharmD

See article, page 6

MCMAHONMEDICALBOOKS.COM

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6 Operations & Management

Pharmacy Practice News • July 2012

ASHP Late-Breaker

Antibiotic Stewardship Program Emphasizes Care, Not Cost Baltimore—Not all health systems have the resources to include a dedicated infectious disease (ID) physician in their antibiotic stewardship programs. But a large community teaching hospital in Florida has shown that a slightly more modest staffing model still can significantly improve the quality of antibiotic care. The program, at Florida Hospital— Orlando, a 1,067-bed acute-care facility, included two infectious-disease phar-

macists and five decentralized clinical pharmacists. Although a dedicated ID physician was not part of the team, “our pharmacists round with ID physicians up to three times per week, and that gives us the opportunity to prospectively review patients’ antibiotic orders and intervene where appropriate,” said Kristie Zappas, PharmD, a clinical specialist in infectious diseases at the hospital. Nearly 90% of the ID pharmacists’

recommendations were accepted in a recent study of the program, which Dr. Zappas presented as a poster at the American Society of Health-System Pharmacists’ 2012 Summer Meeting. The program also showed that those recommendations yielded improvements in several clinical outcomes, including the proper de-escalation or discontinuation of antibiotics and enhanced “bug-todrug” matching, Dr. Zappas reported.

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The study was based on a retrospective chart review of antibiotic stewardship activities performed at Florida Hospital—Orlando from December 2010 to December 2011. Data analyzed during the study included the targeted antimicrobial agent, formulary restriction status, type of intervention, prescriber specialty, outcome of the intervention, and the estimated cost savings for accepted interventions. A total of 1,182 interventions were included in the analysis. According to Dr. Zappas, 72% of the interventions targeted broad-spectrum antimicrobials, including piperacillin/tazobactam, doripenem, daptomycin, cefepime, linezolid, micafungin, tigecycline and meropenem. Twelve percent of the recommendations targeted restricted formulary agents. Prospective audit and feedback resulted in antimicrobials being de-escalated in 40% and discontinued in 58% of cases. Moreover, 48% of the recommendations were made to non-ID physicians, and physicians accepted 87% of the recommendations.

NO SHORTAGE OF COMMITMENT.

Dr. Zappas stressed that although the study itself was retrospective, it is the prospective nature of the antibiotic stewardship program that makes it such an effective tool for improving patient care—and for documenting the value of having pharmacists on the ID care team. “The beauty of having a decentralized pharmacy model is that we are on the floor rounding with physicians and so we can actually see, within minutes, antibiotic orders coming through the system,” Dr. Zappas said. “That allows us to assess those orders up-front, rather than working behind the scenes and trying to retrospectively change a drug order that may not be appropriate, where the patient might have been on that drug for the good part of a day.” The system allows for such rapid-fire interventions in part because the hospi-

Operations & Management 7

Pharmacy Practice News • July 2012

ASHP Late-Breaker

59% (693/1,182) 60

Incidence, %

41% (479/1,182)

40 30 20

0.17%

0.7%

(2/1,182)

(8/1,182)

Bug-Drug Mismatch

IV to PO

Antimicrobial Discontinuation

Antimicrobial De-escalation

biotic selection, de-escalation protocols and IV to PO conversions.” Dr. Martin said he was encouraged to hear that the Florida program is planning to add a dedicated ID physician. “The ID physician is important in stewardship programs to help influence prescribing changes, consult with difficult-to-manage infections and educate other physicians,” he said. Still, “many of the daily routine functions of a successful program can and should be managed by pharmacists.”

Figure. Types of Interventions. —David Bronstein

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tal uses computerized prescriber order entry (CPOE), Dr. Zappas noted. “It’s very real-time,” she said. “The physician enters the antibiotic order for a patient while in that patient’s room, and within a few minutes we are reviewing the order and can make an assessment based on lab values, patient history, drug-drug interactions, formulary restrictions, duration of therapy, order sets, etc.” Dr. Zappas said her team derives considerable satisfaction from ensuring that the right antibiotic is being prescribed for the right infection. “When we do find a bug-drug mismatch, I feel that we have a huge opportunity to intervene [and improve clinical outcomes],” she noted. Although the study showed that such mismatches were the least common target of pharmacist interventions (two of 1,182; 0.17%), “those numbers are definitely an underestimate of what we’ve since been seeing empirically. We now have a lot more tools in place—for example, rapid access to culture sensitivity tests—that help us identify mismatches and act on them accordingly.” Dr. Zappas underscored the benefits of having rapid access to key test results. “Prior to CPOE, where we relied on the physicians to access the results of culture sensitivity testing, we sometimes were at a disadvantage,” she said. “For example, say the culture results came back at 11 am but the prescribing physician had already rounded at 8 am. Pre-CPOE, we may have had to wait another 20 hours of not having those culture results [to guide therapy]. Now that our pharmacists do have access to those values, we can call the physician and let them know that the patient may have the opportunity to have a more optimal antibiotic on board.” The improvements in antibiotic therapy achieved in the study also translated into savings—$122,291 over the course of the 13-month review, Dr. Zappas reported. But she stressed that finances are not a primary driver of the initiative. “We’re sensitive to the idea that a lot of antibiotic stewardship programs are almost exclusively focused on cost. But that’s not us; our goal is not to be the antibiotic police. Rather, we round and partner with the ID physicians and make clinical interventions that are focused on improving patient care.” Dr. Zappas added that future plans include adding a dedicated ID physician to the antibiotic stewardship team. Steven J. Martin, PharmD, BCPS, FCCP, FCCM, professor and chair, Department of Pharmacy Practice, University of Toledo, in Ohio, said that the results of Dr. Zappa’s research are not surprising. “Pharmacists focus on important details in medication use that impact both outcome and costs,” he said. “Since pharmacists do not prescribe, they more strictly follow drug-use pathways, including organism- and susceptibility-based anti-

MediDose.com

8 Clinical

Pharmacy Practice News • July 2012

Practice Pearls

Managing Pisa Syndrome Related to Psychoactive Drugs Abimbola Farinde, PharmD, MS, BCPP, CGP, FASCP

Table 1. Typical Antipsychotic Drugs

Clinical Staff Pharmacist Clear Lake Regional Medical Center Webster, Texas

Average Dose Titrated to mg

Equivalents, mg

D2 Effects

5HT2 Effects

Muscarinic Effects

-1 Adrenergic Effects

Antihistamine Effects

Chlorpromazine T, I

600-800

100

++++

Fluphenazine

T, L, I, LAI

10-20

++++

Dosage Forms

Drug Name

lthough the rise in prescribing of antipsychotic medications and other psychoactive medications has been associated with increases in the number of patients reporting improved quality of life, it also is associated with increased rates of various adverse effects (AEs). One of the identifiable outcomes of increased use of neuroleptic agents is Pisa syndrome, or pleurothotonus. Pisa syndrome, a rare type of truncal dystonia, was first described by Ekbom et al in Germany in 1972 as a side effect of neuroleptic treatment in 3 elderly women taking haloperidol.1,2 Ekbom et al initially attributed the syndrome to long-term neuroleptic use, but other reports suggested that the syndrome is present with other medication classes, such as cholinesterase inhibitors and antiemetics.1,2 Pisa syndrome generally occurs when another agent is added to an already existing antipsychotic or neuroleptic medication regimen, but the condition usually disappears after discontinuation of the offending agent.2 Tables 1 and 2 provide lists of typical and atypical antipsychotic medications and their side-effect profiles.

Hallmark Presentation Of Pisa Syndrome Pisa syndrome is a condition characterized by abnormally sustained posturing with a flexion of the body and head to one side and slight axial rotation of the trunk, so a person appears that they are leaning like the tower of Pisa.3 The syndrome has been described as a spasm of the lower back muscles. The characteristics of its development and prognosis indicate that drug-induced Pisa syndrome can have clinical features of acute dystonia or it can have a similar appearance to tardive dystonia. There are criteria in place for the diagnosis of Pisa syndrome including the tonic flexion of the trunk to one side, a remarkable indifference to grossly abnormal posture, and current narcoleptic (or antidepressant) treatment.

Reviewing the Literature The syndrome is more commonly noted in the elderly female population suffering from dementia, but it also has been reported in adolescents.3 The clinical features of Pisa syndrome suggest a complex pathophysiology; a dopaminergic-cholinergic imbalance or

Perphenazine

60-80

++++

+++

Trifluoperazine

30-40

++++

+++

Thioridazine

600-800

100

++++

Mesoridazinea

300-400

++++

+++

++++

Haloperidol

T, L, I, LAI

10-20

++++

50-100

+++

Thiothixene

30-40

++++

+++

Loxapine

75-100

12.5

+++

++++

+++

++++

Molindone

No longer on market in United States

+, low level; ++, moderate level; +++, high level; ++++, very high level; C, capsule; I, injection; L, liquid; LAI, long-acting injection; T, tablet Adapted from Hahn, Albers, and Reist. Psychiatry, 2008 Edition.

Table 2. Atypical Antipsychotic Drugs

Drug Name

Dosage Forms

Average Dose, mg

Chlorpromazine equiva- D2 lents, mg Effects

5HT2 Effects

Muscarinic Effects

-1 Adrenergic Effects

Antihistamine Effects

Clozapine

T, ODT

300-600

++++

Aripiprazole (Abilify, BristolMyers Squibb)

T, ODT, L, I

15-30

2-4

++++

+++

Risperidone

T, ODT, L, LAI

2-8

1-2

+++

Olanzapine

T, ODT, I

5-20

+++

Quetiapine

T, T (ER)

400-600

Ziprasidone

C, I

80-160

5-10

+++

Paliperidone (Invega, Janssen)

T (ER), I, LAI

6-12

+++

Asenapine (Saphris, Organon)

T (sublingual)

5-10

Iloperidone (Fanapt, Novartis)

12-24

Lurasidone (Latuda, Sunovion)

40-160

+, low level; ++, moderate level; +++, high level; ++++, very high level; C, capsule; ER, extended release I, injection; L, liquid; LAI, long-acting injection, NA, not available; ODT, orally disintegrating tablet; T, tablet Adapted from Hahn, Albers, and Reist. Psychiatry, 2008 Edition.

serotonergic or noradrenergic dysfunction are possible implications. Previous cases of induction of the condition by neuroleptics and improvement with trihexyphenidyl suggest that dopaminergic-cholinergic imbalance is a main factor. Thus, theoretically, cholinergic excess could be another factor in Pisa syndrome, especially the imbalance that is noticed in Alzheimer’s disease.4 There

is the potential for the development of Pisa syndrome in Alzheimer’s disease patients with cholinergic excess. In 1990, Yassa et al evaluated 133 psychogeriatric patients (47 men, 86 women) over a 5-year period, looking for cases of Pisa syndrome.4 Eleven patients developed Pisa syndrome (8 women, 3 men), which ranged in duration from 2 to 120 days after the start of neuroleptic thera-

py. The prevalence rate was 8.3% (9.3% in women and 6.4% in men). Anticholinergics were not an effective treatment, and the only remedy was discontinuation of the neuroleptic. There have been no other systematic studies of Pisa syndrome in patients taking psychoactive agents; the remaining literature describes case reports. In one such case in 2000, Kwak et al

Clinical 9

Pharmacy Practice News • July 2012

Practice Pearls described a 53-year-old woman who had been taking donepezil therapy for 1 month in combination with risperidone. The patient experienced dystonia, which lasted 1 week after discontinuation of donepezil.5 The patient then received rivastigmine, but the dystonia reappeared.5 In 2005, Vanacore et al reported a reaction in an 83-year-old patient who had been taking rivastigmine for 5 months.6 This patient experienced dystonia that resolved 3 weeks after discontinuation of rivastigmine. In 2007, Huvent-Grelle et al identified dystonia in a 78-year-old woman who had been taking galantamine for 11 months and who also was taking an atypical antipsychotic; her dystonia resolved 15 days after galantamine discontinuation.7 While I was training at the North Texas Veterans Healthcare System, in Dallas, a 70-year-old white male veteran presented to the system’s outpatient mental health clinic with complaints of short-lived muscle spasms that caused abnormal postures and disruptive movements. A clinical pharmacist performed a comprehensive review of the patient’s psychotropic medication profile, which showed that the patient was taking perphenazine (4 mg three times a day) for psychosis, diphenhydramine (25 mg once a day) for extrapyramidal side effects, donepezil (10 mg once a day) for mild

dementia, and lorazepam (2 mg as needed) for anxiety. The patient had been on perphenazine for 2 years without significant complaints but recently began to experience persistent spasms that were becoming increasingly bothersome. The attending physician switched the patient’s antipsychotic medication from the typical antipsychotic perphenazine to the atypical antipsychotic risperidone at a dosage of 2 mg daily, with dose assessment and adjustments made when warranted. Approximately 2 weeks after the switch to risperidone, the frequency of dystonic reactions and posturing began to diminish significantly. Donepezil had been considered to be a potential contributing factor to the syndrome, but a risk–benefit assessment led to the decision to continue the donepezil at the current dose. The patient’s clinical team decided that the attending physician and clinical pharmacist would assess the patient during his routine visits to the outpatient mental health clinic to closely monitor for any recurrence of symptoms. No recurrences were identified at the 3-month assessment mark.

Approach and Recommendation(s) When any patient distinctly presents with symptoms that may be suggestive of Pisa syndrome, the clinical team

should perform a thorough evaluation of the patient’s medication regimen to specifically identify long-term use of any antipsychotic medication or cholinesterase inhibitor. To identify the offending agents, it is best to determine which medication the client has been on for a longer period of time. With consideration being given to the pros and cons of discontinuation, the clinical pharmacist can work alongside the prescribing physician to determine which decision would be in the best interest of the patient. If the offending agent is determined to be the antipsychotic medication, an alternative antipsychotic that is less likely to cause extrapyramidal side effects can be considered; if the offending agent is determined to be a cholinesterase inhibitor, a dose reduction may be considered or discontinuation may be warranted based on the severity of the Pisa syndrome. For any patient who presents with Pisa syndrome, there is a high likelihood that discontinuation of the offending agent will result in disappearance of the symptoms.

Future Direction The widespread use of antipsychotic medications and cholinesterase inhibitors can lead to an increasing number of cases of Pisa syndrome, so clinicians should to be aware of this AE. There are no conclusive data on the mecha-

nism by which cholinesterase inhibitors cause Pisa syndrome, only theories, but the available evidence shows that these agents have the potential to cause this AE, and clinicians must be aware of this and address it immediately. Dr. Farinde reported no relevant financial conflicts of interest.

References 1. Shuster J. Institute for Safe Medication Practices adverse drug reactions: Pisa syndrome seen with donepezil. Hosp Pharm. 2001;36(10):1036-1041. 2. Suzuki T, Matsuzaka H. Drug-induced Pisa syndrome (pleurothotonus): epidemiology and management. CNS Drugs. 2002;16(3):165-174. 3. Wyckoff. Behavioral alert: update on Pisa syndrome. Gero Services. http://www.geroservices.com/pisa.asp. Accessed June 4, 2012. 4. Yassa R, Bloom D. Lorazepam and anticholinergics in tardive akathisia. Biol Psychiatry. 1990;27(4):463-464. 5. Kwak YT, Han IW, Baik J, Koo MS. Relation between cholinesterase inhibitors and Pisa syndrome. Lancet. 2000;355(9222):2222. 6. Vanacore N. Suzzareddu G, Maggini M, Casula A, Capelli P, Raschetti R. Pisa syndrome in a cohort of Alzheimer’s disease patients. Acta Neurol Scand. 2005;111(3):199-201. 7. Huvent-Grelle D, Roche J, Camus FE, Dewailly P, Puisieux F. Relationship between cholinesterase inhibitors and Pisa syndrome in a cohort of five French patients with Alzheimer’s disease. J Am Geriatr Soc. 2007;55(9):1472-1475.

Managing Cardiovascular Adverse Effects of Metoclopramide Table. Recommendations For Clinicians

Martha M. Rumore, PharmD, JD, LLM, FAPhA Assistant Director, Pharmacy Clinical & Educational Services Cohen Children’s Medical Center North Shore-LIJ New Hyde Park, New York Adjunct Professor Pharmacy & Health Outcomes Touro College of Pharmacy New York, New York

Recognize factors such as underlying cardiac abnormalities and familial long QT interval. Perform baseline and periodic electrocardiograms. Avoid concomitant use with other QT-prolonging drugs.

lthough metoclopramide has been available for decades, its side-effect profile continues to evolve. In 2009, the FDA required a black box warning regarding the increased risk for tardive dyskinesia when metoclopramide is used at high doses or over long periods of time. Several cardiovascular adverse effects (AEs) are listed in the metoclopramide prescribing information,1 and reports of the drug’s cardiovascular AEs first appeared in the literature in 1974.2 Since then, a number of case reports supporting the view that metoclopramide has significant cardiovascular AEs have appeared in the literature. Between January 1966 and February of this year, dozens of cases of cardiovascular AEs have been reported, including

multiple cases of sinus or cardiac arrest,3-11 extreme bradycardia,4,5,7,9,12 bradycardia followed by total heart block,9,12-14 acute hypotension,14-20 circulatory collapse,20 QT prolongation,21-23 torsades de pointes,8,22,24,25 supraventricular tachycardia (SVT),24,26-28 and ST-segment depression.1,26 Cases of congestive heart failure have occurred following chronic metoclopramide doses of 40 mg per day.27 The metoclopramide prescribing information lists several AEs, including atrioventricular (AV) block, bradycardia, heart failure, hypertension/hypotension, and SVT but not circulatory collapse, cardiac arrest, torsades de pointes, QT prolongation, and ST-segment depression.1 Age and dose do not appear to be contributory factors for cardiovascular AEs

Monitor serum concentrations of magnesium and potassium in critically ill patients. Report any cardiovascular adverse effects to FDA MedWatch. Administer IV metoclopramide slowly over at least 2 minutes.

from metoclopramide. Although the patients in most of the cases were elderly, middle-aged individuals also have had AEs, for example cardiac arrest, following metoclopramide.6 Previous cardiovascular disease, atrial fibrillation,3 autonomous dysfunction,10 hyperbilirubinemia,6 halothane anesthesia,15,17 and the presence of a pericardial drainage

tube all have been suggested as underlying predisposing or contributory factors for development of cardiac AEs with metoclopramide.12 However, in some cases there has been no clear association with any risk factors. The route of administration may be a causative factor. In all cases, metoclopramide was given by IV either peripherally or via a central venous line. The rate of injection also may be causative. In a number of cases, metoclopramide was administered over seconds, rather than over 1 to 2 minutes as recommended in the product labeling.1,16 In most cases the reactions occurred immediately, were associated with normal doses administered via IV or central lines, and resolved. Rechallenge occurred in several of the cases. The likelihood of these events occurring and the mechanism by which metoclopramide affects the cardiovascular system is unclear, but it has been shown to directly affect the heart, to block presynaptic autoreceptors, to enhance catecholamine release and cholinergic neurotransmission, and to cause 5-HT3 receptor blockade and 5-HT4 receptor antagonism. Support for a mechanism involving a

•

see METOCLOPRAMIDE, page 35

Hem/Onc Pharmacy

Pharmacy Practice News • July 2012

In Focus

LENALIDOMIDE continued from page 1

for a new era of treatment for multiple myeloma,” according to C. Ola Landgren, MD, PhD, head of the multiple myeloma section at the National Cancer Institute. “There are a lot of questions still to be answered, but clearly, there is a lot of benefit to patients in having access to oral drugs that can extend the time frame before the disease becomes active.” Philip McCarthy, MD, a professor of oncology and director of the Blood & Marrow Transplant Program at Roswell Park Cancer Institute, in Buffalo, N.Y., and lead investigator on one of the studies, noted that “until these studies, [there was] no confirmed Phase III data suggesting a benefit to using lenalidomide maintenance for multiple myeloma patients after primary therapy.”

Survival Results In the largest of the three trials, a French study involving more than 600 patients (IFM 2005-02), lead investigator Michel Attal, MD, and his colleagues treated patients, all of whom were below the age of 65 years, with induction therapy and transplantation followed by a two-month lenalidomide (Revlimid, Celgene) consolidation. Patients without progressive disease were randomized to maintenance nance treatment with either lenalidom mide (10 mg per day, increased to 15 mgg per day after three months if tolerated) or placebo until relapse. At a median followup of 45 months, the primaary end point, median progressiionfree survival, was 41 month hs in the lenalidomide maintenancce arm versus 23 months in the placebo p

arm (hazard ratio [HR], 0.50; P<0.001). In another of the three trials, the 460-patient CALGB (Cancer and Leukemia Group B) 100104 study, in which patients received lenalidomide doses ranging from 5 to 15 mg per day, investigators found an overall survival (OS) benefit with lenalidomide in addition to improved PFS. At a median follow-up of 34 months, 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) had died ( =0.03). Median time to progression (P was 46 months in the lenalidomide group and 27 months in the placebo group ((P<0.001). Finally, the international MM-015 study, led by the Myeloma Unit at the University of Torino, in Italy, randomized 459 patients aged 65 years or older to melphalan-prednisone induction followed by placebo maintenance (MP) or melphalan-prednisone-lenalidomide induction followed by placebo maintenance (MPR) or melphalan-prednisonelenalidomide induction followed by lenalidomide maintenance (MPR-R). The initial maintenance dose of lenalido-

malignancies. In the three randomized studies, based on small numbers, there are more hematologic secondary malignancies in the lenalidomide arm versus the placebo arm. We don’t yet know the mechanisms, but we are working hard to look into that. Statistically speaking, the benefits are quite profound, but if you happen to be the person who develops that [adverse] outcome, it’s devastating.”

Increased Risk for Secondary Cancers

The cost–benefit ratio of improved PFS versus secondary malignancies might be easier to assess if the OS benefit was clear-cut, said Jacob Laubach, MD, instructor in internal medicine at Harvard Medical School, in Boston, and a hematologist-oncologist at the DanaFarber Cancer Institute, also in Boston. “If an overall survival benefit had been seen in each of the three studies, I think the use of lenalidomide maintenance would be even more clear-cut. But that’s the strength of having three large studies involving over 1,000 patients. Because there’s an overall survival benefit in [only] one of the three studies, there is still an issue of how best to use lenalidomide maintenance.” The subset analysis in the CALGB study suggests a possibility for fine-tuning the use of lenalidomide maintenance. “The analysis shows that all subgroups benefited from lenalidomide maintenance in time to progression whereas only certain subgroups appeared to benefit from lenalidomide in overall survival,” said Dr. Laubach. Specifically, “patients who received lenalidomide as part of their consolidation,” said Dr. McCarthy, “seemed to do better than those who got something else and then lenalidomide maintenance.” Another lingering question: What is the optimal duration of maintenance therapy? “Some progressions do occur late,” Dr. McCarthy said, “and it may be that you need to continue exposure to this drug for a prolonged period.” Dr. Laubach said that the use of lenalidomide maintenance must be considered on a patient-by-patient basis. “Just as we choose induction regimens and whether to use transplant based on unique patient characteristics, we must come to the point of maintenance therapy with lenalidomide with the same questions in mind. What was the patient’s prior treatment? Response to therapy? The toxicities that occurred during prior treatment? All of these questions factor into the decision about whether to employ lenalidomide maintenance.”

Although these studies showed that lenalidomide maintenance increased PFS, all three studies also showed that it significantly increased risks for secondary malignancies. The specific types of secondary cancers varied with the trial: “The French study showed a two- to threefold increase in solid tumors, all different kinds, as well as a two- to threefold increase in hematologic disorders, in particular Hodgkin’s lymphoma and acute lymphoblastic leukemia,” observed Dr. McCarthy, who led the CALGB study. “The Italian

‘Because there’s an overall survival benefit in [only] one of the three studies, there is still an issue of how best to use lenalidomide maintenance.’

Cost, Side Effects fects Remain a Challenge

mide was 10 mg per day for days 1-21, with a seven-day drug-free period; the cycle was repeated until progression. The median follow-up in this trial was 30 months. Patients in the MPR-R arm had a median PFS of 31 months compared with 14 months for those in the MPR arm (P ( <0.001). That benefit appeared to be confined to patients between the ages of 65 and 75; patients over age 75 showed no significant improvement ((P=0.001).

anagement of multiple myeloma patients on long-term maintenance lenalidomide will pose some challenges, noted Kathleen West, BS, PharmD, a clinical pharmacy specialist with Roswell Park Cancer Institute’s Division of Blood and Marrow Transplantation, In Buffalo, NY. “Because of the side effects, particularly secondary cancers, there will be a lot more monitoring and follow-up needed. Patients will have to come in on a regular basis and make sure their counts are okay,” Dr. West noted. Cost will also be a factor. A 10-mg tablet of lenalidomide costs approximately $550, so a year’s worth of the drug on a maintenance schedule like those used in the trials would cost approximately $160,000 per year, according to Dr. West. “Because these are new studies of lenalidomide as maintenance therapy, I’m not sure how insurers will respond in terms of coverage,” she said. “Each company will probably be different; right now, even when we recommend a multiple myeloma patient for transplant, the insurers differ as to whether they’ll approve it.” Don McLeod, a spokesman for the Centers for Medicare and Medicaid Services (CMS), said there currently is no National Coverage Determination on lenalidomide for maintenance therapy in multiple myeloma. “It is left to [local] contractor discretion,” he said. Like CMS, it appears that many private insurers have not yet issued a determination of coverage for lenalidomide as maintenance therapy in this setting. WellPoint, for example, already covers lenalidomide with the combination of dexamethasone in the treatment of multiple myeloma on Tier 2 on its commercial formulary (with prior authorization), but that is for initial therapy. As far as maintenance therapy, said WellPoint corporate communications director Lori McLaughlin, “We are in the process of reviewing the new data and how it pertains to our prior authorization criteria.” —G.S.

—Jacob Laubach, MD —Jac study, in whicch patients did not undergo transplant but had a lot of melphallan exposure, showed an increease of acute myelogenous leukeemia and myelodysplastic ssyndrome in the lenalidomide arm. We also found those cancers increased wiith lenalidomide ... at a similar i il rate but [saw] no increased instance of [acute lymphoblastic leukemia] or Hodgkin’s lymphoma.” This finding is not new; concerns about secondary cancers were raised in December 2010 when preliminary data from the three trials were released. “But if you look at the CALGB 100104 cumulative incidence [CI] risk analysis, the CI risk for secondary malignancy is higher with lenalidomide maintenance, but the CI risk for progression or death is higher in the placebo arm,” Dr. McCarthy noted. Commenting on the findings in an interview, Dr. Landgren said, “Compared with the general population, people with multiple myeloma are at greater risk for certain other malignancies no matter what treatment they undergo.” She noted that although multiple myeloma confers risks, “it’s also obvious that in all three of these studies, there is enrichment of that risk, particularly the risk for hematologic

Is Overall Survival Improved?

—Gina Shaw The MM 015 study was supported by Celgene, manufacturer of lenalidomide (Revlimid). Celgene supplied the lenalidomide and placebo for the American and French studies.

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PREMIXED AMIODARONE. Indications and Usage NEXTERONE (amiodarone HCl) Premixed Injection is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular ﬁbrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. Use NEXTERONE for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary.

Important Risk Information NEXTERONE (amiodarone HCl) Premixed Injection is contraindicated in patients with: s

Known hypersensitivity to any of the components of NEXTERONE, including iodine

Cardiogenic shock

Marked sinus bradycardia

Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available

s NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and beneﬁts of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment.

s Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported in 16% (288/1836) of patients treated with intravenous amiodarone. Monitor the initial rate of infusion closely and do not exceed the recommended rate. In some cases, hypotension may be refractory and result in a fatal outcome. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including: vasopressors, positive inotropic agents and volume expansion.

s In 4.9% (90/1836) of patients in clinical trials, drug-related bradycardia that was not dose-related occurred while patients were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available.

s Like all antiarrhythmics, NEXTERONE may cause worsening of existing arrhythmias or precipitate a new arrhythmia. s The most common adverse reactions leading to discontinuation (1-2%) of intravenous amiodarone therapy are hypotension, asystole/cardiac arrest/pulseless electrical activity, VT, and cardiogenic shock.

s Other important adverse reactions are torsade de pointes (TdP), congestive heart failure, liver function test abnormalities, pulmonary disorders, and thyroid abnormalities. s Drug Interactions: Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone. Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when ﬂuoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. Please see brief summary of Full Prescribing Information on the following pages.

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NEXTERONE (amiodarone HCl) Premixed Injection for intravenous use Brief Summary of Prescribing Information. See PI for Full Prescribing Information. 1 INDICATIONS AND USAGE NEXTERONE is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular ďŹ brillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy [see Dosage and Administration (2) in full prescribing information]. Use NEXTERONE for acute treatment until the patientâ&#x20AC;&#x2122;s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary. 4 CONTRAINDICATIONS NEXTERONE is contraindicated in patients with: s +NOWN HYPERSENSITIVITY TO ANY OF THE COMPONENTS OF .%84%2/.% 0REMIXED )NJECTION INCLUDING iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage BLEEDING FEVER ARTHRALGIAS JOINT PAINS EOSINOPHILIA ABNORMAL BLOOD COUNTS URTICARIA HIVES thrombotic thrombocytopenic purpura, or severe periarteritis (inďŹ&#x201A;ammation around blood vessels). s #ARDIOGENIC SHOCK s -ARKED SINUS BRADYCARDIA s 3ECOND OR THIRD DEGREE ATRIO VENTRICULAR !6 BLOCK UNLESS A FUNCTIONING PACEMAKER IS AVAILABLE 5 WARNINGS AND PRECAUTIONS NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and beneďŹ ts of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment. 5.1 Hypotension Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with intravenous amiodarone. Clinically signiďŹ cant hypotension during infusions was seen most often in the ďŹ rst several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in intravenous amiodarone therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor the initial rate of infusion closely and do not exceed the recommended rate [see Dosage and Administration (2) in full prescribing information]. In some cases, hypotension may be refractory and result in a fatal outcome [see Adverse Reactions (6.2) in full prescribing information]. 5.2 Bradycardia and Atrio-ventricular Block In 90 (4.9%) of 1836 patients in clinical trials, drug-related bradycardia that was not dose-related occurred while they were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available. 5.3 Liver Enzyme Elevations Elevations of blood hepatic enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)] are commonly seen in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difďŹ cult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical deďŹ brillations. Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically signiďŹ cant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment. Acute, centrolobular conďŹ&#x201A;uent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone at a much higher loading dose concentration and much faster rate of infusion than recommended [see Dosage and Administration (2) in full prescribing information]. )N PATIENTS WITH LIFE THREATENING ARRHYTHMIAS THE POTENTIAL RISK OF HEPATIC INJURY SHOULD BE WEIGHED against the potential beneďŹ t of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE FOR EVIDENCE OF PROGRESSIVE HEPATIC INJURY )N SUCH CASES CONSIDER REDUCING THE RATE OF ADMINISTRATION or withdrawing NEXTERONE.

5.4 Proarrhythmia Like all antiarrhythmic agents, NEXTERONE may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving intravenous amiodarone, TdP or new-onset VF occurred infrequently (less than 2%). Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when ďŹ&#x201A;uoroquinolones, macrolide antibiotics, or azoles were administered concomitantly [see Drug Interactions (7) in full prescribing information]. Amiodarone causes thyroid dysfunction in some patients, which may lead to potentially fatal breakthrough or exacerbated arrhythmias. 5.5 Pulmonary Disorders Early-onset Pulmonary Toxicity 4HERE HAVE BEEN POSTMARKETING REPORTS OF ACUTE ONSET DAYS TO WEEKS PULMONARY INJURY IN PATIENTS treated with intravenous amiodarone. Findings have included pulmonary inďŹ ltrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death. ARDS Two percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy. Pulmonary Fibrosis Only 1 of more than 1000 patients treated with intravenous amiodarone in clinical studies developed pulmonary ďŹ brosis. In that patient, the condition was diagnosed 3 months after treatment with intravenous amiodarone, during which time the patient received oral amiodarone. Pulmonary toxicity is a well-recognized complication of long-term amiodarone use (see package insert for oral amiodarone). 5.6 Loss of Vision Cases of optic neuropathy and optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. Perform an ophthalmic examination if symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision. Re-evaluate the necessity of amiodarone therapy if optic neuropathy or neuritis is suspected. Perform regular ophthalmic examination, including fundoscopy and slit-lamp examination, during administration of NEXTERONE. 5.7 Long-Term Use There has been limited experience in patients receiving intravenous amiodarone for longer than 3 weeks. See package insert for oral amiodarone. 5.8 Thyroid Abnormalities Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone is also a potential source of large amounts of inorganic iodine and can cause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function tests may persist for several weeks or even months following NEXTERONE withdrawal. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present [see Adverse Reactions (6.2) in full prescribing information]. Hyperthyroidism and Thyrotoxicosis Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. Consider the possibility of hyperthyroidism if any new signs of arrhythmia appear.

Identify hyperthyroidism by relevant clinical signs and symptoms, subnormal serum levels of thyroid stimulating hormone (TSH), abnormally elevated serum free T4, and elevated or normal serum T3. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. Amiodarone hyperthyroidism may be followed by a transient period of hypothyroidism.

Table 4 lists the most common (incidence *2%) adverse reactions during intravenous amiodarone therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled because none of the adverse reactions appeared to be dose-related. Table 4: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN

The institution of antithyroid drugs, Ƶ-adrenergic blockers or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. Neonatal Hypo- or Hyperthyroidism Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient of the potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patient becomes pregnant while taking NEXTERONE. Hypothyroidism Hypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in some series. This condition may be identiﬁed by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the NEXTERONE dose and considering the need for thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue oral amiodarone in some patients. 5.9 Surgery Perform close perioperative monitoring in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction defects of halogenated inhalational anesthetics. 5.10 Corneal Refractive Laser Surgery Advise patients that most manufacturers of corneal refractive laser surgery devices contraindicate corneal refractive laser surgery in patients taking amiodarone. 5.11 Electrolyte Disturbances Correct hypokalemia or hypomagnesemia whenever possible before initiating treatment with NEXTERONE, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics. 6 ADVERSE REACTIONS 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 practice.

CONTROLLED AND OPEN-LABEL STUDIES (> 2% INCIDENCE) Controlled Studies (n=814)

Open-Label Studies (n=1022)

Total (n=1836)

Body as a whole Fever

Body as a whole 24 (2.9%)

Body as a whole 13 (1.2%)

Body as a whole 37 (2.0%)

Cardiovascular System Bradycardia Congestive heart failure Heart arrest Hypotension Ventricular tachycardia

Cardiovascular 49 (6.0%) 18 (2.2%) 29 (3.5%) 165 (20.2%) 15 (1.8%) Digestive System 35 (4.2%) 29 (3.5%)

Cardiovascular 41 (4.0%) 21 (2.0%) 26 (2.5%) 123 (12.0%) 30 (2.9%) Digestive System 29 (2.8%) 43 (4.2%)

Cardiovascular 90 (4.9%) 39 (2.1%) 55 (2.9%) 288 (15.6%) 45 (2.4%)

Study Event

Digestive System Liver function tests normal Nausea

Digestive System 64 (3.4%) 72 (3.9%)

Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, atrial ﬁbrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting. 6.2 Post-Marketing Experience The following adverse reactions have been identiﬁed during post-approval use of amiodarone. 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. Body as a Whole: anaphylactic/anaphylactoid reaction (including shock), fever Cardiovascular: r hypotension (sometimes fatal), sinus arrest Dermatologic: toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, skin cancer, pruritus, angioedema Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hematologic: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, agranulocytosis, granuloma Hepatic: hepatitis, cholestatic hepatitis, cirrhosis Injection Site Reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing Musculoskeletal:l myopathy, muscle weakness, rhabdomyolysis Nervous System: hallucination, confusional state, disorientation, and delirium, pseudotumor cerebri Pancreatic: pancreatitis

In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received intravenous amiodarone for at least one week, 5% received it for at least 2 weeks, 2% received it for at least 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of severe adverse reactions. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days.

Renal:l renal impairment, renal insufﬁciency, acute renal failure

The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. Overall, treatment was discontinued for about 9% of the patients because of adverse reactions. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%).

Vascular: r vasculitis

Respiratory: y bronchospasm, possibly fatal respiratory disorders (including distress, failure, arrest and ARDS), bronchiolitis obliterans organizing pneumonia (possibly fatal), dyspnea, cough, hemoptysis, wheezing, hypoxia, pulmonary inﬁltrates and /or mass, pleuritis Thyroid: d thyroid nodules/thyroid cancer

Baxter Healthcare Corporation Deerﬁeld, IL 60015 Baxter, Galaxy, Nexterone and the Sphere Graphic are trademarks of Baxter International Inc.

Sourced from: 07-19-65-459 Rev. November 2010

16 Clinical

Pharmacy Practice News • July 2012

Educational Review

Recent Advances and Emerging Therapies in the Systemic Treatment of

Metastatic Melanoma JEFFREY T. YORIO, MD Fellow, Hematology and Oncology

KEVIN B. KIM, MD Associate Professor Department of Melanoma Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

elanoma, the malignant transformation of melanocytes, most commonly occurs in the skin but also may arise from the mucosal surfaces or in the choroid of the eyes.

Melanoma is the fifth and sixth most common cancer in men and women, respectively, in the United States.1 In 2012, more than 76,000 people will be diagnosed with malignant melanoma, and more than 9,000 people will die from the disease nationally.1

Although surgery offers a great cure rate for patients with early-stage melanoma, those who have either metastatic disease or a high risk for recurrence are given a much poorer prognosis. In fact, the median overall survival (OS) of patients with stage IV melanoma is only 6 to 9 months.2-4 Dacarbazine remains the only cytotoxic chemotherapy that is FDA-approved for the treatment of metastatic melanoma. However, dacarbazine has modest clinical efficacy, with a response rate of only about 10%.2,4-6 The FDA also has approved high-dose interleukin-2 (IL-2) for the treatment of advanced melanoma because of the agent’s ability to induce a durable response. Unfortunately, this response is observed in only a small subset of patients, and IL-2 is associated with significant toxicities, such as capillary leak syndrome, that frequently require intensive monitoring in a dedicated unit or intensive care facility.7,8 Other agents—including temozolomide (Temodar, Schering-Plough), cisplatin, carboplatin, vinblastine, paclitaxel, carmustine, and lomustine (CeeNu, Bristol-Myers Squibb)—are commonly used off-label to treat melanoma, but none of these agents or their various combinations have been found to offer a survival advantage over dacarbazine alone.9 Clearly, more active and less toxic drugs are

needed for patients with advanced melanoma. In this article, we review recent advances and emerging therapeutic approaches in the systemic treatment of metastatic melanoma.

Newly Approved Drugs For Late-Stage Melanoma Ipilimumab Immunotherapy has been used to treat melanoma for decades. Cancer cells, such as those that make up melanoma, have tumor-associated antigens that can be recognized by T cells. This recognition leads to a host response that targets the tumor cells.10 The standard immunotherapy, highdose IL-2, enhances this response but elicits a durable clinical response in only a small subset of patients.8,11,12 Accordingly, researchers have actively sought to identify and develop more effective immunologic agents with better safety profiles. Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte antigen-4 (CTLA-4), a co-inhibitory receptor molecule found on the surface of activated T cells. T-cell activation begins when the T-cell receptor binds to an antigen presented by a major histocompatibility complex on

antigen-presenting cells, such as dendritic cells. Cluster of differentiation 28 (CD28), a co-stimulatory receptor molecule found on T cells, binds to B7 (CD80/CD86) found on antigen-presenting cells, leading to T-cell proliferation and IL-2 production. As T cells become activated, CTLA-4 is upregulated to the cell surface, where it competes successfully with CD28 for B7 to halt further cell proliferation in a self-regulatory mechanism. Ipilimumab blocks CTLA-4 on the cell surface, thereby preventing CTLA-4 from binding to B7 molecules and allowing CD28 to bind to these molecules instead, leading to further T-cell proliferation and IL-2 production.13,14 Ultimately, this can help increase the immune response to cancer cells. Initial clinical studies revealed that ipilimumab could be a promising new therapy for metastatic melanoma.15,16 A Phase I/II trial of ipilimumab (≤10 mg/kg every 3 weeks) in 23 patients with metastatic melanoma demonstrated a disease control rate of 39%, with at least 2 patients experiencing a durable response of longer than 21 months.15 These encouraging results led to several Phase III trials of ipilimumab in patients with metastatic melanoma (Table 1).17,18 In the first Phase III study of ipilimumab, 676 previously treated patients with unresectable stage III or IV melanoma were randomly assigned, in a 3:1:1 ratio, to receive ipilimumab with a glycoprotein 100 (gp100) peptide vaccine (n=403), ipilimumab alone (n=137), or the gp100 peptide vaccine alone (n=136).17 Ipilimumab was given at a dose of 3 mg/kg every 3 weeks for 4 doses. The median OS of patients who received ipilimumab alone (10.1 months) was significantly longer than that of patients who received the gp100 vaccine alone (6.4 months; hazard ratio [HR], 0.66; P=0.003). However, the median OS of patients who received ipilimumab with the gp100 vaccine did not differ significantly from that of patients who received ipilimumab alone. The risk for disease progression in patients who received ipilimumab alone was 36% lower than

Clinical 17

Pharmacy Practice News • July 2012

Educational Review Table 1. Clinical Data From Positive Phase III Studies of Melanoma Trial and Regimen

Treatment Setting

Primary End Point Results

Hazard Ratio (95% CI)

136

Second-line

OS, 6.4 mo

Reference

P Value

NCT00094653

Ipilimumab

137

OS, 10.1 mo

0.66 (0.51-0.87)

0.003

Ipilimumab + gp100 vaccine

403

OS, 10.0 mo

0.68 (0.55-0.85)

<0.001

OS, 9.1 mo

Reference

OS, 11.2 mo

0.72 (0.59-0.87)

OSa

Reference

OSa

0.37 (0.26-0.55)

NCT00324155 Dacarbazine + placebo

252

Dacarbazine + ipilimumab

250

First-line

<0.001

NCT01006980 Dacarbazine

338

First-line; V600E BRAF mutation

Vemurafenib

337

Dacarbazine

338

PFS, 1.6 mo

Reference

Vemurafenib

337

PFS, 5.3 mo

0.26 (0.20-0.33)

PFS, 2.7 mo

Reference

PFS, 5.1 mo

0.30 (0.18-0.51)

<0.001

NCT01227889 (BREAK-3) Dacarbazine

Dabrafenib

187

First-line; V600E BRAF mutation

<0.0001

NCT01245062 (METRIC) Chemotherapyb

108

Trametinib

214

≤1 prior systemic therapy; V600E BRAF mutation

PFS, 1.5 mo

Reference

PFS, 4.8 mo

0.45 (0.33-0.63)

<0.001

CI, confidence interval; gp100, glycoprotein 100; OS, overall survival; PFS, progression-free survival a b

The addition of dacarbazine to ipilimumab in the second Phase III trial also resulted in notable elevations in serum liver enzyme levels. Of the 247 patients receiving the combination, elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed in 33% and 27% of the patients, respectively.6 Grade 3 or 4 elevations in ALT and AST were seen in 21% and 17%, respectively. Endocrine immune-related AEs such as hypothyroidism, hypopituitarism, and adrenal insufficiency were observed but were uncommon. Patients who develop grade 2 diarrhea should be considered for treatment with oral steroids such as budesonide, whereas patients with grade 3 and 4 diarrhea should discontinue ipilimumab and receive high-dose systemic corticosteroids until improvement.18 Infliximab, an anti-tumor necrosis factor-α antibody, has been used with some success to treat patients who are unresponsive to high-dose steroids. The use of high-dose IV corticosteroids also has been suggested for grade 3 or 4 elevations in serum liver enzyme levels and endocrinopathies.

Inadequate number of patients in follow-up to provide reliable estimates of the survival curve Dacarbazine or paclitaxel

Vemurafenib The Ras/Raf/MEK/extracellular signal-regulated kinase (ERK) pathway is a key pathway for cell proliferation, particularly in cancer cells (Figure).19 In 2002, Davies et al reported that nearly 60% of melanomas harbor a mutation in BRAF, F which codes for a serine-threonine protein kinase involved in the Ras/Raf/MEK/ERK pathway.20 Most Text continues on page 18

that for patients who received the gp100 vaccine alone (P<0.001). The median progression-free survival (PFS) durations of the 3 groups were similar (2.76 months in the combination group, 2.86 months in the ipilimumab-alone group, and 2.76 months in the gp100 vaccine-alone group). The results of this trial led to the FDA’s approval of the drug for the treatment of metastatic melanoma in March 2011. In the second Phase III study of ipilimumab, 502 treatment-naive patients with metastatic melanoma were randomized to receive dacarbazine with or without ipilimumab.6 During the induction phase, ipilimumab was given at a dose of 10 mg/kg every 3 weeks for 4 doses. During the maintenance phase, patients who did not experience severe toxicity during the induction phase were given additional doses of ipilimumab (10 mg/kg every 12 weeks). The median OS duration of the patients who received dacarbazine plus ipilimumab (11.2 months) was significantly longer than that of the patients who received dacarbazine alone (9.1 months; P<0.001). The 3-year OS rates in the dacarbazine plus ipilimumab group and the dacarbazine-only group were 20.8% and 12.2%, respectively. The risk for disease progression in the patients who received dacarbazine plus ipilimumab was 24% lower than that for the patients who received dacarbazine alone (P=0.006). As with other immune-stimulating agents, ipilimumab induces immune-related adverse events (AEs). In the first Phase III trial, the most common immune-related AEs among those receiving ipilimumab alone were diarrhea (28%), pruritus (24%), rash (19%), and colitis (8%).17 Grade 3 or 4 diarrhea and colitis was seen in 5% of the patients.

Cell membrane receptor

Ras

PI3K PTEN

Raf

AKT

MEK 1/2

mTOR

ERK 1/2

IF4E

Cyclin D1

Transcription factors

p70S6K

MMP-2

Tumor cell survival, proliferation, invasion

Nucleus

Figure. Commonly activated signal transduction pathways in melanoma. ERK, extracellular signal-regulated kinase; MEK, mitogen-activated protein kinase kinase; mTOR, mammalian target of rapamycin

18 Clinical

Pharmacy Practice News â&#x20AC;˘ July 2012

Educational Review Table 2. Ongoing Phase III Clinical Trials for Metastatic Melanoma Text continued from page 17

BRAF F mutations are the result of a single nucleotide substitution in which valine is replaced by glutamic acid at codon 600 (V600E) E of exon 15, leading to the constitutive activation of the MEK protein and ERKs, which are essential to melanoma cell proliferation. Melanoma cells with the BRAF F mutation do not require Ras activation to proliferate, indicating that the BRAF F mutation is a driving force behind melanoma cell growth. To inhibit the Raf/MEK/ERK pathway, researchers investigated sorafenib (Nexavar, Bayer), an inhibitor of multiple kinases, including BRAF, CRAF, and vascular endothelial growth factor receptor (VEGFR). However, 2 Phase II trials of sorafenib at a dose of 400 mg twice daily revealed that the drug elicited little or no response in patients with metastatic melanoma; additionally, F mutation was not correthe presence of the BRAF lated with response.21,22 Similarly, 2 large randomized Phase III trials revealed that the addition of sorafenib to front- or second-line carboplatin or paclitaxel yielded no additional clinical benefit in patients with metastatic melanoma.23,24 Despite the underwhelming results with sorafenib, researchers used scaffold-based drug design methods to develop increasingly selective inhibitors of the mutated Raf kinase. One of these new drugs, PLX4032 (later named vemurafenib [Zelboraf, Roche]), was found to have a high affinity for the mutant BRAF kinase.25 A firstin-human Phase I trial of oral vemurafenib enrolled 55 patients and found the maximum tolerated dose (MTD) of the drug to be 960 mg twice a day.26 Thirty-two patients with metastatic melanoF mutation were then enrolled ma harboring a BRAF in the dose-extension cohort and received vemurafenib at a dose of 960 mg twice a day. Of these 32 patients, 26 had a partial or complete response (CR), for an overall response rate (ORR) of 81% with a confirmed response rate of 56% per Response Evaluation Criteria in Solid Tumors (RECIST). Subsequently, a large Phase II study of vemurafenib was conducted in 132 previously treated patients who had metastatic melanoma harboring a V600E BRAF F mutation.27 The ORR, which was validated by an independent review committee, was 53%, with a median PFS duration of 6.8 months, thus confirming the promising results of the Phase I study. A concurrent, large multicenter randomized Phase III trial was then conducted to compare the clinical benefit of vemurafenib with that of dacarbazine in treatment-naive patients with metastatF mutation ic melanoma harboring a V600E BRAF (Table 1).5 Six hundred seventy-five patients were randomized to receive either vemurafenib or dacarbazine, with the primary end points being OS and PFS. At the time of the interim analysis, the hazard ratio for death in the vemurafenib group was 0.37 (P<0.001), and the estimated median PFS duration of patients in the vemurafenib arm (5.3 months) was significantly longer than that of patients in the dacarbazine arm (1.6 months; HR, 0.26; P<0.001). The study was stopped at the time of the interim analysis so that patients in the dacarbazine arm could receive vemurafenib. Overall, patients in the Phase III trial tolerated vemurafenib fairly well.5 The most common AEs were arthralgias, fatigue, and cutaneous events. Twelve percent of patients experienced grade 2

Trial and Regimen

Treatment Setting

Mutation Criteria

Primary End Point

First-line

V600E BRAF mutation

PFS

340

First-line

V600E/K BRAF mutation

694

First-line

C-Kit OS (juxtamembrane)

200

First-line

Any

700

NCT01584648 Dabrafenib (GSK2118436) plus trametinib (GSK1120212) versus dacarbazine NCT01597908 Dabrafenib plus trametinib versus vemurafenib (Zelboraf, Roche) NCT01280565 Masitinib versus dacarbazine NCT01515189 Ipilimumab (3 mg/kg) versus ipilimumab (10 mg/kg)

OS, overall survival; PFS, progression-free survival

or 3 photosensitivity reactions, but the use of sunblock helped prevent the blistering typically observed in grade 3 reactions. Eighteen percent of patients developed either cutaneous squamous cell carcinomas (SqCC) or keratoacanthomas; fortunately, these were all treated by simple excision with no further complications or evidence of SqCC in other organs. These SqCCs could have been the result of the paradoxical activation of the Ras/Raf/MEK/ERK pathway in premalignant skin lesions that lack a BRAF mutation.28,29 Poulikakos et al demonstrated that the binding of vemurafenib to BRAF, which forms a dimer with another Raf kinase, actually leads to transactivation of adenosine triphosphate (ATP)-bound Raf, causing the downstream activation of MEK and ERK in wild-type BRAF cells.30 Many vemurafenib-induced SqCCs harbor a mutation in Ras that ultimately becomes activated when vemurafenib binds to wild-type BRAF.28,29 Based on the statistically significant improvement in both OS and PFS and the acceptable safety profile, in summer 2011 the FDA approved vemurafenib for the treatment of metastatic melanoma harboring a V600E BRAF F mutation. However, despite the high response rate, a majority of patients will have disease progression within 1 year, and a long-term clinical benefit is expected only in a small subset of patients. Therefore, more effective therapeutic strategies are urgently needed.

Emerging Targeted Therapies Selective Raf Inhibitors The successful development of vemurafenib has generated great interest in the clinical evaluation of selective Raf inhibitors in patients with metastatic melanoma harboring a BRAF mutation. One such agent, dabrafenib (GSK2118436, GlaxoSmithKline) is an orally available, highly potent ATP-competitive inhibitor of BRAF.31 In a Phase I/II study in patients with advanced solid tumors, dabrafenib was well tolerated, and the MTD was not reached.32 Dabrafenib inhibited the phosphorylation of ERK in a dose-dependent manner, and based on the pharmacokinetics and pharmacodynamics of the drug and its early clinical activity in the Phase I study, investigators recommended a dose of 150 mg twice daily for further studies. Of the 16 patients in the study who had metastatic

melanoma harboring a V600 BRAF F mutation and received at least 150 mg of dabrafenib twice daily, 10 (63%) had a partial response. Interestingly, of the 10 patients in the study who had active brain metastases measuring at least 3 mm at baseline, 7 also had a clinical response in the brain lesions.33 Subsequently, a Phase II study of dabrafenib enrolled 76 patients who had metastatic melanoma harboring a V600E/K BRAF F mutation.34 Of these 76 patients, 45 (59%) had a confirmed response to dabrafenib, and the median PFS duration was 27.4 weeks. The common AEs associated with dabrafenib were arthralgia, pyrexia, fatigue, hyperkeratosis, and SqCC of the skin. Recently, a Phase III study (NCT01227889) was conducted to compare the PFS associated with dabrafenib to that associated with dacarbazine in treatment-naive patients with V600E BRAFmutated melanoma. The results demonstrated that patients who received dabrafenib had a significantly longer median PFS over dacarbazine (6.7 vs. 2.9 months, respectively; HR, 0.35, 95% confidence interval [CI], 0.20-0.61).35 The ORR also was superior in the dabrafenib arm (50% vs. 6%). The OS data are not available because the study was not designed to compare the OS, and the followup thus far is too short for OS evaluation. Another promising selective Raf inhibitor is LGX818 (Novartis). The results of a Phase I trial of the drug (NCT01436656) will be available shortly. MEK Inhibitors Another approach to treating metastatic melanoma is to inhibit the mitogen-activated protein (MAP) kinase pathway at the level downstream of BRAF kinase. This pathway is commonly activated in melanoma and is induced not only by mutated BRAF, but also by kinase-activating S mutations or other upstream aberrations, NRAS such as receptor kinase phosphorylation. In this signal transduction pathway, the MAP kinase kinase (MEK) protein is the direct substrate of activated BRAF kinase. Therefore, targeting the MEK protein can inhibit the MAP kinase pathway. The results of clinical trials of first-generation MEK inhibitors were disappointing. For example, CI-1040 (Pfizer) and PD0325901 (Pfizer) had poor clinical activity and caused significant AEs, including retinal vein occlusion, which resulted Text continues on page 20

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20 Clinical

Pharmacy Practice News • July 2012

Educational Review Text continued from page 18

in the discontinuation of their development.36,37 Selumetinib (AZD6244, AstraZeneca) is an orally available, highly selective, allosteric inhibitor of MEK1/2. Although in vitro studies revealed that melanoma cell lines containing a BRAF F mutation were particularly sensitive to selumetinib,38,39 a randomized Phase II study showed that the drug had no clinical benefit over temozolomide in chemotherapy-naive patients with metastatic melanoma.40 The

differences in the median PFS duration (78 vs 80 days) and ORR (5.8% vs 9.4%) between the patients who received selumetinib and those who received temozolomide, respectively, were not statistically significant, and the response rates among patients with melanoma containing a BRAF mutation in each group were both the same, at 11%. Clinical outcomes with the nextgeneration, hydrogen sulfate (Hydsulfate) formulation of selumetinib, which has better oral bioavailability

than does the original crystalline formulation, are more promising. A Phase I dose-finding study revealed the MTD of Hyd-sulfate selumetinib to be 75 mg twice daily.41 In a separate Phase I study of combination regimens containing Hyd-sulfate selumetinib, patients with metastatic melanoma with a BRAF F mutation had a higher clinical response rate and longer median time to progression than did those without a BRAF mutation, suggesting that BRAF F mutation is a positive predictive factor for

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Hyd-sulfate selumetinib.42 A randomized Phase II study comparing dacarbazine plus Hyd-sulfate selumetinib with dacarbazine alone in treatmentnaive patients with BRAF-mutated melanoma (NCT00936221) recently completed patient accrual, and the results of this study are highly anticipated. Another potent, highly selective, non–ATP-competitive MEK1/2 inhibitor is trametinib (GSK1120212, GlaxoSmithKline). Although a Phase I study revealed the MTD of trametinib to be 3 mg per day, 2 mg per day was chosen as the recommended dose for future studies on the basis of pharmacokinetic, clinical activity, and safety data.43 The results of a recent Phase II study of trametinib (2 mg/d) in 97 previously treated patients with metastatic melanoma harboring a V600 F mutation are encouraging.44 BRAF In this study, of the 57 patients who had not been previously treated with a BRAF inhibitor (of whom 81% had a F mutation and 75% had V600E BRAF M1c disease), 14 (25%) had a confirmed response, and the median PFS duration was 4 months (CI, 3.5-5.6 months). However, of the 40 patients who had previously received a BRAF inhibitor, none had a confirmed clinical response, and the median PFS duration was 1.8 months (CI, 1.8-2.0 months). The marked differences in clinical response and PFS between the 2 groups suggest that the mechanisms of resistance to BRAF inhibitors also might confer resistance to MEK inhibitors. The results of an open-label randomized Phase III study (NCT01245062) comparing the PFS associated with trametinib with those associated with dacarbazine or paclitaxel in patients with metastatic melanoma harboring a F mutation was recentV600 BRAF ly announced (Table 1, page 17). The trametinib arm had a statistically significant improvement in all 3 clinical parameters (RR, PFS and OS.)45 The median PFS was 4.8 months for the trametinib arm compared with 1.4 months for the chemotherapy arm (HR, 0.44; CI, 0.31-0.64; P<0.0001). In addition, a HR for OS was 0.54 (CI, 0.32-0.92) with a P value of 0.0136, favoring the trametinib arm. Other MEK inhibitors in the early phases of clinical investigation include AS703026 (EMD/Merck Serono), E6201 (Eisai), MEK162 (Novartis), and GDC-0973 (Genentech). The common AEs of MEK inhibitors include skin rash, diarrhea, nausea, vomiting, peripheral edema, and fatigue.36,37,40,41,43,44 Visual disturbances, such as blurry vision or flashing lights, are common but generally mild. Serious ocular toxicity, including

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Educational Review central serous retinopathy and retinal vein occlusion, is uncommon. The decreased left ventricular ejection fraction associated with the use of MEK inhibitors is mostly asymptomatic and is reversible upon discontinuation of the drugs. Combination Strategies Using Targeted Therapies Despite the high response rates observed with Raf inhibitors and the promising clinical activity of MEK inhibitors in patients with advanced F mutamelanoma harboring a BRAF tion, the durations of response to these drugs are relatively short because of acquired drug resistance. Recent studies have elucidated a number of mechanisms of resistance to these drugs, including acquisition of activating NRAS mutations,46 acquisition of activating MEK mutations,47 upregulation of upstream receptor kinases,48 upregulation of CRAF kinase,49 induction of splicing variants of BRAF kinase,50 increased Cot expression,51 and activation of PI3K/AKT signaling pathways.52,53 Loss of BRAF F mutations and the development of secondary mutations to the drug-binding domain of BRAF kinase have not been observed at the time of drug resistance, however.46,48 A recent study found that although vemurafenib universally inhibited the phosphorylation of tumoral ERK1/2 protein within 14 days of treatment, the phosphorylated-ERK1/2 was reupregulated at the time of disease progression in a subset of patients.54 This finding suggests that in at least some patients, the reactivation of the MAP kinase pathway is associated with resistance to the Raf inhibitors and can, at least partially, bypass F mutations. the inhibition of the BRAF In vitro studies have shown that the addition of a MEK inhibitor can delay the development of drug resistance to a selective Raf inhibitor.47 On the basis of these encouraging findings, a Phase I study of dabrafenib plus trametinib (NCT01072175) was conducted in patients with metastatic melanoma. The clinical data generated from the study’s interim analysis are promising.55,56 Given at the recommended doses for a Phase II study, the combination of dabrafenib (150 mg twice daily) and trametinib (1-2 mg per day) was well tolerated, with mild AEs, the most common of which were pyrexia, chills, nausea, diarrhea, and fatigue.55 Skin toxicity, including the development of cutaneous SqCC, occurred much less commonly than was anticipated based on the safety data of dabrafenib treatment alone, suggesting that treatment with the selective Raf inhibitor paradoxically

activated MAP kinase in the normal skin, and the concurrent treatment with MEK eliminated this paradoxical MAP kinase activation. Of the 65 patients who had metastatic melanoma containing a V600E/K/D BRAF mutation and who had never received a BRAF inhibitor, 43 (66%) had objective responses, including 5 (8%) CRs.55 Of the 26 patients who previously had been treated with a selective Raf inhibitor, 5 (19%) had partial responses.56 The updated results of the Phase II study showed that median PFS was

10.8 months among 24 BRAF inhibitornaive patients who received 150 mg of dabrafenib twice daily and 2 mg of trametinib once daily.57 KIT Inhibitors Preclinical findings demonstrating the essential role of stem cell factor and its receptor, KIT tyrosine kinase, in the proliferation and survival of melanocyte precursors,58,59 and KIT’s frequent expression in melanoma specimens59,60 led investigators to conduct 3 studies evaluating the use

of imatinib (Gleevec, Novartis) in patients with metastatic melanoma in the early 2000s.61-63 Imatinib had minimal clinical activity, with only 1 of 63 patients (who had not been selected on the basis of genomic biomarkers) responding to the drug. Interest in KIT-targeted therapy in melanoma was renewed when CurT mutation tin et al showed that KIT and/or amplification is more common in certain subtypes of melanoma than in others.64 In their analysis Text continues on page 22

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of 102 primary melanomas, they used a comparative genomic hybridization T mutations and/or assay and found KIT increased copy numbers of KIT T in 36% of acral lentiginous melanomas, 39% of mucosal melanomas, and 28% of melanomas that developed in chronically sun-damaged skin. Following this novel discovery, a number of case reports have emerged showing that KIT inhibitors have clinical benefit in patients who have melanoma harboring KIT T mutations.65-68 Additionally,

the interim analysis of a Phase II study of imatinib in patients with advanced acral lentiginous melanoma, mucosal melanoma, or melanoma in chronic sun-damaged skin revealed that 5 of 10 patients with melanoma harboring a KIT T mutation had a clinical response to the drug.69 However, none of 10 patients with KIT T amplification without a mutation had a response. In another Phase II study of imatinib in 43 patients with metastatic T mutation melanoma harboring a KIT or amplification, 10 (23%) patients had

an overall clinical response, and 9 of T mutation the 10 responders had a KIT in exon 11 or 13.70 In a separate Phase II study of imatinib in a similar population, 4 (16%) of 25 patients had a durable clinical response, including 2 patients who had CRs.71 The response rate among patients who had mutations affecting recurrent hotspots of T gene or a higher KIT T mutantthe KIT to-wild-type allele ratio (>1) was 40%, whereas the response rate among patients who did not have these features was 0% (P=0.05), suggesting

that the presence of a functionally relevant KIT T mutation is required for imatinib or other KIT inhibitors to have clinical benefit.

Emerging Immunotherapies Anti-PD1 Antibody Like CTLA-4, programmed death 1 (PD-1) is a member of the CD28 family. PD-1 is expressed in activated T cells, memory T cells, and regulatory T cells and is involved in T-cell regulation. Upon binding to its ligands, PD-L1 and PD-L2 (which are highly expressed in tumor cells and the antigen-presenting cells found in tumors), PD1 suppresses T-cell effector function. Tumoral PD-L1 expression has been associated with negative prognosis in cancer patients.72,73 MDX-1106 (Bristol-Myers Squibb), a fully human immunoglobulin G4 monoclonal antibody against PD-1, can interrupt the binding of PD-1 with its ligands, thereby reactivating T-cell function.74 In a Phase I dose-escalating study evaluating a single dose of the drug (with 2 additional doses every 4 weeks allowed in patients in whom continued clinical benefit was observed), MDX-1106 was well tolerated with only one serious AE (colitis).75 Of the 39 patients in the study, 3 patients, including one with metastatic melanoma, had a clinical response to MDX-1106. Another Phase I study evaluated the safety profile of a biweekly dosing schedule of MDX-1106 in patients with refractory metastatic non-small cell lung cancer, renal cell carcinoma, melanoma, or prostate cancer.76 The MTD of the drug was not reached up to a dose of 10 mg/kg every 2 weeks. Common AEs included fatigue, nausea, diarrhea, xerostomia, and pruritus, but grade 3 or 4 AEs were uncommon. In the preliminary response evaluation, 6 (38%) of 16 patients had objective responses; among these patients, 3 patients with metastatic melanoma had a partial response. The clinical investigation of MDX-1106 is ongoing. Adoptive T-cell Therapy In the mid-1980s, Rosenberg et al found that tumor-infiltrating lymphocytes (TILs) isolated from murine sarcomas and colon adenocarcinomas that had been transplanted into syngeneic mice could be expanded with IL-2 in vitro. When infused back into the donor mice, the TILs could mediate the regression of metastatic tumors.77 They later reported the regression of metastatic melanoma lesions in 11 of 20 patients who were treated with the adoptive transfer of TILs and IL-2 infusion following a Text continues on page 24

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single dose of cyclophosphamide.78 Other researchers found that when the adoptive transfer of TILs and IL-2 infusion were preceded by a 7-day regimen of cyclophosphamide and fludarabine, which depleted the number of endogenous regulatory cells and lymphocytes competing with the transferred TILs for growth-promoting homeostatic cytokines, 6 of 13 patients had a clinical response.79 Notably, this approach resulted in the persistent clonal repopulation of T cells, which proliferated in vivo and traveled to tumor sites in these patients. In an expanded Phase II study conducted by the same group of investigators, lympho-depleting chemotherapy followed by TIL transfer and high-dose IL-2 infusion elicited a response rate of 51% among 35 patients with metastatic melanoma.80 When TIL transfer and IL-2 infusion were preceded by myeloablative chemoradiation (lympho-depleting chemotherapy plus 2 or 12 Gy of total-body irradiation), clinical activity of the regimen was even better, with response rates of 52% and 72%, respectively.81 Of 20 patients who had CRs in these trials of adoptive TIL transfer, only 1 patient’s disease has relapsed. The other patients continue to have CRs 3 to 7 years following the completion of the treatment.81,82 In another study, CD4-positive T-cell clones targeting the DPB1*0401restricted epitope of a peptide derived from NY-ESO-1 were isolated from the peripheral blood mononuclear cells of patients with metastatic melanoma and expanded in vitro, and the antigen-specific CD4-positive T cells were infused back into the patient.83 One patient had a complete resolution of lung and nodal metastases that was accompanied by the persistent presence of the NY-ESO-1–specific CD4positive T cells and lasted for at least 2 years. This finding suggests that the adoptive transfer of antigen-specific CD4-positive T cells may be used to treat advanced melanoma.

Conclusion After a long drought in the development of successful therapies, recent advances in targeted therapy and immunotherapy have set a new standard of treatment for metastatic melanoma. However, the arrival of ipilimumab and vemurafenib in the clinic has generated more questions and challenges. For example, it is not clear which of these agents, ipilimumab or vemurafenib, should be offered first in patients with metastatic disease, especially in those with limited or slowly progressing metastatic lesions; in addition, the optimal sequencing

of high-dose IL-2 with these agents remains unknown. Whether a Raf inhibitor should be added to subsequent therapy following the failure of BRAF inhibition is also unclear. The optimal combination of targeted drugs and/or immunotherapeutic agents will need to be determined to maximize their clinical benefit in patients with metastatic melanoma. We hope that these important questions soon will be addressed with rationally designed clinical studies.

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46. Nazarian R, Shi H, Wang Q, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468(7326):973977, PMID: 21107323. 47. Emery CM, Vijayendran KG, Zipser MC, et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20411-20416, PMID: 19915144. 48. Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell. 2010;18(6):683-695, PMID: 21156289. 49. Montagut C, Sharma SV, Shioda T, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68(12):48534861, PMID: 188559533. 50. Poulikakos PI, Persaud Y, Janakiraman M, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature. 2011;480(7377):387-390, PMID: 22113612. 51. Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468(7326):968-972, PMID: 21107320. 52. Jiang CC, Lai F, Thorne RF, et al. MEKindependent survival of B-RAFV600E melanoma cells selected for resistance to apoptosis induced by the RAF inhibitor PLX4720. Clin Cancer Res. 2011;17(4):721730, PMID: 21088259. 53. Shao Y, Aplin AE. Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer Res. 2010;70(16):6670-6681, PMID: 20647317. 54. McArthur GA, Ribas A, Chapman PB, et al. Molecular analyses from a phase I trial of vemurafenib to study mechanism of action (MOA) and resistance in repeated biopsies from BRAF mutation-positive metastatic melanoma patients (pts). J Clin Oncol. 2011;29(suppl). Abstract 8502. 55. Infante JR, Falchook GS, Lawrence DP, et al. Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212)

dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436). J Clin Oncol. 2011;29:(suppl). Abstract CRA8503. 56. Flaherty KT, Infante JR, Falchook GS, et al. Phase I/II expansion cohort of BRAF inhibitor GSK2118436 + MEK inhibitor GSK1120212 in patients with BRAF mutant metastatic melanoma who progressed on a prior BRAF inhibitor. Pigment Cell Melanoma Res. 2011;24(5):1022. Abstract LBA 1-4. 57. Weber JS, Flaherty KT, Infante JR, et al. Updated safety and efficacy results from a Phase I/II study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. J Clin Oncol. 2012. (suppl). Abstract 8510. 58. Kawa Y, Ito M, Ono H, et al. Stem cell factor and/or endothelin-3 dependent immortal melanoblast and melanocyte populations derived from mouse neural crest cells. Pigment Cell Res. 2000;13(suppl 8):73-80, PMID: 11041361. 59. Shen SS, Zhang PS, Eton O, Prieto VG. Analysis of protein tyrosine kinase expression in melanocytic lesions by tissue array. J Cutan Pathol. 2003;30(9):539-547, PMID: 14507401. 60. Went PT, Dirnhofer S, Bundi M, et al. Prevalence of KIT expression in human tumors. J Clin Oncol. 2004;22(22):45144522, PMID: 15542802. 61. Ugurel S, Hildenbrand R, Zimpfer A, et al. Lack of clinical efficacy of imatinib in metastatic melanoma. Br J Cancer. 2005;92(8):1398-1405, PMID: 15846297. 62. Wyman K, Atkins MB, Prieto V, et al. Multicenter Phase II trial of high-dose imatinib mesylate in metastatic melanoma: significant toxicity with no clinical efficacy. Cancer. 2006;106(9):2005-2011, PMID: 16565971. 63. Kim KB, Eton O, Davis DW, et al. Phase II trial of imatinib mesylate in patients with metastatic melanoma. Br J Cancer. 2008;99(5):734-740, PMID: 18728664. 64. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006;24(26):4340-4346, PMID: 16908931. 65. Hodi FS, Friedlander P, Corless CL, et al. Major response to imatinib mesylate

in KIT-mutated melanoma. J Clin Oncol. 2008;26(12):2046-2051, PMID: 18421059. 66. Lutzky J, Bauer J, Bastian BC. Dosedependent, complete response to imatinib of a metastatic mucosal melanoma with a K642E KIT mutation. Pigment Cell Melanoma Res. 2008;21(4):492-493, PMID: 18510589. 67. Quintas-Cardama A, Lazar AJ, Woodman SE, Kim K, Ross M, Hwu P. Complete response of stage IV anal mucosal melanoma expressing KIT Val560Asp to the multikinase inhibitor sorafenib. Nat Clin Pract Oncol. 2008;5(12):737-740, PMID: 18936790. 68. Handolias D, Hamilton AL, Salemi R, et al. Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT. Br J Cancer. 2010;102(8):1219-1223, PMID: 20372153. 69. Hodi FS, Friedlander P, Corless C, et al. Phase II trial of imatinib in KIT mutant/ amplified melanoma. Presented at: 6th Annual International Melanoma Congress 2009: Boston, MA. Abstract. 70. Guo J, Si L, Kong Y, et al. Phase II, openlabel, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011;29(21):2904-2909, PMID: 21690468. 71. Carvajal RD, Antonescu CR, Wolchok JD, et al. KIT as a therapeutic target in metastatic melanoma. JAMA. 2011;305(22):2327-2334, PMID: 21642685. 72. Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104(9):3360-3365, PMID: 17360651. 73. Thompson RH, Kuntz SM, Leibovich BC, et al. Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term followup. Cancer Res. 2006;66(7):3381-3385, PMID: 16585157. 74. Wong RM, Scotland RR, Lau RL, et al. Programmed death-1 blockade enhances expansion and functional capacity of human melanoma antigen-specific CTLs. Int Immunol. 2007;19(10):1223-1234, PMID: 17898045. 75. Brahmer JR, Drake CG, Wollner I, et

al. Phase I study of single-agent antiprogrammed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167-3175, PMID: 20516446. 76. Sznol M, Powderly JD, Smith DC, et al. Safety and antitumor activity of biweekly MDX-1106 (Anti-PD-1, BMS-936558/ONO4538) in patients with advanced refractory malignancies. J Clin Oncol. 2010;28(15 suppl). Abstract 2506. 77. Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumorinfiltrating lymphocytes. Science. 1986;233(4770):1318-1321, PMID: 3489291. 78. Rosenberg SA, Packard BS, Aebersold PM, et al. Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med. 1988;319(25):1676-1680, PMID: 3264384. 79. Dudley ME, Wunderlich JR, Robbins PF, et al. Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science. 2002;298(5594):850-854, PMID: 12242449. 80. Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346-2357, PMID: 15800326. 81. Dudley ME, Yang JC, Sherry R, et al. Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008;26(32):52335239, PMID: 18809613. 82. Rosenberg SA, Restifo NP, Yang JC, Morgan RA, Dudley ME. Adoptive cell transfer: a clinical path to effective cancer immunotherapy. Nat Rev Cancer. 2008;8(4):299-308, PMID: 18354418. 83. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med. 2008;358(25):2698-2703, PMID: 18565862.

Should G-CSF Be Standard Procedure After AML Consolidation? Orlando, Fla.—Adding granulocyte colony-stimulating factor (G-CSF) to the treatment regimen of patients with acute myeloid leukemia (AML) who have undergone consolidation chemotherapy reduces the incidence of febrile neutropenia–related hospitalizations and potentially has a positive effect on survival, a new study suggests. The research adds to the evidence that G-CSF can be an effective adjunct therapy in patients with the hematologic malignancy, according to Amber Bradley, PharmD, who led the study when she was a postgraduate year 2 hematology/oncology pharmacy resident at the University of North Carolina (UNC) Lineberger Comprehensive Cancer Center, in Chapel Hill. Dr Bradley presented the results at the Hematology/Oncology Pharmacy Association annual meeting (poster pp3).

Study Details In the UNC study, the investigators retrospectively reviewed six years of electronic health records and identified patients who were diagnosed with AML and who received consolidation therapy with high-dose cytarabine (HiDAC). Patients were divided into two groups: those who received G-CSF in the first cycle (n=35) and those who did not (n=43). G-CSF reduced the incidence of febrile neutropenia admissions after cycle 1 of HiDAC: The adverse reaction occurred in five (14%) of the patients in the G-CSF group versus 16 (37%) patients not given the growth factor therapy (P ( =0.039), Dr. Bradley reported. However, there was no statistically significant difference found for admissions after cycles 2 through 4. The difference found in cycle 1 could not be attributed to a dif-

ference in antimicrobial prophylaxis in the two groups, the investigators noted. The researchers added that a variety of factors could have confounded the results seen after cycles 2 to 4, including crossover (n=22), where some patients received G-CSF in cycle 1 but not in subsequent cycles, and vice versa. The discrepancy also may have been due to the fact that “our numbers were not sufficiently powered at that point [in the study],” said Dr. Bradley, who is now clinical assistant professor at the University of Georgia College of Pharmacy, in Augusta. “There is a potential that it could have been statistically significant and we didn’t capture that, based on the lower numbers of patients in cycles 2 to 4.” The secondary end point of study, overall survival (OS), favored patients who received G-CSF during the first

cycle (P ( =0.014), although specific OS data were not included in the poster. In an ongoing analysis examining factors that could have confounded these survival results, more patients who received G-CSF with the first cycle went on to receive a stem cell transplant, Dr. Bradley noted, adding that prospective studies are needed to further evaluate these findings.

A History of G-CSF Efficacy The UNC study is not the first to show that G-CSF can be an effective addon therapy for patients with AML. In 2000, a randomized trial of 194 patients with AML ((J Clin Oncoll 2000;18:780787) showed that those given G-CSF after consolidation therapy with HiDAC plus mitoxantrone had “dramatically” lower rates of neutropenia compared

•

see CONSOLIDATION, page 45

Hem/Onc Pharmacy

Pharmacy Practice News • July 2012

In Focus

Same-Day Pegfilgrastim and Cabazitaxel Urged Orlando, Fla.—Providing growth factor support with pegfilgrastim (Neulasta, Amgen) on the same day as cabazitaxel (Jevtana, Sanofi) was safe and convenient for patients in a study presented at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA). With “same-day pegfilgrastim, patients don’t have to make another visit to the clinic the next day to receive [it, and] they don’t have to pay a copay to selfadminister it at home,” said Adrienne Sevin, PharmD, a postgraduate year 2 oncology pharmacy resident at the University of Texas MD Anderson Cancer Center, in Houston, who led the study. She said that all patients at MD Anderson are being offered same-day pegfilgrastim with cabazitaxel. “This is our standard procedure now.” It is not standard procedure everywhere, however. The National Comprehensive Cancer Network guidelines recommend administration of granulocyte colony-stimulating factor (G-CSF) 24 to 72 hours after a patient completes che-

motherapy. Although there have been mixed results in studies of patients with various cancers—some showing that administering G-CSF on the same day as chemotherapy is safe and others showing that it increases the risk for febrile neutropenia (J Oncol Practt 2010;6:133-140; J Support Oncoll 2009;7:225-228)—there are few studies that provide information on same-day G-CSF in patients with prostate cancer. Furthermore, the high incidence of neutropenia observed in the TROPIC (Treatment of Hormone-Refractory Metastatic Prostate Cancer Previously Treated with a Taxotere-Containing Regimen) trial of cabazitaxel has led to some additional reluctance among clinicians to give growth factor on the same day as this agent. In TROPIC, patients who received cabazitaxel had a roughly 20% greater incidence of grade 3/4 neutropenia, and the product labeling carries a black box warning that neutropenic deaths have been reported among patients treated with the agent. “Because of the high incidence of neu-

tropenia that was found in the TROPIC trial with cabazitaxel, I think people are kind of scared to … provide same-day pegfilgrastim,” Dr. Sevin said. At MD Anderson, however, clinicians have not been observing high rates of neutropenia in their patients who receive cabazitaxel, and thus clinicians chose to offer same-day pegfilgrastim because of the increased convenience for patients.

Study Results Detailed In the study presented at HOPA, the researchers conducted a retrospective chart review of all patients who received pegfilgrastim after cabazitaxel for the treatment of metastatic castraterecurrent prostate cancer at MD Anderson between July 17, 2010 and Oct. 3, 2011. Twenty-nine patients received the growth factor less than 24 hours after receiving cabazitaxel and three patients received pegfilgrastim 25 or more hours after receiving cabazitaxel. Only one patient had febrile neutropenia after receiving same-day pegfilgrastim. This resulted in a dose reduction and

delayed treatment. However, that patient had been very heavily pretreated. “He had received nine cycles of docetaxel, as well as other chemotherapy, and radiation, and he had a performance score of 3, so we think a lot of that contributed to him having a worse response,” Dr. Sevin said. “Because it was only one out of 29 patients, we plan on continuing sameday pegfilgrastim with cabazitaxel.” Commenting on the study, William Figg Sr., PharmD, senior clinician and head of the molecular pharmacology section at the National Cancer Institute’s Center for Cancer Research, in Bethesda, Md., said a prospective, randomized trial is needed before any changes are made to practice. “These data are very encouraging; however, they are not mature enough to justify a change in practice,” Dr. Figg said. “The numbers were small and the study was retrospective.” —Kate O’Rourke Drs. Sevin and Figg reported no relevant financial conflicts of interest.

Metronomic Chemo Shows Modest Benefit in Metastatic Breast Cancer Orlando, Fla.—Metronomic chemotherapy with oral cyclophosphamide and methotrexate provides clinical benefit in 10% of patients and may offer an alternative for those who might not be able to tolerate more aggressive therapy due to residual toxicity from previous treatments, a new study found. The regimen, which employs low doses given in a frequent or continuous schedule, “could be a potential option for patients who have poor performance status, are minimally symptomatic or those who prefer an oral therapy,” said Lauren Radvansky, PharmD, BCPS, a postgraduate year 2 oncology pharmacy resident at the University of Texas MD Anderson Cancer Center, in Houston, who presented the results at the annual meeting of the Hematology/Oncology Pharmacy Association (poster T14). In the study, investigators conducted a retrospective chart review of patients with metastatic breast cancer (MBC) who received metronomic cyclophosphamide and methotrexate at MD Anderson from Jan. 1, 2001 to Aug. 1, 2011. The majority of patients received a standard methotrexate oral dose—2.5 mg twice daily on day 1 and day 2 every week. The cyclophosphamide dose, in contrast, at 50 mg daily, was less than conventional dosing. In the 29 patients who received the therapy, approximately 50% of patients had at least two

‘I am afraid the bottom line is that the [regimen] has insufficient activity to be widely adopted.’ —Robert Livingston, MD sites of metastatic disease and 97% of patients had progressive disease at study entry. Patients had received a median of five lines of prior chemotherapy, with a range of two to 10 lines of therapy. The median time to treatment failure was six weeks. Overall, the clinical benefit rate—defined as no progression of disease at 24 weeks, as documented by the clinical oncologist—was 10%, Dr. Radvansky reported. In patients who had received four or fewer lines of prior chemotherapy, the clinical benefit rate was 23%. The most common non-hematologic toxicity was nausea/vomiting (44%). Anemia was the most common hematologic toxicity, with all-grade anemia occurring in 83% and grade 3/4 anemia occurring in 24% of patients. Other grade 3/4 toxicities included leukopenia (17%), neutropenia (3%) and thrombocytopenia (14%). Before this study, Dr. Radvansky said, two single-arm Phase II studies had been published evaluating low-dose, oral cyclophosphamide and methotrexate in MBC (J ( Egypt Natl Canc Inst 2008;20:134-140; Ann Oncol

2002;13:73-80). Both found an overall clinical benefit of 31%, but the role of this metronomic chemotherapy is not well established in MBC. Dr. Radvansky said her small, retrospective study provides further evidence that metronomic chemotherapy with cyclophosphamide and methotrexate is a “potential therapeutic option for heavily pretreated MBC patients. In metastatic breast cancer, the goal is palliative, so you do not want patients to experience severe toxicities [while you are trying] to control their disease because this can lead to a decreased quality of life.”

Not Enough Strength In Numbers? Robert Livingston, MD, a professor of medicine and hematologic oncology at the University of Arizona Cancer Center, in Tucson, does not think the regimen has enough activity to be used. “I am afraid the bottom line is that the [regimen] has insufficient activity to be widely adopted,” he said. “It is important to understand that ‘clinical benefit’ is a vague, subjective term.” He said a

more useful definition of benefit would be objective response rate or time to progressive disease. Dr. Livingston added that the University of Arizona Cancer Center does not use this metronomic regimen, but researchers at his institution are “interested in a metronomic approach to chemotherapy, with hope that other metronomic regimens of chemo, perhaps combined with anti-angiogenic agents, may be more effective.” —Kate O’Rourke Drs. Radvansky and Livingston reported no relevant financial conflicts of interest.

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Important Safety Information Levetiracetam in Sodium Chloride Injection is an antiepileptic drug indicated when oral administration is temporarily not feasible in adults (16 years and older) with: partial onset seizures; myoclonic seizures in patients with juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures. Levetiracetam should be gradually withdrawn to minimize the potential of increased seizure frequency. Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Levetiracetam in Sodium Chloride Injection causes neuropsychiatric reactions including somnolence and fatigue, muscle coordination difﬁculties and behavioral abnormalities as well as hematological abnormalities. The most common adverse reactions observed with Levetiracetam were somnolence, weakness, infection and dizziness. Important behavioral adverse reactions include hallucinations, delusions, and non-psychotic mood disorders including suicide ideation, aggression, anger, apathy, conduct disorder, irritability, depression, nervousness, anxiety and emotional lability. Dosing must be individualized according to seizure type, patient’s renal function status and therapy objective. Based on animal data, Levetiracetam may cause fetal harm and therefore should be used during pregnancy after consideration of the potential beneﬁt-risk ratio. Levetiracetam should be gradually withdrawn to minimize the potential of increased seizure frequency.

Please see following pages for accompanying full Prescribing Information.

JA037

May 2012

Brief Summary of Risk Information for LEVETIRACETAM IN SODIUM CHLORIDE INJECTION, for intravenous use WARNINGS AND PRECAUTIONS Neuropsychiatric Adverse Reactions Partial Onset Seizures: Levetiracetam can cause central nervous system adverse reactions: 1) somnolence and fatigue: levetiracetam 14.8%, placebo 8.4%. In a study without titration, 45% reported somnolence from 4000 mg/ day; considered “serious” by 0.3% levetiracetam, versus 0% of placebo patients; discontinuation: 3% levetiracetam, versus 0.7% of placebo patients; dose reduction: 1.4% levetiracetam versus 0.9% placebo; 0.3 % levetiracetam patients were hospitalized for somnolence. Asthenia: levetiracetam 14.7%, versus 9.1% placebo; treatment discontinuation: 0.8% versus 0.5% placebo; dose reduction: 0.5% versus 0.2% of placebo; 2) coordination difficulties (ataxia, abnormal gait, or incoordination): 3.4% levetiracetam versus 1.6% placebo; discontinuation from ataxia: 0.4% levetiracetam versus 0% placebo; dose reduction: 0.7% levetiracetam versus 0.2% placebo; one patient hospitalized from worsening of pre-existing ataxia. Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of treatment. 3) behavioral abnormalities (psychotic symptoms and other behavioral and mood symptoms): Psychotic symptoms: 5 (0.7%) levetiracetam versus 1 (0.2%) placebo. Two (0.3%) levetiracetam patients hospitalized and treatment discontinued. Both developed in the first treatment week, resolved in 1 to 2 weeks following discontinuation. Two events of hallucinations, occurred after 1-5 months and resolved within 2-7 days while remaining on treatment. One psychotic depression occurring within a month, resolved within 45 days while treatment continued. Other behavioral symptoms (aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, irritability, etc.): 13.3% levetiracetam versus 6.2% placebo; approximately half reported within the first 4 weeks; treatment discontinued in 1.7% levetiracetam versus 0.2% placebo; dose reduction in 0.8% levetiracetam versus 0.5% placebo. Serious behavioral event causing hospitalization in 0.8% levetiracetam versus 0.2% placebo. Attempted suicide after 4-6 months treatment (one completed suicide) in 4 (0.5%) levetiracetam versus 0% placebo. Myoclonic Seizures: Somnolence and behavioral abnormalities: It is expected that the events seen in partial seizure patients would occur in patients with juvenile myoclonic epilepsy (JME). In JME patients JME experiencing myoclonic seizures: somnolence occurred in 11.7% of levetiracetam versus 1.7% of placebo patients (no treatment discontinuations); dose reduction in 1.7% levetiracetam versus 0% of placebo. Non-psychotic behavioral disorders (aggression and irritability): 5% levetiracetam versus 0% placebo. Non-psychotic mood disorders (depressed mood, depression, and mood swings) 6.7% levetiracetam versus 3.3% placebo. Dose reduction or discontinuation: 5.0% of levetiracetam versus 1.7% placebo. Primary Generalized Tonic-Clonic Seizures: Behavioral symptoms appeared to be associated with levetiracetam. Gait disorders and somnolence were described in patients with primary generalized seizures, but no difference between placebo and levetiracetam groups and no appreciable discontinuations. In some patients levetiracetam causes behavioral abnormalities: irritability 6.3% levetiracetam versus 2.4% placebo. In patients with idiopathic generalized epilepsy, non-psychotic behavioral disorders (abnormal behavior, aggression, conduct disorder, and irritability): 11.4% levetiracetam (one discontinued due to aggression) versus 3.6% placebo; non-psychotic mood disorders (anger, apathy, depression, mood altered, mood swings, negativism, suicidal ideation, and tearfulness): 12.7% levetiracetam versus 8.3 placebo. Suicidal ideation in one levetiracetam patient. Delusional behavior in one patient requiring lowering of the levetiracetam dose. In a long-term open label study of various forms of primary generalized epilepsy, along with the non-psychotic behavioral disorders, 2 of 192 patients studied exhibited psychotic-like behavior, one characterized by auditory hallucinations and suicidal thoughts (led to drug discontinuation), the other as worsening of pre-existent schizophrenia (did not lead to discontinuation). Withdrawal Seizures: Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency. Hematologic Abnormalities: Minor, but statistically significant, decreases in total mean RBC count (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam patients. A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤2.8 x 109/L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1.0 x 109/L) decreased neutrophil count. Of the treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts. Hepatic Abnormalities: No meaningful changes in mean liver function tests

(LFT) in controlled trials in adult patients; lesser LFT abnormalities were similar in drug and placebo patients in controlled trials (1.4%). No patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment. Laboratory Tests: Relatively infrequent abnormalities seen in hematologic parameters and liver function tests. ADVERSE REACTIONS: Most common (≥ 5%) versus placebo include: somnolence, asthenia, infection, and dizziness; important behavioral (< 5%) include depression, nervousness, anxiety, and emotional lability. See full prescribing information for adverse reactions in specific types of seizures and incidence when levetiracetam was added to concurrent AED therapy. Postmarketing Experience: Additional adverse events reported worldwide (alphabetically): abnormal liver function test, hepatic failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression identified in some), thrombocytopenia and weight loss. Alopecia was reported; recovery was observed in majority of cases where levetiracetam was discontinued. Reports of suicidal behavior (completed suicide, suicide attempt and suicidal ideation) with marketed levetiracetam. See Patient Counseling Information. USE IN SPECIFIC POPULATIONS. Pregnancy Category C: No adequate and well-controlled studies in pregnant women. Animal studies: evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. As with other antiepileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. There have been reports of decreased levetiracetam concentration during pregnancy. Discontinuation of antiepileptic treatments may result in disease worsening, which can be harmful to the mother and the fetus. North American Antiepileptic Drug Pregnancy Registry: Physicians are advised to recommend that pregnant levetiracetam patients enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry, toll free number 1-888-233-2334 (must be done by the patients themselves), website http://www.aedpregnancyregistry.org. Effect on Labor and Delivery: unknown. Nursing Mothers: Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Safety in Pediatric Use: Safety and effectiveness below age 16 years have not been established. Geriatric Use: No overall differences in safety were observed compared to younger subjects. Numbers of clinical trial subjects were insufficient to assess effectiveness in the elderly. A study in 16 elderly subjects (age 61-88 years) with oral administration of single dose and multiple twicedaily doses for 10 days showed no pharmacokinetic differences related to age alone. Levetiracetam is substantially excreted by the kidney, with concomitant risk of adverse reactions in patients with impaired renal function. Accordingly, care should be taken in dose selection for the elderly, and it may be useful to monitor renal function. Use in Patients with Impaired Renal Function: Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving levetiracetam and supplemental doses should be given to patients after dialysis. OVERDOSAGE: Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans: The highest known dose of oral levetiracetam received in the clinical development program was 6000 mg/day. Only drowsiness was observed in the few known cases of overdose in clinical trials. Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma observed in overdoses in postmarketing use. Treatment or Management of Overdose: No specific overdose antidote. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions to maintain airway. General supportive care is indicated including monitoring of vital signs and observation of clinical status. A Certified Poison Control Center should be contacted for up to date information. Hemodialysis: Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment. Patient Counseling: Patients should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician as suicide, suicide attempt and suicidal ideation have been reported in patients treated with levetiracetam. To report SUSPECTED ADVERSE REACTIONS, contact Mylan Institutional LLC at 1-877-4RX INFO or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. g /

Clinical 31

Pharmacy Practice News • July 2012

Critical Care

NEUROMUSCULAR

For Dr. Brull, the solution is clear: “I ... feel very strongly that [the] American Society of Anesthesiologists [ASA] should come up with some standards for perioperative monitoring.” Jeffrey L. Apfelbaum, MD, chair of the ASA’s Committee on Standards and Practice Parameters, said the panel will not be reviewing issues related to residual paralysis this year. “We recognize that it’s an area of interest and it is in queue for consideration.”

continued from page 1

“It’s definitely something we all need to be paying more attention to,” said Ishaq Lat, PharmD, FCCM, clinical coordinator of critical care/emergency medicine at University of Chicago Medical Center. Residual paralysis from NMBAs “is a potentially serious adverse event that clearly is contributing to increased morbidity and mortality. And this isn’t just something we need to heed in the post-anesthesia care unit [PACU]; these patients also can present in the ICU if they have trouble being weaned off a ventilator. So critical care pharmacy can play a major role in alerting physicians to this risk and potentially intervening to hasten recovery.”

For Critical Care Pharmacists, Questions Remain

Tactile evaluation for monitoring patients on NMBAs.

Incidence

‘We need to pinpoint exactly what factors predispose

Although there are no firm data on the incidences of NMBA-related residual paralysis and its associated negative effects, Dr. Brull offered some estimates at the 2012 annual meeting of the International Anesthesia Research Society, in Boston. Of the roughly 40 million surgeries performed in the United States each year, about 60%, or 24 million, involve general anesthesia. If residual paralysis occurs in as much as 40% of patients who receive general anesthesia—admittedly near the top end of the range—he said, that equates to 10 million patients. Critical respiratory events will affect 0.8% of those patients, and another 0.1% will require emergent reintubation in the PACU. The total: approximately 100,000 cases per year of potential harm “directly related” to residual paralysis. “I know it doesn’t happen here,” Dr. Brull said facetiously, referring to the anesthesiologists in the audience. “But it does happen.”

patients to incomplete recovery.’

Monitoring Still a Challenge Part of the problem is that the clinical tests for residual paralysis are not especially accurate. That goes for subjective train-of-four monitoring, feeling for the contraction of the affected muscles, or evaluating patients by their clinical correlates—how firmly they can bite a tongue depressor, squeeze a hand or hold up their heads. “All of the clinical tests, all of them, have a very low predictive value,” Dr. Brull said. “Even though 100% of clinicians use them, 99.9% of us are wrong half the time.” That might be an overstatement, but the condition does seem to have a way of eluding anesthesiologists, said Glenn Murphy, MD, director of cardiac anesthesia and clinical research at NorthShore University HealthSystem, in Chicago. Dr. Murphy said that the vast majority of clinicians report never having seen a case of the complication, which seems unlikely, he said, given

—Ishaq Lat, PharmD, FCCM that “I see it a couple of times a month. If quantitative neuromuscular monitors are used in the PACU, most clinicians would discover that adverse respiratory events related to residual neuromuscular block are not rare events.” Nor is it a trivial complication safely ignored. “There’s clearly a patient safety issue involved here,” Dr. Murphy said. Adverse events can range from mild airway obstruction to life-threatening hypoxemic episodes. Residual paralysis also affects the quality of recovery, said Dr. Murphy, who has conducted studies on the issue. “When we leave patients with residual block, they experience a variety of unpleasant symptoms of muscle weakness during the PACU admission.” In one such study, Dr. Murphy’s group randomized patients to quantitative neuromuscular monitoring [TOF-Watch SX, Bluestar Enterprises] or no monitoring in the operating room ((Anesthesiology 2011;115:946-954). “When we evaluated them for symptoms and signs of muscle weakness, they clearly felt a lot worse” when experiencing residual block, he said. The available reversal agents are at least partly to blame, he added. Neostigmine in particular does not work very well. “In the best of circumstances, it takes an average of 10 to 15 minutes to achieve complete neuromuscular recovery. The problem is we are pulling the endotracheal tube out without demonstrating that full recovery of muscle activity has occurred.” As it happens, the muscles that maintain airway tone are exquisitely sensitive to blocking agents. When weak, they can obstruct and collapse. Small degrees of residual block appear to be more threat-

ening for patients who are predisposed to airway difficulties—those with sleep apnea and chronic obstructive pulmonary disease, for example. “The majority of patients with a little bit of residual block in the PACU will feel weak, but won’t develop life-threatening problems,” Dr. Murphy said. “But if a patient with minimal pulmonary or cardiac reserve is left with incomplete neuromuscular recovery, significant adverse respiratory events may occur following tracheal extubation.” As same-day surgeries become more common and the use of short-acting anesthetics like propofol and desflurane broadens, residual paralysis is likely to become a common postoperative occurrence, Dr. Murphy added.

More Research in the Works Aaron Kopman, MD, a retired professor of anesthesiology at New York Medical College, in Valhalla, has been working with Dr. Brull on a journal article about residual paralysis. “While there’s general consensus as to what should be done in terms of monitoring, there is a huge disconnect between what neuromuscular aficionados suggest and what’s done in the real world,” Dr. Kopman said. “Probably 50% of anesthesiologists don’t use proper monitoring even though it’s available.” Why the practice gap? Although Dr. Kopman said the answer is complicated, one issue is that most nerve stimulators do not provide quantitative data. “They don’t give you a number you can deal with. Without that, I think people tend not to use the devices.” The lack of official guidelines doesn’t help, Dr. Kopman added. Another barrier is what he said was the fate of articles and editorials on the subject: “They fall into a black hole.”

Dr. Lat said there are several questions related to residual paralysis and NMBAs that still need to be resolved. “In such a heterogenous population as the U.S.—and given the increasing demand for surgical services, such as same-day surgery—we need to pinpoint exactly what factors predispose patients to incomplete recovery,” he said. “Is it obesity, where the pharmacokinetics of these agents may be poorly understood? Is it age-related? Or a combination of both?” Dr. Latt added that economic factors are also in play. “Reducing patient throughput due to residual paralysis reduces potential efficiency (and revenue), while also introducing adverse events into the surgical/anesthesia system,” he said. “Introducing harm events also introduces the potential for lower reimbursement from third-party payers if they feel that these events at some point can be avoided with better anesthesia care.” Tricia A. Meyer, MS, PharmD, an assistant professor of anesthesiology in the Department of Anesthesiology at Texas A&M University College of Medicine, in Temple, agreed that many challenges remain when it comes to addressing the problem of residual paralysis. First and foremost, she noted, the condition is usually not topof-mind for pharmacists “unless they have a practice in the operating room.” And the condition itself is a puzzle. “Although we understand the use and mechanism of reversal agents such as neostigmine, for example, we do not fully appreciate the many variables that can alter the effectiveness of this agent, such as excessive doses of NMBAs or use of these agents in older patients with lower rates of clearance.” Yet another challenge has to be considered, Dr. Lat pointed out—drug shortages. “Neostigmine may not be 100% effective as a reversal agent, but it has its role— when it’s available,” he said. “Recently, this has not been the easiest drug to procure. So the ongoing drug shortage crisis may exacerbate the problem of hastening patient’s time to recovery.” —Adam Marcus, with additional reporting by David Bronstein

32 Clinical

Pharmacy Practice News • July 2012

Critical Care

Colistin Poses Risks at Both Ends of the Dosing Spectrum Houston—Two new studies presented at the annual meeting of the Society of Critical Care Medicine (SCCM) underscore the pitfalls associated with colistin therapy at divergent ends of the dosing spectrum. Give too little of the antibiotic, one study suggests, and you risk treatment failure. But at higher doses, the risk for nephrotoxicity can be significant—especially compared with other standard therapies.

A Pharmacokinetics Puzzle Colistin’s penchant for causing nephrotoxicity is not new. The drug first became widely used in the 1950s and 1960s, but was abandoned after it was linked to significant nephrotoxicity and neurotoxicity and safer antibiotics became available. With the rise of multidrug-resistant strains of bacteria, however, colistin has gained traction as a last-line treatment

To see how this variability plays out in clinical practice, Dr. Vicari and her colleagues retrospectively reviewed the charts of patients with gram-negative bacteremia who were treated with intravenous colistin between January 2005 and August 2010. The investigators included data from 76 patients in their analysis. Microbiological success was defined as clearance of bloodstream infection or documented clinical improvement by day 7. A total of 52 patients achieved microbiological success and 24 patients fell into the failure group, reported Dr. Vicari, who led the study when she was a postgraduate year 2 (PGY2) resident at the Cleveland Clinic, in Ohio. In a univariate analysis, the average colistin dose was significantly higher in the success group than in the failure group (2.90 vs. 1.50 mg/kg per day; P=0.011). The fact

doses achieve [superior rates of ] clinical and/or microbiological success,” Dr. Vicari said, citing at least one study ((Int J Antimicrob Agents 2010;35:194-199).

More Insights Into Nephrotoxicity In the second study presented at SCCM, researchers showed that colistin may be more nephrotoxic than polymyxin B (abstract 759). Darowan Akajagbor, PharmD, BCPS, led the study when she was a PGY2 resident at the University of Maryland Medical Center, in Baltimore. She is now an assistant professor at D’Youville College of Pharmacy, in Buffalo, N.Y., and a critical care pharmacist at Upstate Medical Center in Syracuse, N.Y. In 2009, the University of Maryland Medical Center switched from using polymyxin B to colistin because of a

‘In our study, we did see a higher incidence of nephrotoxicity with colistin. This means our patients should be monitored more closely.’ —Darowan Akajagbor, PharmD, BCPS

option. But there’s a common problem associated with the drug: a knowledge gap regarding its pharmacokinetics, pharmacodynamics and toxicodynamics. That may be part of the reason why there is significant variability in colistin dosing recommendations, according to Giulia Vicari, PharmD, BCPS, a pharmacist at Community Health Network, in Indianapolis, who presented one of the studies at SCCM (abstract 38). Dr. Vicari pointed out, for example, that for a 60-kg person, labeling in the United States recommends 400 to 800 mg per day colistin base activity (CBA), whereas European labeling recommends 240 to 480 mg per day CBA. But sticking to U.S. labeling does not eliminate dosing variability. According to the label, the drug should be given in 2.5 to 5 mg/kg of CBA per day in two to four divided doses in order to achieve maximum concentrations of approximately 2 mg/L. However, the standard treatment recommendations also include provisions for drastic dose reductions in cases of renal dysfunction.

that the average dose in the failure group didn’t even reach the low end of the recommended dose in U.S. labeling was significant, Dr. Vicari noted. “It probably reflects the fact that many of the physicians in the study did drastically reduce doses in the patients with renal dysfunction, as allowed in the drug’s labeling for renally impaired patients,” she said. Colistin dose in milligram-per-kilogram per day based on body weight and the Pitt Bacteremia Score were independent predictors of microbiological outcome at day 7 of colistin therapy (adjusted odds ratio, 1.705; P=0.036). Patients who were alive at seven days (n=61) received significantly higher colistin doses (2.7 mg/kg per day) than patients who did not survive to seven days (n=15; 1.5 mg/kg per day; P=0.007). Roughly one-third of patients experienced acute kidney insufficiency as determined by the RIFLE (Risk, Injury, Failure, Loss, ESRD) criteria: risk (n=10), injury (n=7) and failure (n=10). “Our results are consistent with recent data demonstrating that higher colistin

polymyxin B shortage and because the doctors thought polymyxin B was more nephrotoxic based on anecdotal evidence. The retrospective study examined outcomes of patients treated with either antibiotic who were seen at the medical center between 2008 and 2010. Patients had to be at least 18 years old and to have received polymyxin B or colistin intravenously for at least 72 hours. The RIFLE criteria were used to determine the incidence of nephrotoxicity. The study cohort included 106 patients who had received colistin and 67 patients who were given polymyxin B. Patients who received colistin had higher rates of acute renal failure than patients who received polymyxin B (60.4% vs. 41.8%; P=0.02). To more fully understand the clinical significance for that difference, the investigators drilled a bit deeper into the type of renal dysfunction that was emerging in the colistin group. They found that the majority of the patients with colistin-induced acute renal failure had reversible kidney injury, and only one patient progressed to

end-stage renal disease. Although there was no direct correlation between higher dose and increased risk for nephrotoxicity, a higher percentage of patients receiving more than 5 mg/kg per day (ideal body weight [IBW]) of colistin developed nephrotoxicity. Colistin dosing varied significantly and was calculated based on either weight (IBW or adjusted body weight) or a fixed dose of 150 mg (every eight to 24 hours). “If you look at the literature, there was nothing that told you that one drug is more nephrotoxic than the other,” Dr. Akajagbor said. “In our study, we did see a higher incidence of nephrotoxicity with colistin. This means our patients should be monitored more closely.”

Lessons Learned Douglas Fish, PharmD, BCPS, chair of the Department of Clinical Pharmacy at the University of Colorado Skaggs School of Pharmacy and Pharmaceutical Science, in Aurora, said that the two SCCM studies hold some important clues for dosing colistin in a way that balances safety and efficacy. In the case of Dr. Vicari’s study, he noted, the results suggest that once the decision to use colistin has been made, the dosing should be as aggressive as possible to achieve the best possible efficacy. “Nephrotoxicity will likely occur in a sizable number of patients, especially with higher doses,” he said. “However, if a patient is already being exposed to the risks of drug therapy, the drugs should be dosed in such a way as to maximize the potential benefits.” Because most cases of nephrotoxicity were reversible, achieving clinical success through adequate dosing should be the primary consideration, instead of avoidance of toxicity, Dr. Fish added. As for the University of Maryland Medical Center study, he said clinicians should definitely take the results into account when managing patients. “Whether colistin is truly more nephrotoxic than polymyxin B needs confirmation from other studies, but the 42% nephrotoxicity seen in polymyxin B– treated patients in Dr. Akajagbor’s study still represents an important limitation to the use of the drug,” he said. Dr. Fish added that careful monitoring for nephrotoxicity is required in every patient receiving either of these agents, but especially in higher-risk patients with factors such as advanced age or greater severity of illness, or those with previous renal impairment. —Kate O’Rourke

Drs. Akajagbor, Vicari and Fish reported no relevant financial conflicts of interest.

Rapid sleep induction.

Rapid recovery.

Think you don’t have options for an ultrashortacting anesthetic? Here’s your wake-up call. Brevital® Sodium is the alternative you’ve been looking for. For an updated Preparation and Dosing Guide, visit www.brevital.com/brevitaldosing.pdf Brevital® Sodium is an ultrashort-acting anesthetic indicated in adult and pediatric (>1 month) patients as: An induction agent of anesthesia prior to the use of other general anesthetics Anesthesia for short surgical, diagnostic or therapeutic procedures associated with minimal painful stimuli An adjunct to subpotent inhalational anesthetic agents for short surgical procedures

In adults, when administering intravenously, the onset of action occurs within 30 seconds resulting in rapid sleep induction. The induction dose usually provides anesthesia for 5 to 7 minutes In children, when administering intramuscularly, the onset of action occurs within 2 to 10 minutes; when administered rectally, the onset of action occurs within 5 to 15 minutes Chemically stable for 24 hours at room temperature post reconstitution1 Latex-free, preservative-free and sulfur-free1 formulation Robust Supply

SAFETY INFORMATION

Brevital ® should be used only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory (e.g. pulse oximetry) and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a designated individual other than the practitioner performing the procedure should be present to continuously monitor the patient. Brevital ® Sodium S is contraindicated in patients in whom general anesthesia is contraindicated, in those with latent or manifest f porphyria, or in patients with a known hypersensitivity to barbiturates. Intra-arterial injection of barbiturate solutions can result in necrosis, which may lead to gangrene and possible amputation and thereby should be avoided. Caution should be exercised in debilitated patients or patients with impaired function of respiratory, circulatory, renal, hepatic or endocrine systems and in those with severe anemia or those who are extremely obese. Side effects include but are not limited to circulatory depression, hypotension, respiratory depression (including apnea), skeletal muscle hyperactivity (twitching), seizures, emergence delirium, restlessness, anxiety, nausea, hiccups, emesis, coughing and pain at the injection site. Following massive exposure to any barbiturate, pulmonary edema, circulatory collapse with loss of peripheral vascular tone, and cardiac arrest may occur. How Supplied NDC 42023-105-01 42023-106-01

Name

Strength

Brevital® Sodium 500 mg (methohexital sodium for injection, USP) ®

Brevital Sodium 2.5 gm (methohexital sodium for injection, USP)

References: 1. JHP Pharmaceuticals, Brevital Sodium Prescribing Information. Rochester, MI. January 2009.

Vial Size

Pack Size

50 mL MDV

See Full Prescribing Information

For more information about Brevital, please visit www.brevital.com, or call JHP Customer Service at 877-JHP-4JHP (877-547-4547). MK354A

34 Clinical

Pharmacy Practice News • July 2012

Infectious Disease

HEPATITIS C continued from page 1

open-label study of patients who participated in the peginterferon and ribavirin control arms of Phase II and III studies of boceprevir (Victrelis, Merck) and who failed to achieve SVR. After treatment with the triple-drug regimen, SVR was achieved in 40% (19 of 47) of prior null responders (defined as <2 log10 decline in hepatitis C virus [HCV] RNA at treatment week 12 in the prior study), according to the study, which

‘The role you can play as a pharmacist with patients’ adherence to [antiviral] therapy can save their lives.’ —Janet Nguyen, PharmD was presented in Barcelona, Spain at the International Liver Congress/annual meeting of the European Association for the Study of the Liver (EASL). The triple-drug combination also was effective in prior partial responders/relapsers: 68% (62 of 91) of those patients achieved an SVR. The total

proportion of patients in whom SVR was achieved was 59% (81 of 138), noted lead study researcher, Jean-Pierre Bronowicki, MD, PhD, of the University Henri Poincare of Nancy, in Vandoeuvreples-Nancy, France. Seven percent of patients discontinued treatment due to adverse events; 48% had anemia, 34%

had dysgeusia and 22% had neutropenia, Dr. Bronowicki reported. The degree of interferon responsiveness after lead-in with peginterferon and ribavirin correlated with prior response and could help predict SVR for prior null responders, the researchers concluded. Although impressed with the results, Dr. Nguyen offered a few caveats to keep in mind when evaluating the study. First and foremost, she noted, “the sample size is small.” Concerning the null responders who achieved SVR, she said, “This is giving patients a treatment option, but 40% is still low. I would like to see upwards of 60% to 70%.” Nevertheless, she said there was enough evidence “to start acting on it with patients who have tried and failed before. This gives us some data that there could potentially be efficacy.”

More Data on Boceprevir A related study, presented in a poster (1141) at EASL by Cooper et al, addressed the absence of head-tohead clinical trials between boceprevir and telaprevir (Incivek, Vertex). The researchers used an indirect comparison meta-analysis and meta-regression of the current evidence to evaluate the relative efficacy of the two drugs in combination with peginterferonalfa and ribavirin. Included were Phase II and III randomized placebocontrolled trials evaluating the efficacy of boceprevir or telaprevir in adult patients infected with HCV genotype 1; four boceprevir trials and six telaprevir trials met inclusion criteria. No significant differences were found between boceprevir and telaprevir in SVR among treatment-naive patients (relative risk [RR], 1.14; 95% confidence interval [CI], 0.93-1.37; P=0.20) or treatment-experienced patients (RR, 0.80; 95% CI, 0.18-3.45; P=0.30). Nor were there significant differences between boceprevir and telaprevir in relapse or in discontinuation of therapy among both groups. Boceprevir and telaprevir were shown to be comparable in efficacy, whether with standard-dose therapy durations or response-guided therapy durations. Among treatmentnaive response-guided patients, telaprevir was associated with increases in rash (RR, 1.43; P=0.01) and pruritus (RR, 1.49; P=0.001), whereas boceprevir was associated with increased neutropenia (RR, 1.46; P=0.05). Asked to comment on the method used in this study, Steven D. Pearson, MD, MSc, FRCP, president of the Institute for Clinical and Economic Review, in Boston, said that it had some merit. “Indirect comparisons can be ‘valid’ if the technique is well done,” he said. “Many coverage decisions require indirect comparisons. They are more open to question than direct comparisons, but often direct comparisons

Pharmacy Practice News • July 2012

Clinical 35

Infectious Disease are not available or even feasible.” The researchers noted that dosing schedule and side-effect profiles are key factors that allow for differentiation between the drugs—a point echoed by Dr. Nguyen. “Telaprevir has a much easier dosing schedule compared with boceprevir, with a three-month duration [compared with six to eight months for boceprevir] and one less blood draw,” she said. As for side effects, she noted that the study “called out the most significant [adverse reactions]—rash for telaprevir and neutropenia for boceprevir.”

METOCLOPRAMIDE continued from page 9

direct effect of metoclopramide on the heart may be found in the structural similarity of metoclopramide with procainamide; metoclopramide differs from procainamide by only a 2,5 aryl substitution.1 Procainamide prolongs AV conduction and may produce tachycardia and peripheral vasodilation. Procainamide and cholinergic stimulation, in general, have long been known to cause sinus arrest.9 Metoclopramide also is structurally related to cisapride (Janssen; withdrawn from the market), which is known to trigger tachycardia and SVT through stimulation of 5-HT4 atrial receptors. The cardiotoxic potential of cisapride is mainly due to QT prolongation and development of torsades de pointes. This effect was deemed especially problematic in patients concomitantly treated with drugs known to inhibit the cytochrome P450 (CYP)3A4 isoenzyme.29,30 As recently as 5 years ago, a new metabolic pathway for metoclopramide, involving the CYP2D6 isoenzyme, was identified.31 Whether or not the cardiovascular AEs of metoclopramide also can be linked to the CYP isoenzymes is unknown. Cardiovascular AEs of metoclopramide are rare, but some can be fatal. It is recommended that patients be monitored for cardiovascular AEs immediately after receiving IV metoclopramide. It also is appropriate to warn against rapid IV injection, especially via the central venous route. Due to cardiovascular risks associated with the use of IV metoclopramide, recommendations are provided in the Table.

References 1. Package insert. Metoclopramide Injection, U.S.P. Deerfield, IL: Baxter Healthcare Corporation; April 2010. 2. Shaklai M, Pinkhas J, de Vries A. Metoclopramide and cardiac arrhythmia (letter). Br Med J J. 1974;2(5915):385. 3. Pollera CF, Cognetti F, Nardi M, Mazza D. Sudden death after acute dystonic reaction to high-dose metoclopramide. Lancet. 1984;324(8400):460-461.

•

see METOCLOPRAMIDE, page 36

Helping patients manage those adverse reactions can have a positive effect on compliance, Dr. Nguyen stressed. That in turn can be a cost-saver—“these are expensive drugs,” she noted. “But they have the potential for curing hepatitis C. So the role you can play as a pharmacist with patients’ adherence to therapy can save their lives.” —George Ochoa

Drs. Nguyen and Pearson reported no relevant financial conflicts of interest.

36 Clinical

Pharmacy Practice News • July 2012

Practice Pearl

METOCLOPRAMIDE continued from page 35

4. Withington DE. Dysrhythmias following intravenous metoclopramide. Intensive Care Med. 1986;12(5):378-379. 5. Misis Del Campo M, Garro Martinez P, Mesalles Sanjuán E, Gener Reixac J. [Sinus arrest after the administration of intravenous metoclopramide] (letter). Med Clin (Barc). 2001;117(6):238-239. Spanish. 6. Bentsen G, Stubhaug A. Cardiac arrest after intravenous metoclopramide—a case of five repeated injections of metoclopramide causing five episodes of cardiac arrest. Acta Anaesthesiol Scand. 2002;46(7):908-910.

7. Tung A, Sweitzer B, Cutter T. Cardiac arrest after labetalol and metoclopramide administration in a patient with scleroderma. Anesth Analg. 2002;95(6):1667-1668.

11. Rumore MM. Lee S, Wang S. Metoclopramide-induced cardiac arrest: case report and review of the literature. Clinics and Practice. 2011;1: e83:174-176.

8. Grenier Y, Drolet P. Asystolic cardiac arrest: an unusual reaction following iv metoclopramide. Can J Anaesth. 2003;50(4):333-335.

12. Midttun M, Oberg B. Total heart block after intravenous metoclopramide. Lancet. 1994;343(8890):182-183.

9. Schwartz BG. Metoclopramide and digoxin cause 22 episodes of bradyarrhythmias. Am J Med. 2010;123(6):e5-e6. [Epub 4 June 2010]. doi: 10.1016/j.amjmed.2009.10.01.

13. Maroto Rodríguez B, Jimenez Martin MJ, Rodríguez Aguirregabiria M, Cabezas Martin MH. [Complete atrio-ventricular block from intravenous infusion of metoclopramide]. Med Intensiva. 2006;30(3):124-125. Spanish.

10. Malkoff MD, Ponzillo JJ, Myles GL, Gomez CR, Cruz-Flores S. Sinus arrest after administration of intravenous metoclopramide. Ann Pharmacother. 1995;29(4):381-383.

14. Huerta Blanco R, Hernandez Cabrera M, Quinones Morales I, Cardenes Santana MA. Complete heart block induced by intra-

venous metoclopramide. An Med Interna. 2000;17(4):222-223. 15. Park GR. Hypotension following the intravenous injection of metoclopramide (letter). Anaesthesia. 1981;36(1):75-76. 16. Hughes RL. Hypotension and dysrhythmia following intravenous metoclopramide (letter). Anaesthesia. 1984;39(7):720. 17. Pegg MS. Hypotension following metoclopramide injection (letter). Anaesthesia. 1980; 35(6):615. 18. Park GR. Hypotension following metoclopramide administration during hypotensive anaesthesia for intracranial aneurysm (letter). Br J Anaesth. 1978;50(12):1268-1269. 19. Gupta VK. Recurrent syncope, hypotension, asthma, and migraine with aura: role of metoclopramide. Headache. 2005;45(10):1413-1416. 20. Lau KK, Chan KW, Lok CM, et al. Circulatory collapse in a patient with gastrinoma after metoclopramide administration. Hong Kong Med J. 2009;15(6):478-481. 21. Ellidokuz E, Kaya D. The effect of metoclopramide on QT dynamicity: double-blind, placebo-controlled, cross-over study in healthy male volunteers. Aliment Pharm Ther. 2003;18(1):151-155. 22. Siddique SM, Shariff N, Vesuwala N, Hafiz T. Metoclopramide as a possible cause of prolonged QT syndrome and torsade de pointes in a patient with heart failure and renal insufficiency. Ann Intern Med. 2009;150(7):502-504. 23. Bilgin S, Ustun FE, Eksi A, Sener EB, Kocamanoglu IS, Sarihasan B. The effects of ondansetron and metoclopramide used for postoperative nausea and vomiting prophylaxis on the QT interval. Ondokuz Mayis Universitesi Tip Dergisi. 2008;25:117-124. 24. Bevacqua BK. Supraventricular tachycardia associated with postpartum metoclopramide administration. Anesthesiology. 1988; 68(1): 124-125. 25. Chou CC, Wu D. Torsade de pointes induced by metoclopramide in an elderly woman with preexisting complete left bundle branch block. Chang Gung Med J. 2001;24(12):805-809. 26. Baguley WA, Hay WT, Mackie KP, Cheney FW, Cullen BF. Cardiac dysrhythmias associated with the intravenous administration of ondansetron and metoclopramide. Anesth Analg. 1997;84(6):1380-1381. 27. Ahmad S. Metoclopramide-induced acute congestive heart failure (letter). South Med J. 1991;84(2):283-284. 28. Magnifico F, Pierangeli G, Contin M, Barletta G, Cortelli P. Acute hypotensive effect of metoclopramide in autonomic failure. Clin Auton Res. 1998;8(1):63-72. 29. Tonini M, De Ponti F, Di Nucci A, Crema F. Review article: cardiac adverse effects of gastrointestinal prokinetics. Aliment Pharmacol Ther. 1999;13(12):1585-1591. 30. Ishizahi T, Horai Y. Review article: cytochrome P450 and the metabolism of proton pump inhibitors-emphasis on rabeprazole. Aliment Pharmacol Ther. 1999;13(suppl 3): 27-36. 31. Yu J, Paine MJ, Marechal J, Kemp CA, Ward CJ, Brown S, et al. In silico prediction of drug binding to CYP2D6: identification of a new metabolite of metoclopramide. Drug Metab Dispos. 2006;34(8):1386-1392.

Dr. Rumore reported no relevant financial conflicts of interest.

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Pharmacy Practice News • July 2012

Infectious Disease

Switch to Extended Piperacillin/Tazo Infusion Cuts Cost C “The clinical impact is really only seen in patients with Pseudomonas isolates with an MIC greater than 4 mg/L who are critically ill, and in 2010 there were only eight isolates [meeting that criterion]. So the impact of a switch on clinical outcomes is minimal, but that is because of our patient population. Because we are a community-based teaching hospital, our patients are not as sick as patients in academic hospitals.” The extra work involved in converting to an extended infusion protocol is worth it, he added. “We have now put this into practice. Ultimately, the major impetus for us to make this change was

the cost savings, while maintaining or improving clinical outcomes.”

More Savings from Continuous Infusions Israeli researchers reported similarly favorable results with regard to cost of treatment with continuous P/T infusion. A retrospective study of 99 critically ill patients, led by Yifat Dudik, from Barzilai Medical Center, in Ashkelon, Israel, compared outcomes in 56 patients who received P/T continuously (9 g/150 mL or 13.5 g/150 mL over 24 hours) or intermittently (4.5 g/100 mL every eight hours during 0.5 hours).

Photo credit: CDC.

onverting from intermittent infusions of piperacillin/tazobactam to extended infusions of the antibiotic combination is anticipated to save one community-based teaching hospital nearly $31,000 a year, a new study has shown. The tradeoff is that the switch entails “a fair amount” of extra work, said lead author Timothy Reilly, PharmD, a clinical assistant professor at the Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, in New Brunswick, and a clinical pharmacist at University Medical Center, in Princeton, N.J. Dr. Reilly told Pharmacy Practice News that he and his colleagues had seen clinical trials conducted in academic centers that documented the clinical and financial benefits of extended infusions. In one such study (Clin Infect Dis 2007;44:357-363), the 14-day mortality rate among critically ill patients infected with Pseudomonas aeruginosa who received extended-infusion therapy or intermittent-infusion therapy was 12.2% and 31.6%, respectively ((P=0.04). Median duration of hospital stay was 21 and 38 days, respectively ((P=0.02). To see if those benefits could be obtained at their community-based hospital, a teaching affiliate of the University of Medicine and Dentistry of New Jersey, Dr. Reilly and his colleagues collaborated to determine the changes necessary to implement a successful switch to extended piperacillin/tazobactam (P/T) infusion. The Rutgers team, which included a nurse educator, epidemiologist and pharmacy administrator, assessed all patients who received P/T in 2010 and calculated how much money they would have saved had they used extended infusions compared with intermittent infusions. “The extended infusions allow you to give less drug, so you save about a dose a day,” he explained. They also took into account the costs for protocol development, nursing, pharmacy and physician education, additional compounding and labeling, re-routing of P/T to the IV medication record and increased volumetric pump usage. The study showed that in 2010, 78% of all P. aeruginosa isolates had a minimum inhibitory concentration (MIC) greater than 4 mg/L. Eight of these isolates were obtained from critical care areas. The researchers also found that the hospital spent $110,856 on 11,472 doses of brand and generic P/T. Based on this usage, the researchers calculated they could save at least $30,749.93 per year, which represents a 28% decrease in expenditures for P/T alone, Dr. Reilly said.

Extended infusions of piperacillin/tazobactam in critically ill patients infected with Pseudomonas aeruginosa significantly reduced mortality and the cost of care.

Doripenem in the ICU

xtending the infusion time doesn’t just work for piperacillin/tazobactam; other antibiotics used in the ICU can benefit from the dosing strategy. For example, a study presented at the 2011 ASHP Midyear Clinical Meeting that looked at intermittent versus extended infusions of the ultra-broad spectrum antibiotic doripenem (Doribax, Janssen) among critically ill patients in the ICU found that extended infusion showed a trend toward decreased mortality rates and 30-day readmission rates. The authors note that doripenem exhibits time-dependent bactericidal activity when the concentration of free drug exceeds the minimum inhibitory concentration (MIC) for at least 40% of the dosing interval. Extending the infusion over four hours allows for more time above the MIC and lengthens the duration of active antibiotic concentrations compared with intermittent infusions over 30 minutes, they explained. The investigators compared results in 35 ICU patients who received intermittent doripenem infusions in 2010 with results in 30 ICU patients who received extended infusion doripenem in 2011. They found a trend toward decreased mortality, which went from 34% in 2010 to 23% in 2011. Length of stay also trended downward, at 25.17 days in 2010 compared with 24.87 days in 2011. Readmission rates at 30 days were also lower in the patients who received extended versus intermittent doripenem infusions (17.39% in 2010 vs. 5.77% in 2011). “At a time when there is increasing antimicrobial resistance, we have to keep investigating new ways to optimize the few antibiotics that we have left,” said Mena Abaskharoun, PharmD, from Morristown Memorial Hospital, Morristown, N.J., who led the study. —F. L.

There were no significant differences between the two groups with regard to baseline characteristics. The study found no differences in length of stay, mortality during treatment, length of treatment and clinical outcomes between the two groups. However, use of continuous infusion resulted in a “significant” reduction in rehospitalization and treatment expenditures compared with intermittent infusions. Yet another study has reported similar findings of cost savings with extended P/T infusion. Roy Guharoy, PharmD, MBA, a professor of medicine at University of Massachusetts Medical School and chief pharmacy officer at UMass Memorial Health Care, in Worcester, doumented a 20% reduction in use during the six months after extended infusion of P/T was implemented; this was accompanied by an 18% decrease in pharmacy expenditures. This was achieved without any adverse changes in resistance trends against gram-negative pathogens, Dr. Guharoy said. “Implementation of extended piperacillin/tazobactam went very well; we had no glitches whatsoever,” he told Pharmacy Practice News. “We involved everyone in the process: physicians, pharmacists, nurses and residents. We used intensive education, that’s why it went so well.” Investigations of the pharmacokinetics and pharmacodynamics of extended infusion P/T date back more than 10 years, commented Samantha P. JellinekCohen, PharmD, BCPS, CGP, an assistant clinical professor at St. John’s University and emergency medicine clinical pharmacy specialist at Beth Israel Medical Center, in New York City. “For the β-lactams, it is the duration of exposure that determines the degree of bacterial killing activity. For piperacillin/tazobactam, the goal is to achieve free drug concentrations that exceed the mean inhibitory concentration for 40% to 60% of the dosing interval.” The likelihood of this occurring is greater with extended infusions, increasing the opportunity for a favorable clinical response, she said. “Under the assumption that a change to the extended infusion will improve clinical outcomes,” Dr. Jellinek-Cohen added, “the authors of these two studies also demonstrated that this change can result in significant cost savings for an institution.” —Fran Lowry The studies were first reported at the American Society of Health-System Pharmacists 2011 Midyear Clinical Meeting, in New Orleans.

38 Clinical

Pharmacy Practice News • July 2012

Journal Scan

More Evidence of Pharmacists’ Impact on Diabetes Outcomes From American Journal of Health-System Pharmacy

atients who participated in an employer-sponsored diabetes management program led by pharmacists achieved significant improvements in hemoglobin (Hb) A1c levels and blood pressure, according to a study from Wake Forest University Baptist Medical Center, in Winston-Salem, N.C. (Am ( J Health-Syst Pharm 2012;69:69-73). In the study, researchers conducted a retrospective, chart-based evaluation of HbA1c among 98 first-year partici-

pants in the Health Outcome Partnership for Employees (HOPE) with Diabetes Program who had been enrolled in the program for at least six months. Thirteen participants had type 1 diabetes and 85 participants had type 2. HOPE Program patient visits take place free of charge in the pharmacistdirected ambulatory care clinic at the medical center, and copayments are waived for oral and injectable diabetes medications, glucose testing supplies and prescriptions for angiotensin-converting enzyme inhibitors and angiotensin receptor blockers that are

COMMENTARY Candis M. Morello, PharmD, CDE, FCSHP Associate Professor of Clinical Pharmacy Associate Dean for Student Affairs Skaggs School of Pharmacy and Pharmaceutical Sciences University of California–San Diego San Diego, California

his study demonstrated how diabetes management is a perfect opportunity for pharmacists to use their skills and education. Pharmacists have been collaborating with physicians and other care providers for years, but we’ve finally begun to

document our efforts and show how our involvement affects outcomes. This will help us get recognized as prescribers by Medicare and Medicaid, so that payers will accept pharmacists as care providers for billing purposes.

filled at the health system’s outpatient pharmacy. The average length of enrollment at follow-up was 8.2 months. In that time, the mean HbA1c value among participants decreased from 7.8% at baseline to 7.1% at follow-up (P ( <0.01). Mean systolic blood pressure decreased from 128.8 to 124.9 mm Hg ((P<0.01), and mean diastolic blood pressure dropped from 77.6 to 74.2 mm Hg ((P<0.01). Among the participants, 34 had HbA1c values of at least 8% at enrollment, and they experienced a mean reduction in HbA1c of 1.7 percentage points, from

9.5% to 7.8% ((P<0.01). However, nine of these 34 still had HbA1c values of 8% or higher at follow-up. The team noted that there were reductions in total cholesterol (TC) and triglycerides (TG) among the 92 participants for whom baseline data were available. In this group, the mean TC value dropped from 178.5 to 167.0 mg/dL (P ( <0.01), and the mean TG value decreased from 160.2 to 135.3 mg/ dL ((P=0.02). There were no significant differences in the participants’ high-density lipoprotein cholesterol values, body mass index or weight.

In terms of study design, the baseline HbA1c was a bit on the low side. There were 13 patients with type 1, and although it is not clear from the article, individuals with type 1 diabetes tend to have more finely tuned disease, so that may have contributed to the low mean baseline. The 34 patients with HbA1c values of 8% or higher is more typical of what I see for the general population with diabetes. The drop from 9.5% to 7.8% is tremendous, and speaks to the pharmacists’ impact on outcomes. It is the patients with higher HbA1cs who are most at risk for developing very costly compli-

cations of diabetes, and these are the patients for whom collaborative care between pharmacists and physicians will have the greatest effect. One limitation to the study is that the participants served as their own control group. Having a separate control group of patients who were not enrolled in the HOPE Program would have helped: Comparing outcomes between enrollees and non-enrollees would demonstrate the effect of the program as a whole. The same would be true if the program was compared with one led by physicians or other primary care providers.

degree of familiarity and awareness of autism, medications, resources and common myths associated with the condition. The questionnaire also asked participants about their training regarding autism and confidence in medication management. The team received 147 usable responses, a return rate of 5.8%. After

analyzing the data, the researchers found that 23% of respondents did not know that autism is a developmental disorder, 32% did not believe that genetics has a major role in autism etiology, and 18.4% believe that vaccines can cause autism. More than 90% felt they could benefit from continuing education in the area of autism, and 68% felt there should be an autism course or lecture included in pharmacy school curricula.

pharmacy education will have to start with young pharmacists. I was trained in the 1970s and we didn’t talk about it at all. The only reason I became familiar with it is because my specialty is pediatrics. It was disappointing to see that 18% thought vaccines could cause autism. There is no science for that. [A study appearing in The Lancet in 1998 that suggested an association between the measles-mumps-rubella vaccine and autism was later retracted and declared fraudulent.] This just tells me that we’re no different than the public—we are influenced by com-

mon myths, especially about things for which we don’t have a lot of training. One thing I would suggest the researchers do is follow up with a survey of pharmacy schools to determine what percentage offer education on autism. Pharmacists who want to learn more about autism can approach local community organizations involved with autism, and possibly develop teaching sites where students can learn about the condition. Pharmacists also can work with these organizations and talk to their members about the medications involved in treating people with autism.

Pharmacists Need Help Understanding Autism From Research in Social and Administrative Pharmacy

harmacists may benefit from education about autism, say researchers at the University of Mississippi’s School of Pharmacy. A survey conducted by the team revealed that despite the increased prevalence of autism in the

United States in recent years, many pharmacists are unfamiliar with the condition and its medical management ((Res Soc Adm Pharm 2012 Jan 3. [Epub ahead of print]). Researchers emailed 2,543 pharmacists registered in Mississippi to invite them to participate in a online survey. The survey questionnaire assessed pharmacists’

COMMENTARY James Colbert, PharmD Associate Clinical Professor Associate Dean for Experiential Education Skaggs School of Pharmacy and Pharmaceutical Sciences University of California–San Diego San Diego, California

he first thing I noticed was the response rate, which was less than 6%. However, the design was appropriate and typical of studies where the central component is an online survey. In some ways, the results are not surprising. Autism education is not something that is part of the core curriculum

in pharmacy schools. However, when one considers that autism has been in the forefront of public discussion, and when one looks at the medications involved in managing patients with autism, it is clear it should be part of a pharmacist’s core competency. The push for adding education about autism to

Drs. Morello and Colbert reported no relevant financial conflicts of interest.

—Compiled by Terri D’Arrigo

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40 Policy

Pharmacy Practice News • July 2012

Addiction Medicine ‘We are beginning to see some

DRUG MISUSE

preliminary data indicating that young people’s perception of risk regarding prescription drugs is increasing—an important trend that we hope is a harbinger for declines in abuse.’

continued from page 1

instructions to be flushed, not thrown away; this tragedy indicates that a safety and disposal gap still exists in our homes and hospitals.” The press briefing was timed to occur immediately prior to the DEA’s 2012 prescription drug Take-Back Day. Michele Leonhart, DEA administrator, said that when the first Take-Back Day was held four years ago, 121 tons of expired and/or unused prescription drugs were turned in to thousands of sites nationwide; through 2011, nearly 500 tons of prescription drugs available for potential misuse have been taken out of circulation via this program, she noted. Despite such efforts to remove unused or expired prescription drugs from the community, ready access to the medications remains a major source of abuse, according to a new data analysis presented during the teleconference. For example, more than 70% of the 2.4 million Americans who abuse prescription drugs for the first time each year get them from family and friends; roughly one-third are teenagers, according to the analysis, which was based on 2009-2010 data from the National Survey on Drug Use and Health. About 55% of casual abusers of prescription drugs (less than once a week over the past year) reported getting them for free from family and friends, whereas 11% purchased them from the same individuals. About 5% took them from these sources without permission. Among chronic users (those misusing or abusing pain relievers once a week or more over the past year), roughly 41% obtained prescription drugs from family or friends, with or without permission, whereas 25% reported purchasing them from dealers or the Internet; roughly the same percentage obtained the medications from doctors. Gil Kerlikowske, ONDCP director, said the new data “[show that] prevention is key. Since we know most of these pills are coming from home medicine cabinets, we all have a role to play in properly disposing of the unused, expired or unneeded medications that are available in too many of our homes.”

High Stakes for Gaining A Measure of Control The stakes for eliminating easy access to prescription drugs are high, given the steep rise in abuse of the medications, teleconference speakers stressed. In fact, the current abuse problem is “unprecedented,” noted Ieana Arias, PhD, CDC principal investigator. Dr. Arias related how drug overdose deaths have quadrupled from 10 years ago, and now occur more frequently than

—Gil Kerlikowske, MD

‘There are people going to jail for setting up these pill mills, and they are nothing more than major drug traffickers.’ —Michele Leonhart

‘Fentanyl patches have instructions to be flushed, not thrown away; this tragedy indicates that a safety and disposal gap still exists in our homes and hospitals.’ —Margaret Hamburg, MD

automobile-related fatalities. More than 75% of the prescription drug– related overdoses involve opioids, she said. What’s more, for every 2009 death involving the use of an opioid, there were nine drug rehabilitation admissions, and the annual economic impact now approaches $72 billion. Still, ready access to prescription drugs can’t fully explain the abuse epidemic; there is a wide range of other contributing factors, including the rise of disreputable pain clinics or “pill mills” and pharmacies that are complicit in the filling of prescriptions from those clinics. That’s why the telebriefing participants used the event as an opportunity to highlight the successes of the Obama Administration’s year-old plan to combat the national prescription drug abuse problem on several fronts. The administration’s program includes a strong focus on prescription drug monitoring programs; the development of convenient and environmentally responsible disposal methods; more effective substance abuse treatment; better education for patients and health care providers; law enforcement efforts geared toward shutting down disreputable pain clinics or “pill mills” and reducing diversion and doctor shopping; more effective pharmacy practices; and improved clinical practice through clinical guideline development. The goal, said Dr. Arias, is to “use sci-

ence to inform policy, finding the best practices for prevention and the best models for laws.” At the end of the Obama Administration’s efforts, “I can report that substantial progress has been made,” said Mr. Kerlikowske, citing that online prescription drug databases have been instituted in 48 states. He added that the DEA also has successfully “taken down operators of pill mills through targeted enforcement efforts. And finally, we are beginning to see some preliminary data indicating that young people’s perception of risk regarding prescription drugs is increasing—an important trend that we hope is a harbinger for declines in abuse.” He stressed the continued importance of getting the message out to the public. “Last year, Congress did not fund our media campaign; this year we will try and push forward funding.” Yet according to Mr. Kerlikowske, the efforts to increase awareness of the prescription drug abuse epidemic have put it squarely in the public consciousness, to the point where he has heard accounts of realtors instructing homeowners to lock up the medications in their homes prior to open houses.

‘Whole Supply Chain’ Involved According to Ms. Leonhart, the current prescription drug epidemic is being driven largely by availability and demand, both of which need to be addressed.

“There are people going to jail for setting up these pill mills, and they are nothing more than major drug traffickers,” she said. “If you are breaking the Controlled Substances Act—whether you are a practitioner or drug dealer on the corner—we have ways of catching you.” She stressed that most of the nation’s 1.2 million medical practitioners “do their very best, but a few do not, and it is the DEA’s responsibility to find them.” Ms. Leonhart added that the DEA is “monitoring the whole supply chain, from manufacturers to pharmacists,” and is wholly supportive of state efforts on drug monitoring. “This is all new to a lot of prosecutors,” she said of pill mill and doctor-shopping cases, adding, however, that “the penalties are [in place]; now, it is really about education.”

Not Just Florida For several years, said Ms. Leonhart, Florida was the “national epicenter of pill mills and doctor shopping,” but through DEA efforts like Operation Pill Nation 1 and Operation Pill Nation 2, nearly 100 Florida doctors were caught, and dozens of pill shops were closed. She cited examples of major dealers being apprehended, such as twin brothers in South Florida who were convicted of distributing nearly 20 million oxycodone pills.

•

see DRUG MISUSE, page 45

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9LVLW www.RECOTHROM.com RU VFDQ WKH 45 FRGH ZLWK \RXU VPDU WSKRQH

RECOTHROM is a registered trademark of ZymoGenetics, Inc. Â&#x2039; =\PR*HQHWLFV ,QF $OO ULJKWV UHVHUYHG 57

7KURPELQ PDGH ZLWK D WZLVW RECOTHROM is human thrombin produced using recombinant DNA technology Â˛ ,Q D JHQHWLFDOO\ PRGLĂ&#x20AC;HG &+2 &KLQHVH KDPVWHU RYDU\ FHOO OLQH Q 1RW GHULYHG IURP FDWWOH RU KXPDQ SODVPD Q &RQYHQLHQW DQG HDV\ WR XVH Â˛ 5(&27+520 &RQYHQLHQFH .LWV DOORZ IRU TXLFN DQG HDV\ UHFRQVWLWXWLRQ Q )OH[LEOH SURGXFW OLQH ZLWK PXOWLSOH DSSOLFDWLRQ PHWKRGV Â˛ 0D\ EH DSSOLHG GLUHFWO\ RU LQ FRQMXQFWLRQ ZLWK DEVRUEDEOH JHODWLQ VSRQJH 863

INDICATION RECOTHROM Thrombin, topical (Recombinant) is indicated as an aid to hemostasis whenever oozing blood and minor bleeding from capillaries and small venules is accessible and control of bleeding by standard surgical techniques (such as suture, ligature, or cautery) is ineffective or impractical. IMPORTANT SAFETY INFORMATION Contraindications Â&#x2021; Topical use only â&#x20AC;&#x201C; DO NOT INJECT directly into the circulatory system Â&#x2021; Do not use for the treatment of massive or brisk arterial bleeding Â&#x2021; Do not administer to patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM or hamster proteins Warnings and Precautions Â&#x2021; Potential risk of thrombosis if absorbed systemically Â&#x2021; In patients with known hypersensitivity to snake proteins, there may be a potential for allergic reaction Adverse Reactions Â&#x2021; 7 KH VHULRXV DGYHUVH HYHQW WKDW RFFXUUHG LQ Â&#x2022; Q RI SDWLHQWV H[SRVHG WR 5(&27+520 LQ FRPSOHWHG FOLQLFDO WULDOV ZDV DWULDO ÂžEULOODWLRQ 7KH PRVW FRPPRQ DGYHUVH HYHQWV UHSRUWHG LQ WKHVH WULDOV 1 ZHUH LQFLVLRQ VLWH SDLQ SURFHGXUDO SDLQ DQG QDXVHD $GYHUVH HYHQWV UHSRUWHG LQ WKHVH WULDOV were consistent with those commonly observed in surgical patients Please see Brief Summary of Full Prescribing Information on following page.

44 Policy

Pharmacy Practice News • July 2012

Infectious Disease

SSIs After Joint Surgery Cost Hospitals Millions

significant percentage of patients who develop surgical site infections after hip or knee replacement surgery will be readmitted to the hospital for further complications related to wound infections, new research shows. Preventing such readmissions could save the U.S. health care system as much as $65 million a year, according to research led by Keith Kaye, MD, of Detroit Medical Center/Wayne State

University. Dr. Kaye’s group presented its findings at the 2012 annual meeting of the Association of Professionals in Infection Control and Epidemiology (APIC). The research team analyzed data from 40 million individuals’ health insurance claims. Their goal was to uncover the rate of readmission and the financial effects of surgical site infections (SSIs) beyond the initial treatment of the complications. “The prosthetic joint population was

important to study because these patients are particularly vulnerable to adverse events following [SSIs], leading to unnecessary pain, suffering and medical costs,” Dr. Kaye said. “Given the government’s focus on reducing readmission rates, such complications could likely be a future target for decreased reimbursement.” Of the 174,425 patients in the database who underwent hip or knee replacement in 2007, 1.2% were hospitalized for an

SSI within one year of their procedure. Of those, more than 12% were readmitted in the following year due to SSI-related issues. The average hospital stay for the readmission was 8.6 days, at a cost of approximately $7,000 per patient. In a statement, APIC president Michelle Farber, RN, said, “Infection preventionists need to be familiar with health care quality incentive programs to demonstrate the value of the infection prevention program to the financial health of their organizations and patient experience.” —Maureen Sullivan

New Product Immunogenicity The potential development of antibodies to RECOTHROM has been evaluated in multiple clinical trials. These pre-speciﬁed evaluations were performed in order to characterize the immunogenicity of RECOTHROM and the neutralizing potential of any detected antibodies. In completed clinical studies 5 of 552 (0.9%) patients exposed to RECOTHROM with both baseline and post-treatment antibody specimens available developed speciﬁc anti-RECOTHROM product antibodies. None of these antibodies were found to neutralize native human thrombin.

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BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION RECOTHROM® Thrombin, topical (Recombinant) Rx Only The following is a brief summary of the full prescribing information for RECOTHROM Thrombin, topical (Recombinant). CONTRAINDICATIONS Do not inject directly into the circulatory system. Do not use for the treatment of massive or brisk arterial bleeding. Do not administer to patients with known hypersensitivity to RECOTHROM, any components of RECOTHROM, or hamster proteins. WARNINGS AND PRECAUTIONS Potential risk of thrombosis if absorbed systemically. In patients with known hypersensitivity to snake proteins, there may be a potential for allergic reaction. ADVERSE REACTIONS The serious adverse event that occurred in ≥ 1% (n=6/583) of patients exposed to RECOTHROM in completed clinical trials was atrial ﬁbrillation. The most common adverse events in patients exposed to RECOTHROM in clinical trials (N=583) were incision site pain (51%), procedural pain (30%), and nausea (28%). Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug product cannot be directly compared to rates in the clinical trials of another drug and may not reﬂect the rates observed in clinical practice. Clinical trials have been performed with RECOTHROM applied with absorbable gelatin sponge (Phase 2, Phase 3, and Phase 3b studies) and applied with a spray applicator (Phase 2 study). Adverse events reported in clinical trials were consistent with those commonly observed in surgical patients. Clinical Trials of RECOTHROM Used in Conjunction with Gelatin Sponge Among the 411 patients treated with study drug in the randomized, double-blind, Phase 3 study that compared RECOTHROM to bovine thrombin, both applied with gelatin sponge, in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, all but 2 patients (1 patient/treatment group) reported adverse events. Most events were moderate in severity and had a similar incidence in the RECOTHROM and bovine thrombin treatment groups. The most common adverse events were incision site pain (63% for both treatment groups), procedural pain (RECOTHROM 29%; bovine thrombin 34%), and nausea (RECOTHROM 28%; bovine thrombin 35%). Serious adverse events were reported by 18% of patients treated with RECOTHROM and 22% with bovine thrombin.

In the randomized, double-blind, Phase 3 study that compared RECOTHROM to bovine thrombin, both applied with gelatin sponge, in patients undergoing spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, the development of specific anti-product antibodies was evaluated in both treatment groups. Blood samples were collected at baseline and at day 29 for 97% of the patients in both treatment groups. For patients randomized to RECOTHROM, the samples were analyzed by ELISA for antibodies to RECOTHROM, Chinese hamster ovary (CHO) host cell protein, and pro-thrombin activator (used in the conversion of single chain precursor to active RECOTHROM). For patients randomized to bovine thrombin, the samples were analyzed by ELISA for antibodies to bovine thrombin product. At baseline 1.5% of patients (n=3/198) in the RECOTHROM group had positive anti-product antibody titers compared with 5% of patients in the bovine thrombin group (n=10/200). Of the patients who had detectable anti-product antibodies at baseline, 0 of 3 in the RECOTHROM group and 8 of 10 in the bovine thrombin group exhibited ≥ 1.0 titer unit (≥ 10-fold) increases in antibody levels after study treatment. Treatment with RECOTHROM applied with absorbable gelatin sponge resulted in a statistically significantly lower incidence of specific anti-product antibody development. Three of 198 (1.5%; 95% CI, 0 to 4%) of the patients in the RECOTHROM arm developed specific anti-thrombin product antibodies (1 patient also developed anti-CHO host cell protein antibodies). No patients developed antibodies to pro-thrombin activator. Forty-three of 200 patients (22%; 95% CI, 16 to 28%) in the bovine thrombin arm developed specific antibodies to bovine thrombin product. None of the antibodies in the RECOTHROM group neutralized native human thrombin. Antibodies against bovine thrombin product were not tested for neutralization of native human thrombin. Because the study was not powered to detect a difference in clinical outcomes attributable to antibody formation, no conclusions can be drawn regarding the clinical significance of the difference in antibody formation based on the results of this study. In the open-label, single group, Phase 3b study in patients with a high likelihood of prior bovine thrombin exposure undergoing spinal, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access, 15.6% of patients (n=32/205) had anti-bovine thrombin product antibodies at baseline prior to treatment with RECOTHROM. Following treatment, none of the 200 evaluable patients (patients for whom specimens were available for antibody testing at baseline and post-RECOTHROM treatment) developed antibodies to RECOTHROM. In the randomized, double-blind, controlled Phase 2 studies of RECOTHROM compared to placebo (RECOTHROM excipients reconstituted with 0.9% sodium chloride, USP) applied in conjunction with absorbable gelatin sponge, which were performed across a range of surgical settings (spinal surgery, hepatic resection, peripheral arterial bypass surgery, or arteriovenous graft formation for hemodialysis access), the incidence of antibody development to RECOTHROM was 1.2% in the RECOTHROM group (n=1/83) compared to 2.4% (n=1/41) in the placebo group. In the open-label, single group Phase 2 study of RECOTHROM applied with the spray applicator to excised burn wounds, 1 patient developed antibodies following treatment (1.6%, n=1/62).

Adverse events of interest were pre-speciﬁed, based on the thrombin mechanism of action, use of absorbable gelatin sponge, USP, historical reporting in association with cross-reacting antibodies to bovine thrombin product, and results from Phase 2 clinical trials of RECOTHROM applied with absorbable gelatin sponge. The incidences of these pre-speciﬁed adverse events were similar between treatment groups (see Table 1).

The detection of antibody formation is highly dependent upon the sensitivity and speciﬁcity of the assay. The absolute immunogenicity rates reported here are difﬁcult to compare with results from studies of other products due to differences in assay methodology, patient populations, and other underlying factors.

Table 1. Events of Interest in the RECOTHROM Phase 3 Study

To report p SUSPECTED ADVERSE REACTIONS,, contact ZymoGenetics, y , Inc. at 1-888-784-7662,, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. g

AE Category* Patients with any event category Bleeding Cardiac Hypersensitivity Nausea + vomiting Other infection Post-operative wound infection Thromboembolic

RECOTHROM (N=205) n (%) 124 (60%) 27 (13%) 41 (20%) 30 (15%) 68 (33%) 26 (13%) 19 (9%) 12 (6%)

Thrombin-JMI† (N=206) n (%) 136 (66%) 24 (12%) 38 (18%) 37 (18%) 83 (40%) 31 (15%) 22 (11%) 10 (5%)

Adverse events were included in event categories based on a blinded review of the investigator verbatim and coded terms. † THROMBIN-JMI® Thrombin, Topical (Bovine). In an open-label, single-group Phase 3b study, 209 patients with documented or highly likely prior exposure to bovine thrombin within the previous 3 years were treated with RECOTHROM when undergoing surgeries (spinal or peripheral arterial bypass or arteriovenous graft formation for hemodialysis access). The most common adverse events were incision site pain (45%), procedural pain (39%), and nausea (27%). Similar to the Phase 3 study, serious adverse events were reported by 22% of patients treated with RECOTHROM. Clinical Trials of RECOTHROM Applied with Spray Applicator In an open-label, single-group, Phase 2 study in burn patients, 72 patients were treated with RECOTHROM applied with a spray applicator at the burn wound excision site prior to autologous skin grafting. This study included both adults (≥ 17 years of age, n=68) and pediatric patients ≤ 16 years of age (n=4). The most common adverse events in the adult and pediatric age groups included procedural pain (35%), pruritis (25%), and constipation (19%).

fizer Injectables announced the addition of cytarabine injection to the company’s portfolio of generic oncology products. In March 2012, the FDA approved the abbreviated new drug application for cytarabine injection in the following presentations: 100 mg/5 mL (20 mg/mL) single-dose vials, 500 mg/25 mL (20 mg/mL) multidose vials, 1,000 mg/50 mL (20 mg/mL) pharmacy bulk packages, and 2 g/20 mL (100 mg/mL) single-dose vials. The drug is FDA-approved for remission induction in acute non-lymphocytic leukemia of adults and children. Full prescribing information on cytarabine injection can be accessed at http://www. pfizer.com/products/#cytarabine.

Continuing Education Introducing Online CE from The unSUMMIT for Bedside Barcoding

DRUG INTERACTIONS Drug interactions have not been formally studied. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with RECOTHROM. It is also not known whether RECOTHROM can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. RECOTHROM should be given to a pregnant woman only if clearly needed. Pediatric Use Of the 72 patients undergoing burn wound excision and grafting treated with RECOTHROM applied with the spray applicator in the open-label, single group, Phase 2 study, 4 were pediatric patients. All were age 12 to 16 years. The safety and effectiveness of RECOTHROM in all pediatric age groups have not been fully established. Geriatric Use Of the total number of patients in Phase 2 and Phase 3 clinical studies of RECOTHROM with absorbable gelatin sponge, 38% were 65 years old and over, while 16% were 75 years old and over. No substantive differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identiﬁed differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. For Full Prescribing Information, access www.RECOTHROM.com Manufactured for ZymoGenetics, Inc. RT022-06, January 2011

2012 Summer Session June 27: IV Barcode Workflow Systems: A Best Practice for the Near Future* July 25: BYOD: Mobile Computing Options for BPOC* August 29: Infusion Management: Working Smarter, Not Harder* More information at www.unsummitu.com *Earn 1.0 ACPE hours per session

Policy 45

Pharmacy Practice News • July 2012

Addiction Medicine

DRUG MISUSE

with pharmacies and law enforcement. “Clearly, when you are in the disease of addiction you are going to do almost anything,” said Mr. Kerlikowske. Yet, money plays a major role as well, he said, citing a recent robbery and shooting in a Harlem pharmacy where the perpetrators asked specifically for oxycodone and Percocet. “With street values of $50, $60, $70 and $80 a pill, there is a financial incentive even if you are not involved in the addiction issue, and it is quite concerning and quite frightening to pharmacy staff,” he said.

continued from page 40

Yet although Florida has served as a focal point for the problems of pill mills and doctor shopping, Mr. Kerlikowske stressed that these are issues faced across the country, citing Texas and California as other examples of prescription drug abuse hotbeds. Dr. Hamburg added that the pharmaceutical industry continues to play an important role in diffusing both these issues by developing products “that are less subject to abuse … that serve medical needs but don’t serve the pleasure-oriented goals of [some] end users.” Pharmacy holdups and thefts—like the

quadruple homicide in Long Island last year—are another byproduct of the epidemic, and another focus of the agencies, who are organizing their efforts

Don’t Demonize Opioids Still, the FDA’s Dr. Hamburg stressed that with the strong focus on prevent-

ing the misuse and abuse of prescription drugs, the need for opioid medications for those who suffer from chronic pain must not be lost. “The FDA will continue to work closely with other agencies to help prevent misuse and abuse, while improving the safe utilization of opioids,” she said. “Opioids must continue to be available to those in pain, and combating abuse while still allowing for use is a problem that touches all of us.” —Donald M. Pizzi Film-geek alert: the accompanying art for this story was inspired by the original Italian movie poster for the 1966 Clint Eastwood film, “The Good, the Bad, and the Ugly.”

Not-So-Sweet 16: Mid-teens Most Apt To Start Painkiller Misuse

oung people aged 16 years are at peak risk for initiating misuse of prescription pain relievers—despite previous estimates suggesting that peak risk comes late in high school or soon after.

cal use of prescription pain relievers before the year in which they were surveyed. Extramedical use was defined as use of prescription pain relievers “to get high or for other unapproved indications outside the boundaries set

risk i k estimates i were found f d at ages 12 to 14 years and ages 19 to 21 years. “We suspect that many physicians, other prescribing clini-

In li light h off their h i fi findings, di the authors stressed the need for prevention programs and early outreach timed to midadolescence. “With the

‘Any strict focus on college students or 12th graders might be an example of too little too late in the clinical practice sector and in public health work.’ In a new study ((Arch Pediatr Adolesc Med doi:10.1001/archpediatrics.2012.209), the authors from Michigan State University analyzed 20042008 data from the National Survey on Drug Use and Health, an annual, nationally representative, cross-sectional assessment. They included in their sample 119,877 participants aged 12 to 21 years who self-reported that they had never engaged in extramedi-

by prescribing clinicians.” The sample included both youth in school and youth who had dropped out. Approximately one in 60 young people aged 12 to 21 years started extramedical use of prescription pain relievers, the study found. Peak risk was concentrated at about 16 years, when approximately one in 30 to 40 youth initiated extramedical use (meta-analysis summary estimate, 2.8%). Lower

CONSOLIDATION

likely to lessen those concerns, at least in this specific population.” Still, there are no guidelines stating that G-CSF therapy should be given to alll patients after consolidation, Dr. Bradley pointed out. A report from the American Society of Clinical Oncology on the use of growth factors (http:// jco.ascopubs.org/content/24/19/3187. long) states only that the treatment “can be recommended” after consolidation therapy in AML. “That’s why we saw the need for our study,” she noted. “There really isn’t much consensus on this issue.”

continued from page 25

with patients not given G-CSF (12 vs. 19 days, respectively; P<0.001). The median duration of hospitalization also was significantly shorter in the G-CSF group (24 vs. 27 days; P<0.001). However, several key clinical outcomes did not improve, including the incidence of microbiologically documented infections, two-year disease-free survival and two-year OS rates. Dr. Bradley said she was familiar with the 2000 study and is encouraged that, in her small group of patients, there was “a trend toward improved OS.” She added that those gains are especially promising, given the fact that there has been some concern that G-CSF–type growth factors can stimulate the formation of leukemic blast cells and worsen the course of AML. “Our results are

No Change in Practice? Asked to comment on the poster, Daisy Yang, PharmD, BCOP, clinical pharmacy specialist at the University of Texas MD Anderson Cancer Center, in Houston, said that a large prospective study is needed before any changes are made

cians and public health professionals will share our surprise that for youth in the United States, the peak risk for starting extramedical use of prescription pain relievers generally occurs before the final year of high school, not during the post-secondary school years,” the authors wrote.

peak risk at age 16 years and a notable acceleration in risk between ages 13 and 14 years,” they wrote, “any strict focus on college students or 12th graders might be an example of too little too late in the clinical practice sector and in public health work.” —George Ochoa

‘It is a pretty interesting study and it [was] done fairly well. But I think we need to do some prospective studies to confirm [the results].” —Daisy Yang, PharmD, BCOP in guideline recommendations or other clinical policies. “It is a pretty interesting study and it [was] done fairly well,” Dr. Yang said. “But I think we need to do some prospective studies to confirm [the results].” Dr. Yang added that the study is a good starting point for further discussion on providing growth factor prophylactically to patients with AML who are in remission after intensive chemotherapy. “The authors implied that overall survival seemed to be a little bit longer for patients who received growth factors; however, there are a lot of different

variables that play into that,” she said. In particular, Dr. Yang said she would have liked to see the breakdown on which patients had favorable, intermediate or unfavorable cytogenetic abnormalities. Dr. Bradley agreed that more research is needed. In fact, she noted, UNC investigators are continuing to analyze data from the study, including those pertaining to cytogenetic and other risk factors. —Kate O’Rourke Drs. Bradley and Yang reported no relevant financial conflicts of interest.

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LQ WROYDSWDQ WUHDWHG SDWLHQWV 7DEOH OLVWV WKH DGYHUVH UHDFWLRQV UHSRUWHG LQ WROYDSWDQ WUHDWHG SDWLHQWV ZLWK K\SRQDWUHPLD VHUXP VRGLXP P(T / DQG DW D UDWH DW OHDVW JUHDWHU WKDQ SODFHER WUHDWHG SDWLHQWV LQ WZR GD\ GRXEOH EOLQG SODFHER FRQWUROOHG WULDOV ,Q WKHVH VWXGLHV SDWLHQWV ZHUH H[SRVHG WR WROYDSWDQ VWDUWLQJ GRVH PJ WLWUDWHG WR DQG PJ DV QHHGHG WR UDLVH VHUXP VRGLXP $GYHUVH HYHQWV UHVXOWLQJ LQ GHDWK LQ WKHVH WULDOV ZHUH LQ WROYDSWDQ WUHDWHG SDWLHQWV DQG LQ SODFHER WUHDWHG SDWLHQWV Table 1. Adverse Reactions (>2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials System Organ Class MedDRA Preferred Term

Tolvaptan 15 mg/day-60 mg/day (N = 223) n (%) ( )

Placebo (N = 220) n (%)

Gastrointestinal Disorders 'U\ PRXWK

Constipation

General Disorders and Administration Site Conditions a 7KLUVW

Asthenia

Pyrexia

Metabolism and Nutrition Disorders b +\SHUJO\FHPLD

Anorexia c Renal and Urinary Disorders

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Nursing: $GYLVH SDWLHQWV QRW WR EUHDVWIHHG DQ LQIDQW LI WKH\ DUH WDNLQJ 6$06&$ >VHH 8VH ,Q 6SHFLÂ¿F 3RSXODWLRQV @ )RU PRUH LQIRUPDWLRQ DERXW 6$06&$ FDOO RU JR WR ZZZ VDPVFD FRP 0DQXIDFWXUHG E\ 2WVXND 3KDUPDFHXWLFDO &R /WG 7RN\R -DSDQ 'LVWULEXWHG DQG PDUNHWHG E\ 2WVXND $PHULFD 3KDUPDFHXWLFDO ,QF 5RFNYLOOH 0' SAMSCA is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

UNMET NEED. FILL IT.

FREE VVATER V2

CLEARANCE

Order SAMSCA® (tolvaptan)

15 mg

30 mg

NDC: 59148-020-50

NDC: 59148-021-50

Unique oral treatment for clinically significant hypervolemic and euvolemic hyponatremia

100 %

of physicians surveyed (N=57) would recommend SAMSCA to a colleague 1 In this same survey (patient cases; N=150), physicians were satisﬁed or very satisﬁed with SAMSCA 90% of the time1

Indication and important limitations • SAMSCA is indicated for the treatment of clinically significant hypervolemic and euvolemic hyponatremia (serum sodium <125 mEq/L or less marked hyponatremia that is symptomatic and has resisted correction with fluid restriction), including patients with heart failure, cirrhosis, and Syndrome of Inappropriate Antidiuretic Hormone (SIADH) • Patients requiring intervention to raise serum sodium urgently to prevent or to treat serious neurological symptoms should not be treated with SAMSCA. It has not been established that raising serum sodium with SAMSCA provides a symptomatic benefit to patients

Important safety information SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. Contraindications: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, anuric patients. • Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium or develop neurologic sequelae, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction should generally be avoided during the first 24 hours • Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended • Gastrointestinal bleeding in patients with cirrhosis: Use in cirrhotic patients only when the need to treat outweighs this risk • Avoid use with: CYP 3A inhibitors and CYP 3A inducers. Reduced dose of SAMSCA may be needed if used with P-gp inhibitors • Co-administration with hypertonic saline is not recommended • Monitor serum potassium in patients with levels >5 mEq/L and in those receiving drugs known to increase serum potassium Commonly observed adverse reactions: (SAMSCA vs placebo) thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%). Reference: 1. Market Rx 2010.

For more information about SAMSCA, visit samsca.com or call 1-877-726-7220.

Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the following page. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. Samsca is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

March 2012

0712A-4220K