October 2010 digital edition of Pharmacy Practice News by McMahon Group

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The Pharmacist’s News Source

pharmacypracticenews.com

Volume 37 • Number 10 • October 2010

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1,000 deaths per year spur action

McMahon Publishing

in this issue

Anesthesiology Group Calls for Pharmacists To Boost OR Drug Safety

Up Front

Operations & Mgmt

o improve patient safety in the operating room, a consensus conference convened by the Anesthesia Patient Safety Foundation (APSF) has produced a series of recommendations that could eventually alter how perioperative anesthesia is conducted. Studies have indicated there is one anesthetic medication error in every 133 drugs administered. One in 250 of those errors is fatal. As a result, nearly 1,000 people die in the United States each year from anesthesia medication mistakes. The hope is that implementation of these new standards—one of which includes a more aggressive adoption of pharmacists in the operating room (OR)—will avert dangerous errors in the future. But the campaign to reduce these numbers might require some sacrifices from anesthesiologists.

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Capsules FDA expands warnings on contrast agents.

What motivates your staff? The answer may hold key to effective management.

Gaithersburg, Md.—Ceftaroline, a broad-spectrum cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA), has received an enthusiastic endorsement by the FDA’s AntiInfective Drugs Advisory Committee for the treatment of two indications: community-acquired bacterial pneumonia (CABP) and complicated skin and skin structure infection (cSSSI). The committee voted 21 to 0 in favor of ceftaroline for use in CABP and 18 to 0 in favor of its use in cSSSI. Both votes were unequivocal, with no abstentions. In its New Drug Application (NDA), the sponsor (Cerexa Inc., a wholly owned subsidiary of Forest Laboratories, Inc) presented data from two Phase III trials see CEFTAROLINE, page 44

Lit Review Affirms Impact Of Pharmacist Patient Care

Practice Pearl Medication reconciliation: bringing nurses and pharmacists into the fold.

Clinical

Transplant Medicine Texting, Web-based care plans and other drug compliance tools.

Hem/Onc Pharmacy

Panel Urges Ceftaroline Approval for Pneumonia, Skin Structure Infections

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Results support larger role for the profession

Leadership in Action

see OR DRUG SAFETY, page 42

Unanimous vote for two indications

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Medical isotope shortage nearing end—for now.

Cardiology Pretreatment with statins could be lifesaver for surgery patients.

Educational Reviews

Anesthesia Information Management Systems: Clinical and Operational Impact 15 Managing GI Issues in the Rheumatology Patient on Chronic NSAID Therapy

systematic review of nearly 300 studies demonstrates that pharmacistprovided care improves patient outcomes across several disease states in various settings and has a significant beneficial impact on the rate and severity of adverse drug events (ADEs). The review (Medicare Care 2010;48:923-933), led by Marie A. ChisholmBurns, PharmD, MPH, FASHP, professor and head of the Department of Pharmacy Practice and Science at The University of Arizona College of Pharmacy in Tucson, assessed the effect of pharmacists’ direct patient care on measurements such as hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP). A smaller systematic review, also led by Dr. Chisholm-Burns and appearing in The American Journal of Health-Systems Pharmacy (doi:10.2146/ajhp100077),

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see DIRECT CARE, page 8

ASP Plus 6% Not a Done Deal 2% outpatient payment boost ‘encouraging’ but not guaranteed

ospital pharmacy gained one significant improvement in the 2011 drug reimbursement rates proposed by the Centers for Medicare & Medicaid Services (CMS) for its Hospital Outpatient Prospective Payment System (OPPS). In place of this year’s rate of Average Sales Price (ASP) plus 4% for separately payable drugs, CMS says the methodology it uses to calculate payments should yield a 2011 rate

of ASP plus 6%. The increase would help cover pharmacy overhead costs and bring hospital outpatient drug reimbursement levels into line with those of physician offices. “I have to say I’m cautiously optimistic,” said Timothy Tyler, PharmD, director of pharmacy services at the Desert Regional Medical Center’s Comprehensive Cancer Center in Palm Springs, Calif. “Having spent

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see OUTPATIENT, page 46

New Product Bedford Laboratories now shipping Sumatriptan Succinate Injection in pre-filled syringes. See page

Pharmacy’s Most Dispensed Name… now appearing on our tablets and capsules

We know you trust our products. On average, pharmacists fill 1 out of every 6 prescriptions with a Teva product*. We want patients to share your trust and confidence in Teva. That’s why, over the next few months, you’ll begin to see tablets and capsules imprinted with the Teva name. In some cases, this new Teva imprint will replace the company identifier code. Ultimately, all our capsules and most of our tablets will proudly bear the Teva name. Patients will come to know us better, making your job a little easier every time you confidently dispense quality Teva products.

*data on file, Teva Pharmaceuticals

888 TEVA USA • www.tevausa.com

8618

Up Front 3

Pharmacy Practice News • October 2010

Safety Alert

NSAIDs Increase Stroke Risk STOCKHOLM—Any use of nonsteroidal anti-inflammatory drugs (NSAIDs) may increase the risk for stroke among healthy individuals, according to a study presented at the 2010 European Society of Cardiology Congress. The increased risk was highest with diclofenac and lowest with ibuprofen, reported senior author, Gunnar Gislason, MD, from Gentofte University Hospital,

surf

Hellerup, Denmark. Dr. Gislason and his group previously reported that diclofenac and rofecoxib were associated with increased risk for cardiovascular death (coronary death or nonfatal myocardial infarction, and fatal or nonfatal stroke) in healthy Danes. The increased risk was dose-dependent (Circ Cardiovas Qual Outcomes 2010;3:395-405). In this study, Dr. Gislason and his

OCTOBER 2010

watch

The five most-viewed articles last month on pharmacypracticenews.com: 1. DEA: Propofol Headed for Controlled Substance Schedule 2. Compatibility of Commonly Used IV Drugs [Educational Review] 3. Antimicrobial Efficacy [Educational Review] 4. IVIG Medication Safety: A Stepwise Guide ... [Educational Review] 5. Drug Combination Improves Survival in Pancreatic Cancer Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

MCMAHONMEDICALBOOKS.COM

The Book Page

Clinical Pharmacy in the United States: Transformation of a Profession Robert M. Elenbaas, PharmD, FCCP; Dennis B. Worthen, PhD See page

team, led by Emil L. Fosbøl, MD (Gentofte University Hospital), analyzed cerebrovascular risk. From the entire Danish population of 4,614,807 aged 10 years or older on Jan. 1, 1997, 2,663,706 (57.8%) claimed at least one prescription for NSAIDs during 1997 to 2005. After excluding patients hospitalized within the past five years or prescribed medications within the past two years, they were left with a cohort of 450,792 individuals deemed to be healthy. Any use of NSAIDs was associated with increased risk for fatal or nonfatal stroke. The hazard ratio for ibuprofen was 1.28 (95% confidence interval [CI], 1.14-1.44); for naproxen, 1.35 (95% CI, 1.01-1.79); for rofecoxib, 1.61 (95% CI, 1.14-2.29); for celecoxib, 1.69 (95% CI, 1.11- 2.26) and for diclofenac, 1.86 (95% CI, 1.58-2.19). As in the cardiovascular risk study, the increased risk was dose-dependent. “NSAIDs affect the system in many different ways,” Dr. Fosbøl told Pharmacy Practice News. “The most frequent side effect is still gastrointestinal bleeding, which should be included in the decision chain when starting NSAID treatment.” Naproxen and low-dose ibuprofen show the most neutral cardiovascular safety profile, he added. “However, the risk for upper gastric bleeding should always be incorporated in the decision.” Dr. Fosbøl agreed that the dangers posed by NSAID use are a public health problem. “NSAIDs are sold OTC [over the counter] in many countries and the general perception is they are not harmful.” However, based on the current data, ”some NSAIDs are not suited for

OTC sales [even at lower doses], and those sales should be reevaluated.”

Pharmacists’ Perspective Amy Seybert, PharmD, interim department chair and associate professor, University of Pittsburgh Medical Center, said the new NSAID study data are limited with regard to selection criteria, other medications and comorbidities in the Danish population, which makes it difficult to draw definitive conclusions for the population in the United States. “But, the authors accurately conclude there is a need for more awareness of the risks of NSAIDs,” she said. C. Michael White, PharmD, professor of pharmacy at the University of Connecticut, Storrs, told Pharmacy Practice News that he would have liked to see a number-needed-to-harm calculation. “While the risk in a healthy person might be increased markedly by NSAID use, if 10 million people have to be treated for five years to get one event, then the risk to society is very modest. However, if only 200 people need to be treated, we have an important public health issue.” Pharmacists should have a conversation with patients who are taking chronic NSAIDs about the potential heart and brain risks so patients can make informed choices, he added. “Acetaminophen is heart (and likely brain) risk-neutral and even if you can’t avoid having to take an NSAID every now and again, decreasing the intensity of NSAID dosing or avoiding it from time to time is likely worthwhile.” —Fran Lowry

More ESC news: pages 28, 30

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Volume 37 • Number 10 • October 2010 • pharmacypracticenews.com

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4 Up Front

Pharmacy Practice News • October 2010

Capsules

good month/ bad month for ... Medical marijuana, after researchers from McGill University, in Montreal, reported that smoking weed can yield modest reductions in neuropathic pain. Average daily pain scores in patients who toked the most potent mix fell by 0.7 points on an 11-point scale (5.4 vs. 6.1 in smokers and placebotreated patients, respectively; 95% confidence interval, 0.02-1.4.) Tokers also reported several sleep-related improvements, such as less wakefulness (P=0.01), according to the study (CMAJ 10.1503/cmaj.091414). CPOE systems, after a study in the Archives of Internal Medicine (2010;170:1331-1336) showed that the technology can help reduce the number of potentially inappropriate medications (PIMs) prescribed to hospitalized elderly patients. The system, in use at Beth Deaconess Medical Center, in Boston, issued alerts at the point of care when alternative drugs or dosage adjustments were needed. The mean rate of ordering PIMs dropped from 11.56 to 9.94 orders per day post-implementation (P<0.001). Fondaparinux (Arixtra, GlaxoSmithKline), after a study showed that a side effect of the drug—catheter thrombosis—can be reduced via additional anticoagulation with standard-dose unfractionated heparin in patients undergoing angioplasty. The FUTURA/OASIS-8 trial, reported at the European Society of Cardiology, in Stockholm, found that catheter thrombosis occurred in one of 2,026 (0.1%) patients who were given a standard heparin dose (85 or 60 U/kg), versus five patients (0.5%) given a low, fixed-dose heparin (50 U/kg).

Fish oil supplements, after the Alpha Omega trial showed that lowdose supplementation with eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) failed to reduce cardiovascular disease or the need for cardiac interventions such as angioplasty in 4,837 patients who had suffered a myocardial infarction. Even plant-based supplements largely failed, prompting the authors of the study in The New England Journal of Medicine to write that any benefits from the supplements—at least for patients such as theirs, who were receiving “state-of-the-art” supportive cardiac care—“[are] difficult to prove.” (NEJM 10.1056/ nejmoa1003603) Huber safety needles, after the FDA sent out a safety alert warning that the needles, which are labeled “non-coring,” can in fact produce cores of material when inserted into IV ports. The cores may cause infection, severe tissue damage, swelling and other serious adverse outcomes, according to the agency. As a result of the coring risk, the FDA announced class 1 recalls of Huber safety needles from MultiMed Inc. and Navilyst Medical Inc. (For more details, see http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm198719.htm.) Tigecycline (Tygacil, Pfizer), after a MedWatch alert was issued, warning health care practitioners that the drug’s labeling now includes data on a risk for increased mortality. Patients most at risk were given the IV drug for hospital-acquired pneumonia (an off-label use)—especially ventilator-associated pneumonia. —David Bronstein

by the FDA watch:

Agency Expands Warnings on Labeling For Contrast Agents Due to Kidney Risk N

early four years after the first reports linking gadolinium-based contrast agents (GBCAs) to rare but life-threatening nephrogenic systemic fibrosis (NSF), the FDA is requiring all five manufacturers of the agents to expand NSF warnings on product labeling. Five GBCAs are marketed in the United States: Magnevist, Bayer; MultiHance and ProHance, Bracco Diagnostics; Omniscan, Chalfont; and OptiMark, Mallinckrodt. All include gadolinium, a metal ion that moves predictably within a magnetic field—a trait that makes gadolinium useful for magnetic resonance imaging (MRI). But in patients who have impaired kidney clearance, the metal acccumulates, which is thought to contribute to NSF, according to the FDA. Evidence linking NSF to GBCAs first surfaced in April 2006, when a study on the side effect was published by Grobner et al in Nephrology, Dialysis and Transplantation (2006;21:1104-1108). Then in May 2006, drug safety officials in Denmark issued a press release describing a possible association between NSF and the contrast agents. Both reports documented the side effect in patients with severe renal disease. Spurred by these developments, in 2007, the FDA asked the manufacturers of all five GBCAs to add a boxed warning and a new Warnings section to their products’ labels stating that patients are at risk for NSF if they have severe kidney insufficiency.

That link to severe kidney disease is retained in the expanded labeling announced last month. The revised labeling states that three of the GBCAs most commonly linked to NSF—Omniscan, Magnevist and OptiMark—should not be used in patients with acute kidney injury or with chronic, severe kidney disease (glomerular filtration rate [GFR] <30 mL/ min/1.73 m2). The revised labeling also states that health care professionals should: • Measure GFR in patients who are at risk for chronic kidney dysfunction before administering GBCAs. Examples of at-risk patients are those over 60 years old, patients with high blood pressure and those with diabetes. • Avoid using GBCAs in patients with suspected or known impaired drug clearance, “unless the need for the diagnostic information is essential” and not available via other imaging modalities. • Monitor patients for NSF following GBCA administration. Signs and symptoms of the disease include scaling, hardening and tightening of the skin; red or dark patches on the skin; and joint stiffness. The FDA warned that NSF can be lethal, in many cases due to fibrosis of internal organs. There is no effective treatment for the disorder, according to the agency. —David Bronstein

numbers 298|

30|

The number of studies in a meta-analysis (Am J Health Syst Pharm 2010;67:e20-e30) which showed that pharmacist-provided direct patient care yielded “favorable results” across multiple outcomes, including medication errors, adverse drug events and improvements in blood glucose, blood pressure and cholesterol. (See news article, page 1.) The percent increase in the risk for myocardial infarction that occurs when calcium supplements are taken without vitamin D, according to a new meta-analysis. The results support the theory that calcium supplements may promote vascular calcification and increase mortality in certain patients (BMJ 2010;341:c3691).

percent reduction in patients prescribed 3| The clopidogrel and a proton pump inhibitor at a Texas hospital after publication of an FDA alert on interactions between the two drugs. The slight reduction suggests that prescribing physicians are not heeding the safety alert (Abstract No. 2, ACCP Annual Meeting).

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The percent increase in hospitalizations for septicemia or sepsis in persons aged 65-74 years over a seven-year period (2000 to 2007), according to data in the CDC’s Morbidity and Mortality Weekly Report (2010;59:1108).

21|

The number of unanimous votes cast by an FDA advisory panel in favor of approval for Forest Laboratories’ ceftaroline fosamil, a broad-spectrum injectable cephalosporin. The two indications being sought for the drug are community-acquired bacterial pneumonia and complicated skin and skin structure infections. (See news article, page 1.) —Staff

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Important Safety Information Privigen is indicated for the treatment of patients with primary immunodeficiency (PI) associated with defects in humoral immunity, including but not limited to common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. WARNING: Renal dysfunction, acute renal failure, osmotic nephrosis, and death may be associated with the administration of Immune Globulin Intravenous (Human) (IVIg) products in predisposed patients. Administer IVIg products at the minimum infusion rate possible. Renal dysfunction and acute renal failure occur more commonly in patients receiving IVIg products containing sucrose. Privigen does not contain sucrose. See full Prescribing Information for complete Boxed Warning.

In patients at risk for developing renal failure, monitor urine output and renal function, including blood urea nitrogen and serum creatinine. Thrombotic events have been reported with Privigen and other IVIg treatments. Monitor patients with risk factors for thrombotic events, including a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, and/or known or suspected hyperviscosity. Aseptic meningitis syndrome (AMS) may occur infrequently with Privigen and other IVIg treatments; AMS may occur more frequently with high doses and/or rapid infusion of IVIg. Hemolysis, hemolytic anemia, and pulmonary adverse events have also been reported. There have been reports of noncardiogenic pulmonary edema in patients administered IVIg. If transfusion-related acute lung injury is suspected, test product and patient for antineutrophil antibodies.

Privigen is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin, in patients with hyperprolinemia, and in IgA-deﬁcient patients with antibodies to IgA and a history of hypersensitivity.

Privigen is derived from human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated.

Privigen is manufactured by CSL Behring AG and distributed by CSL Behring LLC. Privigen is a registered trademark of CSL Behring AG.

Please see brief summary of full Prescribing Information on following pages.

In clinical studies, the most common adverse reactions with Privigen were headache, pain, nausea, pyrexia/hyperthermia, fatigue, and chills.

6 Operations & Management

Pharmacy Practice News • October 2010

Leadership in Action

What Motivates Your Employees? R ecently, a reader of Pharmacy Practice News asked me about the role of a pharmacy leader in “developing” others. I shared my belief that it is the responsibility of every manager to develop those they lead. It is part of succession planning and it communicates the fact that you care. It also makes your job more productive and fulfilling, while fostering loyalty and satisfaction among your staff. At Caritas Christi, we have found that

staff development is not only rewarding, but also has created a safer medicationuse process. Why? Because employees are more motivated when they feel that their managers are interested in their success. When an employee’s job is to safely dispense medications, this motivation counts—a lot. It is important to understand what motivates each employee as a unique individual. After all, people differ in their strengths, weaknesses and learn-

ing styles. As such, your communication style should be tailored to all employees who report to you. Reldan Nadler’s book, “Leaders’ Playbook: How to Apply Emotional Intelligence—Keys to Great Leadership” (Santa Barbara, CA: Psyccess Press; 2006) outlines a set of strategies for developing and mentoring others, all of which have practical application in pharmacy. I paraphrase some of these approaches:

CSL Behring BRIEF SUMMARY OF PRESCRIBING INFORMATION

Privigen®, Immune Globulin Intravenous (Human), 10% Liquid Before prescribing, please consult full prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information. WARNING: ACUTE RENAL DYSFUNCTION/FAILURE Use of Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death.1 Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs (see Warnings and Precautions [5.2]). Privigen does not contain sucrose. For patients at risk of renal dysfunction or failure, administer Privigen at the minimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and Precautions [5.2]). 1 INDICATIONS AND USAGE Privigen is an Immune Globulin Intravenous (Human), 10% Liquid indicated for the treatment of the following conditions. 1.1 Primary Humoral Immunodeficiency Privigen is indicated as replacement therapy for primary humoral immunodeficiency (PI). This includes, but is not limited to, the humoral immunodeficiency in common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. 1.2 Chronic Immune Thrombocytopenic Purpura Privigen is indicated for the treatment of patients with chronic immune thrombocytopenic purpura (ITP) to raise platelet counts. 3 DOSAGE FORMS AND STRENGTHS Privigen is a liquid solution containing 10% IgG (0.1 g/mL) for intravenous infusion. 4 CONTRAINDICATIONS Privigen is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. Because it contains the stabilizer L-proline, Privigen is contraindicated in patients with hyperprolinemia. Privigen is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Severe hypersensitivity reactions may occur (see Contraindications [4]). In case of hypersensitivity, discontinue the Privigen infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. Privigen contains trace amounts of IgA ( 25 mcg/mL) (see Description [11]). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Privigen is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction (see Contraindications [4]). 5.2 Renal Failure Ensure that patients are not volume depleted before administering Privigen. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Privigen. For patients judged to be at risk of developing renal dysfunction, administer Privigen at the minimum infusion rate practicable (see Boxed Warning, Dosage and Administration [2.3]). 5.3 Hyperproteinemia Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving Privigen and other IGIV product treatments. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events.2 5.4 Thrombotic Events Thrombotic events may occur following treatment with Privigen and other IGIV products.3-5 Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients judged to be at risk of developing thrombotic events, administer Privigen at the minimum rate of infusion practicable (see Dosage and Administration [2.3]). Weigh the potential risks and benefits of IGIV against those of alternative therapies in all patients for whom Privigen therapy is being considered. 5.5 Aseptic Meningitis Syndrome (AMS) AMS may occur infrequently with Privigen (see Adverse Reactions [6, 6.1]) and other IGIV product treatments. Discontinuation of IGIV treatment has resulted in remission of AMS

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, System Vice President of Pharmacy, Caritas Christi, Boston. Mr. Anderson welcomes your input on leadership issues, at ernest.anderson@ caritaschristi.org.

Ernest R. Anderson Jr., MS, RPh

Hire people with strong Emotional Intelligence. As I interview people for jobs in pharmacy, I always try to “feel out” each candidate’s emotional intelligence. Much of our pharmacy practice is about relationships and teamwork, so people who exhibit a capacity for

within several days without sequelae.6 AMS usually begins within several hours to 2 days following IGIV treatment. AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting (see Patient Counseling Information [17]). Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. 5.6 Hemolysis Privigen may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.7-9 Hemolytic anemia can develop subsequent to Privigen therapy due to enhanced RBC sequestration and/or intravascular RBC destruction.10 Hemolysis, possibly intravascular, occurred in two subjects treated with Privigen in the ITP study (see Adverse Reactions [6, 6.1]). These cases resolved uneventfully. Six other subjects experienced hemolysis in the ITP study as documented from clinical laboratory data. Monitor patients for clinical signs and symptoms of hemolysis (see Patient Counseling Information [17]). If these are present after Privigen infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis. 5.7 Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients following IGIV treatment.11 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment. Monitor patients for pulmonary adverse reactions (see Patient Counseling Information [17]). If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and the patient’s serum. TRALI may be managed using oxygen therapy with adequate ventilatory support. 5.8 Volume Overload The high-dose regimen (1 g/kg/day for 2 days) used to treat patients with chronic ITP is not recommended for individuals with expanded fluid volumes or where fluid volume may be of concern (see Dosage and Administration [2.2]). 5.9 Transmissible Infectious Agents Privigen is made from human plasma. Based on effective donor screening and product manufacturing processes (see Description [11]), Privigen carries an extremely remote risk of transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered to be extremely remote. No cases of transmission of viral diseases or CJD have been associated with the use of Privigen. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare professional to CSL Behring Pharmacovigilance at 1-866-9156958. Before prescribing Privigen, the physician should discuss the risks and benefits of its use with the patient (see Patient Counseling Information [17]). 5.10 Monitoring: Laboratory Tests Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter. Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. If signs and/or symptoms of hemolysis are present after an infusion of Privigen, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum. 5.11 Interference With Laboratory Tests After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test. 6 ADVERSE REACTIONS The most serious adverse reaction observed in clinical study subjects receiving Privigen for PI was hypersensitivity in one subject. The most common adverse reactions observed in >10% of clinical study subjects with PI were headache, pain, nausea, fatigue, and chills. The most serious adverse reactions observed in clinical study subjects receiving Privigen for chronic ITP were aseptic meningitis syndrome in one subject and hemolysis in two subjects. Six other subjects in the ITP study experienced hemolysis as documented from clinical laboratory data (see Warnings and Precautions [5.5, 5.6]). The most common adverse reactions observed in >10% of clinical study subjects with chronic ITP were headache, pyrexia/hyperthermia, and anemia. 6.1 Clinical Trials Experience Because different clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in practice. Treatment of Primary Humoral Immunodeficiency In a prospective, open-label, single-arm, multicenter clinical study, 80 subjects with PI (with a diagnosis of XLA or CVID) received Privigen intravenously every 3 or 4 weeks for up to 12 months (see Clinical Studies [14.1]). All subjects had been on regular IGIV replacement therapy for at least 6 months prior to participating in the study. Subjects ranged in age from 3 to 69; 57.5% were male and 42.5% were female. The safety analysis included all 80 subjects, 16 on the 3-week schedule and 64 on the 4-week schedule. The median doses of Privigen administered intravenously ranged from 200 to 888 mg/kg every 3 weeks (median dose 428.3 mg/kg) or 4 weeks (median dose 440.6 mg/kg). A

Operations & Management 7

Pharmacy Practice News • October 2010

Leadership in Action self-management are most likely to be successful. Careful questions about how candidates have handled past issues elicit answers that are usually good indicators of how they will handle future similar situations. Watch how the candidate thinks on his or her feet in response to your questions. Are they “canned” answers or do they show spontaneity? Once I’ve made a hire, I try to play to the strengths of each individual, in order to give them opportunities for success and personal satisfaction. I also try to create a team in which the different members complement one another.

It is important to understand what motivates each employee as a unique individual, [because] people differ in their strengths, weaknesses and learning styles.’ —Ernest R. Anderson Jr., MS, RPh It is a pleasure to watch people “soar with success,” as Nadler describes it. It reinforces their loyalty and professional development. Nadler (and I) recommend having one-on-one meetings on a regular basis with each staff member. These meetings

total of 1038 infusions of Privigen were administered, 272 in the 3-week schedule and 766 in the 4-week schedule. Of the 1038 infusions, 435 were administered to females and 603 to males. Routine premedication was not allowed. However, subjects who experienced two consecutive infusion-related adverse events (AEs) that were likely to be prevented by premedication were permitted to receive antipyretics, antihistamines, NSAIDs, or antiemetic agents. During the study, 8 (10%) subjects received premedication prior to 51 (4.9%) of the 1038 infusions administered. Temporally associated AEs are those occurring during or within 72 hours after the end of an infusion, irrespective of causality. In this study, the upper bound of the 1-sided 97.5% conﬁdence interval for the proportion of Privigen infusions temporally associated with one or more AEs was 23.8% (actual proportion: 20.8%). This is below the target of 40% for this safety endpoint. The total number of temporally associated AEs was 397 (a rate of 0.38 AEs per infusion), reﬂecting that some subjects experienced more than one AE during the observation period. Table 2 lists the temporally associated AEs that occurred in more than 5% of subjects during a Privigen infusion or within 72 hours after the end of an infusion, irrespective of causality. Table 2: Adverse Events* Occurring in >5% of Subjects With PI During a Privigen Infusion or Within 72 Hours After the End of an infusion, Irrespective of Causality Adverse Event Subjects (%) [n=80] Infusions (%) [n=1038] Headache 35 (43.8) 82 (7.9) Pain 20 (25.0) 44 (4.2) Fatigue 13 (16.3) 27 (2.6) Nausea 10 (12.5) 19 (1.8) Chills 9 (11.3) 15 (1.4) Vomiting 7 (8.8) 13 (1.3) Pyrexia 6 (7.5) 10 (1.0) Cough 5 (6.3) 5 (0.5) Diarrhea 5 (6.3) 5 (0.5) Stomach discomfort 5 (6.3) 5 (0.5) *Excluding infections.

Of the 397 temporally associated AEs reported for the 80 subjects with PI, the investigators judged 192 to be related to the infusion of Privigen (including 5 serious, severe AEs described below). Of the 187 non-serious AEs related to the infusion of Privigen, 91 were mild, 81 were moderate, 14 were severe, and 1 was of unknown severity. The most common temporally associated AEs judged by the investigators to be “at least possibly” related to the infusion were headache (29% of subjects), pain (14% of subjects), nausea (11% of subjects), fatigue (11% of subjects), and chills (11% of subjects). Sixteen subjects (20%) experienced 41 serious AEs. Five of these were related severe AEs (hypersensitivity, chills, fatigue, dizziness, and increased body temperature) that occurred in one subject and resulted in the subject’s withdrawal from the study. Two other subjects withdrew from the study due to AEs related to Privigen treatment (chills and headache in one subject; vomiting in the other). Seventy-seven of the 80 subjects enrolled in this study had a negative direct antiglobulin test (DAT) at baseline. Of these 77 subjects, 36 (46.8%) developed a positive DAT at some time during the study. However, no subjects showed evidence of hemolytic anemia. During this study, no subjects tested positive for infection due to human immunodeﬁciency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or B19 virus (B19V). Treatment of Chronic Immune Thrombocytopenic Purpura In a prospective, open-label, single-arm, multicenter clinical study, 57 subjects with chronic ITP and a platelet count of 20 x 109/L or less received a total of 2 g/kg dose of Privigen administered as 1 g/kg intravenous infusions daily for 2 consecutive days (see Clinical Studies [14.2]). Subjects ranged in age from 15 to 69; 59.6% were female and 40.4% were male. Concomitant medications affecting platelets or other treatments for chronic ITP were not allowed. Thirty-two (56.1%) subjects received premedication with acetaminophen and/or an antihistamine. Table 3 lists the temporally associated AEs that occurred in more than 5% of subjects with chronic ITP during a Privigen infusion or within 72 hours after the end of a treatment cycle (two consecutive infusions) with Privigen, irrespective of causality. Table 3: Adverse Events Occurring in >5% Subjects With Chronic ITP During a Privigen Infusion or Within 72 hours After the End of a Treatment Cycle*, Irrespective of Causality Adverse Event Headache Pyrexia/hyperthermia Nausea Epistaxis Vomiting Blood unconjugated bilirubin increased Blood conjugated bilirubin increased Blood total bilirubin increased Hematocrit decreased

Subjects (%) [n=57] 37 (64.9) 21 (36.8) 6 (10.5) 6 (10.5) 6 (10.5)

Infusions (%) [n=114] 41 (36.0) 22 (19.3) 6 (5.3) 6 (5.3) 6 (5.3)

6 (10.5)

6 (5.3)

5 (8.8)

5 (4.4)

4 (7.0) 3 (5.3)

4 (3.5) 3 (2.6)

can be an opportunity to mentor each individual. Help your team members identify their personal goals and take an interest in their progress toward achieving them. Work to develop high levels of trust by listening and providing honest feedback.

Three subjects experienced three serious AEs, one of which (aseptic meningitis) was related to the infusion of Privigen. One subject withdrew from the study due to gingival bleeding, which was not related to Privigen. Eight subjects, all of whom had a positive DAT, experienced transient drug-related hemolytic reactions, which were associated with elevated bilirubin, elevated lactate dehydrogenase, and a decrease in hemoglobin level within two days after the infusion of Privigen. Two of the eight subjects were clinically anemic but did not require clinical intervention. Four other subjects with active bleeding were reported to have developed anemia without evidence of hemolysis. In this study, there was a decrease in hemoglobin after the first Privigen infusion (median decrease of 1.2 g/dL by Day 8) followed by a return to near baseline by Day 29. Fifty-six of the 57 subjects in this study had a negative DAT at baseline. Of these 56 subjects, 12 (21.4%) developed a positive DAT during the 29-day study period. 6.2 Postmarketing Experience Because postmarketing reporting of adverse events is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. Evaluation and interpretation of these postmarketing reactions is confounded by underlying diagnosis, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance. Privigen Postmarketing Experience Adverse reactions reported during worldwide postmarketing use of Privigen do not differ from what has been observed in clinical studies with Privigen and from what is known for IGIV products. General The following mild to moderate reactions may occur with the administration of IGIV products: headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, skin reactions, wheezing or chest tightness, nausea, vomiting, rigors, back pain, chest pain, myalgia, arthralgia, and changes in blood pressure. Immediate hypersensitivity and anaphylactic reactions are also a possibility. The following adverse reactions have been identified and reported during the post-approval use of IGIV products.12 Renal: Acute renal dysfunction/failure, osmotic nephropathy Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test Musculoskeletal: Back pain Gastrointestinal: Hepatic dysfunction, abdominal pain General/Body as a Whole: Pyrexia, rigors 7 DRUG INTERACTIONS Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, and rubella.13 The immunizing physician should be informed of recent therapy with Privigen so that appropriate measures may be taken (see Patient Counseling Information [17]). 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Privigen. It is not known whether Privigen can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Privigen should be given to pregnant women only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation.14,15 8.3 Nursing Mothers Use of Privigen in nursing mothers has not been evaluated. 8.4 Pediatric Use Treatment of Primary Humoral Immunodeficiency Privigen was evaluated in 31 pediatric subjects (19 children and 12 adolescents) with PI. There were no apparent differences in the safety and efficacy profiles as compared to those in adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. The safety and effectiveness of Privigen have not been established in pediatric patients with PI who are under the age of 3. Treatment of Chronic Immune Thrombocytopenic Purpura Safety and effectiveness of Privigen have not been established in pediatric patients with chronic ITP who are under the age of 15. 8.5 Geriatric Use Clinical studies of Privigen did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Use caution when administering Privigen to patients age 65 and over who are judged to be at increased risk of developing renal insufficiency (see Boxed Warning, Warnings and Precautions [5.2]). Do not exceed recommended doses, and administer Privigen at the minimum infusion rate practicable. Manufactured by: CSL Behring AG Bern, Switzerland

* Two consecutive daily infusions.

Of the 183 temporally associated AEs reported for the 57 subjects with chronic ITP, the investigators judged 150 to be related to the infusion of Privigen (including the one serious AE described below). Of the 149 non-serious AEs related to the infusion of Privigen, 103 were mild, 37 were moderate, and 9 were severe. The most common temporally associated AEs judged by the investigators to be “at least possibly” related to the infusion were headache (65% of subjects) and pyrexia/hyperthermia (35% of subjects).

US License No. 1766 Distributed by: CSL Behring LLC Kankakee, IL 60901 USA

Based on November 2009 revision.

Circles of Influence. Stephen R. Covey, in his book “The Seven Habits of Highly Effective People” (New York, NY: Simon and Schuster; 1989), describes what he calls a “circle of influence.” The concept is to identify the set (or circle) of things we can control and focusing our attention on them. Letting go of what we cannot control helps us broaden our spheres of influence, says Covey. Some of the items you may be able to control within your circle of influence might include your group’s time management, its lack of closure regarding problems and solutions, conflict avoidance, lack of focus, poor listening and probably many other issues. You will be most successful if you help employees to identify their own circles of influence, as well. Covey also recommends delegating responsibility and authority to your staff. This empowers people and gives them autonomy. He also notes that you must hold these staff members accountable for the outcomes of their performance, as well. Coaching for Performance. Show each employee that he or she has been “heard” and understood. You can help boost this impression by asking clarifying questions and asking the employee for ideas regarding solutions to problems. After all, they might have been considering an issue long before they brought it to you. You might also ask whether someone wants feedback or just “a listening ear.” Strive to work with each employee to discover solutions and make plans together. Keep in mind that you must take a different approach and leadership style with each individual. It will take some time to discern the right style as you get to know someone. Some staffers may require you to be very direct and detailoriented in giving directions. For others, you may need to be more of a coach— asking about their thoughts and opinions, while gently guiding them. Still another type of individual may do best if you empower them to figure out solutions to problems on his or her own. Have each individual evaluate his or her own performance on a scale of one to 10, and ask them to give input on what it will take to help them move up a notch or two. Work with the individual on specifics in this area and re-evaluate every few months. This self-assessment technique helps employees gain insight into their own performance and makes them feel good about their achievements. (For a self-assessment worksheet, see the Web version of this article on pharmacypracticenews.com.) For me, developing others is the best part of my job. I have several people whom I personally mentor. The satisfaction that comes from watching others grow and develop is exhilarating. I hope that these points will help you find the same level of satisfaction in managing your teams, too.

8 Operations & Management

Pharmacy Practice News â&#x20AC;˘ October 2010

Patient Care 3Nc\_NOYR

DIRECT CARE continued from page 1

examined the economic effects of direct patient care by pharmacists. Although the results were less profound, there is evidence that pharmacist-provided care can have a positive economic effect as well.

Clinical Impact The studies included in the Medical Care review looked at several outcomes, including therapeutic outcomes; humanistic outcomes such as patient quality of life, knowledge and adherence to medication protocols; and safety outcomes such as ADEs and medication errors.. The Arizona team found favorable results in 51.4% to 100% of the studies that reported therapeutic outcomes, depending on how the studies were grouped together for the review. For example, 18 (51.4%) of 35 studies about hospital readmissions reported favorable results for pharmacist-provided care. All seven studies (100%) about eye exams reported favorable results for pharmacistsâ&#x20AC;&#x2122; care. The most frequently reported therapeutic outcomes were BP, LDL-C and HbA1c. Researchers found favorable results for pharmacist-provided care in 50 (84.7%) of the 59 BP studies, 44 (81.5%) of the 54 LDL-C studies and 32 (88.9%) of the 36 HbA1c studies. Results for several other therapeutic outcomes are shown in the Figure. Among studies measuring safety outcomes, the researchers found favorable results in nine (60%) of 15 studies reporting ADEs and nine (81.8%) of 11 studies reporting medication errors. In fact, there was a 47% reduction in the odds of ADEs in settings where pharmacists provided direct patient care as part of a collaborative health care team compared with settings where pharmacists did not provide such care. â&#x20AC;&#x153;Results like this reaffirm the role of the pharmacist in a collaborative care model,â&#x20AC;? said James E. Tisdale, PharmD, FCCP, BCPS, president of the American College of Clinical Pharmacy and professor in the Department of Pharmacy Practice at the Purdue University College of Pharmacy in Indianapolis. â&#x20AC;&#x153;Health care is not a single-professional activityâ&#x20AC;&#x201D; itâ&#x20AC;&#x2122;s not just physicians or nursesâ&#x20AC;&#x201D;and in a changing care system that is moving toward team-based care, without pharmacy itâ&#x20AC;&#x2122;s possible that optimal outcomes may not be achieved.â&#x20AC;? Among studies measuring humanistic outcomes, the Arizona team found favorable results in 26 (48.1%) of 54 studies reporting patient adherence to medication protocol, 20 (57.1%) of 35 studies reporting patient knowledge and 20 (48.8%) of 41 studies reporting patient satisfaction. â&#x20AC;&#x153;The humanistic outcomes are interesting because we donâ&#x20AC;&#x2122;t often see that

in papers like this,â&#x20AC;? said Dr. Tisdale. â&#x20AC;&#x153;But they show the impact our unique training as pharmacists can have on the lives and health of patients.â&#x20AC;?

Economic Impact The economic effects of pharmacistprovided care are somewhat less clear than the clinical effects. In the AJHP review, the team categorized results five ways: Results were â&#x20AC;&#x153;favorableâ&#x20AC;? if a study indicated significant improvement because of pharmacistsâ&#x20AC;&#x2122; interventions or services; â&#x20AC;&#x153;not favorableâ&#x20AC;? if there was significant improvement because of nonpharmacist care, such as in a tradi-

depending on the perspective of the researchers,â&#x20AC;? she said. â&#x20AC;&#x153;In one study, the perspective might be to see how pharmacy services affect a budget. In another, the cost of a drug might be the primary concern. From a consumer point of view, I might be interested in the number of days missed from work because of a specific disease. It all depends on where youâ&#x20AC;&#x2122;re coming from.â&#x20AC;? She added that the studies showing no effect (no significant differences between pharmacistsâ&#x20AC;&#x2122; interventions and those of other health professionals) do not necessarily translate into bad news. â&#x20AC;&#x153;When you consider the cost of running a service, it

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â&#x20AC;&#x2DC;These studies provide a rigorous review of â&#x20AC;Ś outcomes and demonstrate our value as pharmacists. They make a case for pharmacistsâ&#x20AC;&#x2122; expansion as participants in the health care team.â&#x20AC;&#x2122; â&#x20AC;&#x201D;Daniel Cobaugh, PharmD, CAACT, DABAT tional care setting; â&#x20AC;&#x153;mixedâ&#x20AC;? if there were favorable results on one measure but not favorable results or no effect on another; â&#x20AC;&#x153;no effectâ&#x20AC;? if there were no significant differences between pharmacistsâ&#x20AC;&#x2122; interventions and those of another health professional; and â&#x20AC;&#x153;unclearâ&#x20AC;? if the outcome could not be determined based on a studyâ&#x20AC;&#x2122;s data. Results were favorable in 20 (19.9%) of the 126 studies in the review. Among the favorable studies, pharmacistsâ&#x20AC;&#x2122; services resulted in decreased length of stay in hospitals and inpatient facilities for conditions such as infection, HIV and epilepsy. Pharmacy services were associated with significant differences in hospital charges for readmissions and fewer emergency department visits for asthma and heart failure. Pharmacist-provided care reduced copayments for patients with dyslipidemia who converted from simvastatin to lovastatin in a health maintenance organization, and decreased mean direct medical costs by $1,200 to $1,872 per patient per year and cut sick days for one employer group, with estimated increases in productivity of $18,000 annually for employersâ&#x20AC;&#x2122; health plans. Results were mixed in 53 (42.1%) and unclear in 47 (37.3%) of the remaining studies in the review. Six studies (4.8%) found no effect. It makes sense that the results were less clear in the economic review than in the clinical review, said Dr. Chisholm-Burns. â&#x20AC;&#x153;Whereas clinical results are clear cutâ&#x20AC;&#x201D;you want to reduce blood pressure, blood glucose and adverse drug eventsâ&#x20AC;&#x201D;there is more variability in economic results,

might be less expensive for a pharmacy team than for a physicianâ&#x20AC;&#x2122;s team, and the care is no better and no worse,â&#x20AC;? she said. â&#x20AC;&#x153;You want the most cost-effective way to go. If you look at the same car at two different dealers, youâ&#x20AC;&#x2122;re going to buy it from the one who gives you the better price.â&#x20AC;? Dr. Chisholm-Burns noted that all systematic reviews carry a risk for publication bias: There may be unpublished studies on the effects of pharmacist-provided direct patient care. Also, studies showing negative results are less likely to be published. Daniel J. Cobaugh, PharmD, CAACT, DABAT, vice president of the American Society of Health-System Pharmacists (ASHP) Research and Education Foundation in Bethesda, Md. (which provided financial support for the studies), sees a connection between the results of the two reviews. â&#x20AC;&#x153;In terms of cost avoidance, look at adverse drug events,â&#x20AC;? he said. â&#x20AC;&#x153;If you can prevent those, you are more likely to decrease a number of costs, such as a prolonged hospital visit, a readmission or an emergency department visit.â&#x20AC;?

Implications for Pharmacy Practice Dr. Cobaugh said the results of the Arizona teamâ&#x20AC;&#x2122;s work have major implications for pharmacy practice. â&#x20AC;&#x153;It has long been evident in hospitals and health systems that pharmacists can bring benefits to patient care and help ensure the safe and effective use of medications,â&#x20AC;? he said. â&#x20AC;&#x153;These studies provide a rigorous review of the outcomes and demonstrate our value as pharmacists. They make a case for pharmacistsâ&#x20AC;&#x2122; expansion as participants in the health care team.â&#x20AC;?

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Figure. Therapeutic outcomes in studies of pharmacist-provided patient care.

He added that the results will bolster advocacy efforts on behalf of pharmacists and provide a framework for ASHPâ&#x20AC;&#x2122;s Pharmacy Practice Model Initiative, which seeks to establish pharmacists as direct patient care providers. Dr. Chisholm-Burns sees a mission in the results. â&#x20AC;&#x153;By pulling the literature together and doing this review, we came away with some clear, favorable results indicating that pharmacists can make a difference in direct patient care,â&#x20AC;? she said. â&#x20AC;&#x153;Thatâ&#x20AC;&#x2122;s a message I want to get out to the public. I know weâ&#x20AC;&#x2122;ll talk about it within pharmacy, but I want patients to know. I want my grandmother to know that if she goes into the hospital, she should ask to talk to a pharmacist. When consumers start asking for our services, it will show the need and the niche for our role.â&#x20AC;? Dr. Tisdale agrees. â&#x20AC;&#x153;Patients are not as aware of the impact pharmacists can have on their health,â&#x20AC;? he said. â&#x20AC;&#x153;We as pharmacists could do a better job of communicating to patients what we do, and in educating patients as well as other health professionals. Reviews like this will help.â&#x20AC;? â&#x20AC;&#x201D;Terri Dâ&#x20AC;&#x2122;Arrigo

Web Exclusive Bill Jones, RPh, comments on what the Chisholm-Burns study means for pharmacy practice.

pharmacypracticenews.com

WHEN CHOOSING AN IV SEDATIVE

Different situations require different solutions

Precedex : A right ﬁt ®

FOR TODAY’S SEDATION MANAGEMENT PRACTICES

FASTEST GROWING IV SEDATIVE1

DIFFERENT SITUATIONS REQUIRE DIFFERENT SEDATIVE SOLUTIONS The ﬁrst and only alpha2 agonist indicated for sedation2,3 —Nonintubated patients prior to and during surgical and other procedures2 —Intubated and mechanically ventilated patients during treatment in an intensive care setting2 Can be used alone or in combination with other sedatives or opioid analgesics to provide sedation and added patient comfort.2 Should be administered by continuous infusion not to exceed 24 hours.2 Effective for intubated patients not just before—but also during—and after extubation.2 More than 4.5 million vials administered to millions of patients since launch.4

IMPORTANT PRECEDEX SAFETY INFORMATION Clinically signiﬁcant episodes of bradycardia, sinus arrest and hypotension have been associated with Precedex infusion and may necessitate medical intervention. Moderate blood pressure and heart rate reductions should be anticipated when initiating sedation with Precedex. Please see the brief summary of Prescribing Information on adjacent page.

The right ﬁt

FASTEST GROWING IV SEDATIVE1

FOR TODAY’S SEDATION MANAGEMENT PRACTICES

For step-by-step instructions on how to start using Precedex and what to expect, please visit us at www.Precedex.com. Moderate blood pressure and heart rate reductions should be anticipated when initiating sedation with Precedex.2 Clinically signiﬁcant episodes of bradycardia and sinus arrest have occurred in young, healthy volunteers with high vagal tone or with different routes of administration such as rapid intravenous or bolus administration.2 Transient hypertension has been observed primarily during the administration of the loading dose. Treatment has generally not been necessary, although a reduction in loading dose infusion rate may be desirable.2

Hypotension and bradycardia can occur and may necessitate medical intervention such as —Decreasing or stopping Precedex infusion —Increasing rate of IV ﬂuid administration —Elevating lower extremities —Administering pressor agents such as atropine, ephedrine or glycopyrrolate2 Use with caution in patients with advanced heart block or severe ventricular dysfunction.2 The most common adverse effects (incidence >2%) are hypotension, bradycardia and dry mouth.2

Please see the brief summary of Prescribing Information on adjacent page. References: 1. Based on increases in weight of active ingredient sold (either mcg or mg). IMS Health National Sales Perspective 2Q 2009. US nonretail market, all channels injectables. 2. Precedex [package insert]. Lake Forest, IL: Hospira, Inc; 2008. 3. Kamibayashi T, Maze M. Clinical uses of B2-adrenergic agonists. Anesthesiology. 2000;93:1345-1349. 4. Data on file. Hospira, Inc. Hospira, Inc. 275 North Field Drive, Lake Forest, IL 60045 P10-2830 Aug., 10. Printed in the USA.

Advancing Wellness™

For more information on Advancing WellnessTM, contact your Hospira representative at 1-877-9HOSPIRA (1-877-946-7747) or visit www.hospira.com.

10 Operations & Management

Pharmacy Practice News • October 2010

Practice Pearl

Comparing Pharmacists and Nurses in Med Reconciliation Kristi Hysan, PharmD

Diane Pepe, PharmD, BCPS

Table 2. Medication Errors Incurred During the Reconciliation Process

The Medical Center of Aurora Aurora, Colorado

edication reconciliation is a pressing issue in medication safety and has been the target of many national safety programs. For example, the Institute for Healthcare Improvement (IHI) implemented the 5 Million Lives Campaign, challenging hospitals to protect patients from 5 million incidents of medical harm during the 2006 to 2008 period.1 One of the 12 interventions the IHI recommended was to prevent adverse drug events by conducting medication reconciliation. The IHI has found that poor communication of medical information during the transition of care is responsible for as many as 50% of all medication errors that occur in the hospital and 20% of adverse drug events.2 For its part, the American Society of Health-System Pharmacists has devised a medication reconciliation toolkit in an attempt to improve this problem with transition of care.3 The American Medical Association addresses the issue by providing an “AMA My Medications” patient medication card for members to give to their patients.4 Additionally, since 2005, the Joint Commission has made medication reconciliation, specifically accurate and complete reconciliation of medications across the continuum of care, a National Patient Safety Goal.5 However, the Joint Commission has decided not to factor this goal into the accreditation process in 2010 because of the difficulties that the nation’s hospitals are experiencing with medication reconciliation. Although the Commission is holding off on implementing this goal until it is able to gather enough information to recom-

Table 1. Patient Demographics

Patient Population

N=100

Mean age, y

56.3

Male, %

Female, %

Mean LOS, d

3.89

Mean LOS in ICU, da

3.11

Mean time required to interview, min

15.61

English-speaking

97%

Mean LOS in the ICU is calculated only for patients who were admitted to the ICU during their hospital stay.

ICU, intensive care unit; LOS, length of stay

Error: Missing or Incorrect

ED Nurse

Floor Nurse

Pharmacist

Frequency

169

Dose

174

104

Administration

237

150

Incorrect medication

Omissions

376

296

Total points

2,665a

1,993a

80b

P=0.37

P<0.0001

ED, emergency department

An environment of open communication between patients, nurses, pharmacists, and physicians is ideal for medication reconciliation. mend opportunities for improvement, the Commission does recommend that on admission, transfer, and discharge, the patient’s medication history be reviewed and compared with the current regimen for omissions and discrepancies.

Evaluating Pharmacist-led Medication Reconciliation To compare the accuracy and completeness of medication reconciliation by a pharmacist with that of the nursing team, staff at The Medical Center of Aurora, in Colorado, conducted a prospective study of 100 patients aged 18 and older who were admitted to the level II trauma center and were able to respond to questioning (Table 1). The medication history was documented initially by the emergency department (ED) nurse, then by the ED pharmacist, and once the patient was brought to the floor, by the admitting floor nurse. The 3 histories were entered into a Microsoft Access Database and subsequently entered into NCSS Statistical & Power Analysis Software. The initial medication history was taken by the ED nurse and recorded in T-Systems (T-System Inc), a point-ofcare ED information system, to which admitting physicians had access. Once a physician decided to admit a patient, the patient was flagged in T-Systems, and the ED pharmacist was able to speak with patients awaiting beds about their home medications. A reference list of questions was asked of every patient to generate a second history. The pharmacist recorded the information obtained during the interview and entered it into the paper chart in the ED for reference by the admitting physician. Once the patient was brought to the

floor, this history was put into the chart under the “Home Medications” tab, and the floor nurse had immediate access to the information. The floor nurse then performed a third medication history of the patient and entered this information into MediTech (Medical Information Technology Inc.), the hospital-wide electronic medical record. The floor nurses had access to the pharmacist medication history, but only 14% of the nurses used this information. It is not known why only a small percentage of nurses accessed this information; however it may be due to the fact that they were not accustomed to having this pharmacistprovided medication list available. At this point in the process, the ED pharmacist compared all 3 medical records. If there were inconsistencies, the pharmacist would verify the information with the patient, the patient’s family, physician, the community pharmacy, or other sources, and record how the information was obtained. When discrepancies were identified, a point system was designed to place a value on each piece of missing information. The complete omission of a medication and the inclusion of an incorrect medication were each worth 5 points. The omission of a dose, frequency, or last time of administration, were each worth 1 point. A total of 763 medications were reconciled during the 3-month study period. The ED nurses documented an average of 3.87 medications per patient (P<0.0001), the floor nurses an average of 4.18 medications per patient (P<0.0001), and the pharmacist an average of 7.48 medications per patient, (P<0.0001). Omissions were the most common errors that occurred,

with vitamins and over-the-counter medications being omitted most frequently (Tables 2 and 3). The medication with the most total errors was multivitamins, with 48 errors, followed by aspirin with 40 errors, lisinopril with 35 errors, and ibuprofen with 34 errors. When the points were tallied, the ED nurses accrued 2,665 points, the floor nurses 1,993 points, and the pharmacist 80 points. The difference between the ED nurses and the floor nurses was not statistically significant (P=0.37), but the difference between the pharmacist and the ED and floor nurses was (P<0.0001). During the study, pharmacists were significantly more accurate and complete when taking a patient’s medication history. However, there are several factors that could contribute to the significant discrepancy between pharmacist and

•

see RECONCILIATION, page 38

Table 3. Top Medication Classes Omitted During Reconciliation Medication

Omissions

Vitamins

155 a

OTC drugs

NSAIDs

Antihypertensives

Herbals

Inhalers

Minerals

Benzodiazepines

PPIs/H2RAs

Sleep aids

Antihyperglycemics and insulins

Antidepressants

Muscle relaxants

Antihyperlipidemics

All OTC agents except vitamins and minerals, herbal supplements, NSAIDs, and PPIs/H2RAs.

H2RAs, histamine-2 receptor antagonists; NSAIDs, nonsteroidal anti-inflammatory drugs; OTC, over-the-counter; PPIs, proton pump inhibitors

IN TODAY’S

LEAN

ECONOMIC TIMES, MANY OF OUR FAVORITE CHARITIES* ARE LACKING THE FUNDING THEY NEED TO HELP THOSE THEY SERVE. Help them by showing us how you used the LEAN process and Baxter Drug Delivery Products† to successfully reduce waste in your hospital. INTRODUCING

LEAN Excellence Award in Pharmacy from Baxter The LEAN process is one of continuous improvement with a reduction in waste that adds value to everyone associated with your pharmacy. Many of you have applied the principles of LEAN within your pharmacy. Now there is an opportunity to share this information with your colleagues and support your favorite charity* at the same time.

www.pharmacyadvisor.com

This year, ten (10) recipients will be selected to receive a contribution to the charity of their choice ranging from $750 to $1,500. Winners will also be honored at a reception at the 2010 ASHP Midyear Clinical Meeting in Anaheim, California. To learn more about the LEAP Awards, please ask your Baxter representative, log on to www.pharmacyadvisor.com and download the information packet and submission form, or contact Tara Williams at Educational Resource Systems, Inc. 732-842-0202. * Only 501(c)(3) Charitable organizations are eligible to receive the award. Applicants can have no direct relationship with the charity they are nominating to receive the award. Applicants cannot work for any organization afﬁliated with the charity nor have any family members who work for that charity, organization, or Baxter Healthcare Corporation. †

MINI-BAG, MINI-BAG Plus, VIAL-MATE, Liquid Premix and Frozen Premix Medications

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12 Clinical

Pharmacy Practice News • October 2010

Drug Compliance

Texting Boosts Compliance in Organ Transplant Patients T

exting while driving can be a deadly mix. But the electronic prompts may well be a lifesaver in the case of solid organ transplant patients, according to a company that offers a system for sending text messages to the phones of adolescent patients, reminding them to take their immune-suppressing medications. The developer, CareSpeak Communications Inc., recently announced that the system will be in use for a one-year tryout at the pediatric heart transplant program at NewYork-Presbyterian/Morgan Stanley Children’s Hospital. A better method for motivating teens to take their antirejection medications is sorely needed, according to Linda Addonizio, director of the hospital’s heart transplant program. “Despite extensive educational programs for families and pediatric heart transplant recipients, significant medication noncompliance still occurs with alarming frequency, particularly with adolescents, which can prove deadly,” Ms. Addonizio noted in a press release from CareSpeak. “The outlook for longterm survival in noncompliant patients can be as low as 30%, compared to 90% in compliant pediatric heart transplant recipients.” Serge Loncar, chief executive officer of CareSpeak, told Pharmacy Practice News that texting is “the perfect tool” for reaching out to teenagers with drug compliance reminders “because they’re notorious text messagers.” Although CareSpeak does not have any data on the degree to which texts are opened by teens, Mr. Loncar cited data from Neustar, a multiplatform communications provider: The data show that it takes recipients an average of four minutes to open SMS text messages, compared with 48 hours for e-mails. Another benefit: Cell phones “are nearly ubiquitous, and they’re a familiar technology—there’s really no learning curve with this system,” he said. But the texting approach really shines in comparison with pharmacy compliance letters sent home via “snail mail,” Mr. Loncar said. “Our clinical partners tell us that these letters are rarely opened, or if they are, there is no way to track their impact.” With the phone texting system, in contrast, impact can be tracked—and documented in clinical studies. In a Pediatrics study (2009;124:e844-e850) by researchers at Mount Sinai Medical Center, two episodes of organ rejection occurred in liver transplant patients enrolled in the CareSpeak texting program, versus 12 cases of rejection pre-rollout. Edward Y. Zavala, administrator of the transplant center at Vanderbilt University Medical Center in Nashville, Tenn., agreed that the “open” rate for traditional

compliance letters, which are often sent by retail pharmacies, “is probably rather low.” Asked to review the basics of the CareSpeak system, he replied, ‘Texting seems to be supported by good data, and it does take advantage of very easy-touse technology. So this is something we would certainly consider.” The only downside, Mr. Zavala noted, “is something I’ve seen in my own kids—keeping their cell phones charged can be its own compliance challenge. Texts going to a dead phone aren’t

going to be much help to anyone.” In the Pediatrics study, similar problems did emerge: Nearly one-third of the patients had to drop out because they lost their phone privileges or could no longer afford a cell phone. And that’s despite the researchers paying for

‘When you explain to teens that their lives are at stake if they don’t take these medications, that’s a very powerful motivator to keep their cell phones charged and to respond honestly to the text prompts.’ —Serge Loncar

More Compliance Strategies

waku Marfo, PharmD, clinical pharmacy manager, solid organ transplantation at Montefiore Medical Center in New York City, and Edward Y. Zavala, administrator of the transplant center at Vanderbilt University Medical Center in Nashville, Tenn., offered the following strategies for boosting drug compliance in solid organ transplant patients: Start immediately. “We begin educating teens and their parents/caregivers right after the patients come out of surgery,” Dr. Marfo said. “That sends the right message that compliance is critical.” Focus on side effects. Teens are particularly sensitive to side effects and will stop taking their meds if you don’t prepare them for the adverse effects. “We let them know what to expect,” Dr. Marfo said. “It reduces anxiety and they know how to respond.” In the case of weight gain related to prednisone, for example, Dr. Marfo will tell patients they can be placed on a “Quick Taper” regimen, where they are started at a fairly high dose (20 mg) for the first month and then tapered down to 5 mg thereafter. “That approach will limit weight gain and growth inhibition,” Dr. Marfo said. Offer alternatives. Cyclosporine can be problematic because it causes gingival hyperplasia, which is cosmetically unsightly. For patients who are concerned about that side effect, Dr. Marfo noted, a viable option is tacrolimus. Use reminder tools. Dr. Marfo gives all of his transplant patients calendars with a medication sheet that outlines the timing, dose and duration of all drug therapy. Telephone follow-up, e-mails and patient visits all can be used as needed. Mr. Zavala suggests using visual aids as well. At his hospital, they give patients medication guides that have images of every medication they’re taking. “It helps them to distinguish all the different meds they’re taking, and to ensure no errors in dispensing have been made,” he said. Use the Internet. Vanderbilt pharmacists teach patients how to use an Internetbased system called medactionplan.com, a Web site that records a patient’s drug regimens and any subsequent changes made to those regimens. Patients can access the system and schedule e-mail reminders to take and also to refill their medications. Reminders can also be sent to parents, health care providers and other care-givers. “It’s not only a great tool for the patients,” Mr. Zavala said. “It also helps us keep track of what’s going on with their drug therapy.” Offer a compliance contract. Dr. Marfo: “We will go into contract with the patient or caregiver for them to be able to demonstrate being compliant with their medications for at least six months, before we consider them ready to be a bit more independent in managing their disease.” —David Bronstein

the texting charges.

How the System Works

Assuming teens can manage to keep their cell phones, here’s how the CareSpeak system works: Patients or caregivers are sent an SMS text whenever a dose of antirejection medication is scheduled to be taken. “The patient has 15, 30, 45 or 60 minutes, depending on the settings of the system, to respond that he’s taken the medication by sending a coded reply,” Mr. Loncar said. “If he doesn’t reply, then a parent or other caregiver can get an “escalation alert” via text, warning them that there is a problem with compliance. That message has the young patient’s cell phone number embedded in it. By clicking on that number, caregivers can call the child and remind them to take the meds.” Physicians can also get involved. For a snapshot of overall compliance, they can access an online dashboard and view patient self-reported compliance and the number of escalation alerts that were sent, Mr. Loncar added. Clinicians also can receive e-mail reports in case they forget to check the dashboard, he noted. Mr. Loncar said this approach addresses a major challenge when managing organ transplant patients—keeping the continuity-of-care loop intact. “With adolescents, you have a transition of care from parents to child,” he explained. “So you need a tool for reaching these younger patients. Text alerts, in our experience, are the easiest and most effective way to accomplish that.” Kwaku Marfo, PharmD, clinical pharmacy manager, solid organ transplantation at Montefiore Medical Center in New York City, pointed out that although texting may help teens comply with their organ transplant medications, it’s not a fail-safe technology. “Texting that they’ve taken their medication is no guarantee that they’ve actually done so,” he said. Dr. Kwaku’s strategy for ensuring compliance? “We bring teenage patients into the clinic two, three, maybe even four times a week immediately post-transplant. Then we use the direct observation method to make sure they’ve taken their meds.” (For more compliance tips from Dr. Marfo, see sidebar.) Mr. Loncar agreed that the CareSpeak program is not foolproof. But in the Pediatrics study, he noted, blood levels of anti-rejection drugs showed that for at least some patients, it can be effective. Before participation, the standard deviation of tacrolimus in the 41 patients studied was 3.46 g/L. After participation, that fell to 1.37 g/L (P=0.05),

•

see TEXTING, page 14

14 Clinical

Drug Compliance

TEXTING TYGACIL® (tigecycline) Brief Summary See package insert for full Prescribing Information. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556. INDICATIONS AND USAGE TYGACIL is indicated for the treatment of adults with complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillinsusceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis. TYGACIL is indicated for the treatment of adults with complicated intra-abdominal infections caused by Citrobacter freundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros. TYGACIL is indicated for the treatment of adults with community-acquired pneumonia infections caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila. CONTRAINDICATIONS TYGACIL is contraindicated for use in patients who have known hypersensitivity to tigecycline. WARNINGS AND PRECAUTIONS Anaphylaxis/Anaphylactoid Reactions Anaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including TYGACIL, and may be life-threatening. TYGACIL is structurally similar to tetracycline-class antibiotics and should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics. Hepatic Effects Increases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Adverse events may occur after the drug has been discontinued. Mortality Imbalance and Lower Cure Rates in Ventilator-Associated Pneumonia A study of patients with hospital acquired pneumonia failed to demonstrate the efficacy of TYGACIL. In this study, patients were randomized to receive TYGACIL (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received TYGACIL had lower cure rates (47.9% versus 70.1% for the clinically evaluable population) and greater mortality (25/131 [19.1%] versus 14/122 [11.5%]) than the comparator. Use During Pregnancy TYGACIL may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline [see USE IN SPECIFIC POPULATIONS]. Tooth Development The use of TYGACIL during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Results of studies in rats with TYGACIL have shown bone discoloration. TYGACIL should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated. Clostridium difficile-Associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Patients With Intestinal Perforation Caution should be exercised when considering TYGACIL monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with TYGACIL and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/ septic shock. The 6 patients treated with TYGACIL had higher APACHE II scores (median = 13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established. Tetracycline-Class Effects TYGACIL is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACIL. Superinfection As with other antibacterial drugs, use of TYGACIL may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken. Development of Drug-Resistant Bacteria Prescribing TYGACIL in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS 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. In clinical trials, 2514 patients were treated with TYGACIL. TYGACIL was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of treatment-emergent adverse reactions through test of cure reported in 2% of patients in these trials. Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in 2% of Patients Treated in Clinical Studies Body System Adverse Reactions Body as a Whole Abdominal pain Abscess Asthenia Headache Infection Cardiovascular System Phlebitis Digestive System Diarrhea Dyspepsia Nausea Vomiting Hemic and Lymphatic System Anemia Metabolic and Nutritional Alkaline Phosphatase Increased Amylase Increased Bilirubinemia BUN Increased Healing Abnormal Hypoproteinemia SGOT Increasedb SGPT Increasedb Nervous System Dizziness Skin and Appendages Rash

TYGACIL (N=2514)

Comparatorsa (N=2307)

6 3 3 6 8

4 3 2 7 5

12 2 26 18

11 2 13 9

4 3 2 3 4 5 4 5

3 2 1 1 3 3 5 5

Vancomycin/Aztreonam, Imipenem/Cilastatin, Levoﬂoxacin, Linezolid. b LFT abnormalities in TYGACIL-treated patients were reported more frequently in the post therapy period than those in comparator-treated patients, which occurred more often on therapy. In all Phase 3 and 4 studies that included a comparator, death occurred in 3.9% (147/3788) of patients receiving TYGACIL and 2.9% (105/3646) of patients receiving comparator drugs. An increase in all-cause mortality has been observed across phase 3 and 4 clinical studies in TYGACIL treated patients versus comparator. The cause of this increase has not been established. This increase should be considered when selecting among treatment options. (See Table 2.) Table 2. Patients with Adverse Events with Outcome of Death by Infection Type TYGACIL Infection Type

n/N

Approved Indications cSSSI 12/834 cIAI 40/1382 CAP 12/424 Combined 64/2640 Unapproved Indications HAP 65/467 Non-VAPa 40/336 25/131 VAPa RP 11/128 DFI 7/553 Combined 84/1148

n/N

Comparator %

Risk Difference* % (95% CI)

1.4 2.9 2.8 2.4

6/813 27/1393 11/422 44/2628

0.7 1.9 2.6 1.7

0.7 (-0.5, 1.9) 1.0 (-0.3, 2.2) 0.2 (-2.3, 2.7) 0.7 (-0.0, 1.6)

13.9 11.9 19.1 8.6 1.3 7.2

56/467 42/345 14/122 2/43 3/508 61/1018

12.0 12.2 11.5 4.7 0.6 6.0

1.9 (-2.6, 6.4) -0.3 (-5.4, 4.9) 7.6 (-2.0, 16.9) 3.9 (-9.1, 11.6) 0.7 (-0.8, 2.2) 1.2 (-1.0, 3.4)

CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; RP = Resistant pathogens; DFI = Diabetic foot infections. * The difference between the percentage of patients who died in TYGACIL and comparator treatment groups. a These are subgroups of the HAP population. Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis). In comparative clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with TYGACIL (7%) versus comparators (6%). Serious adverse events of sepsis/septic shock were more frequently reported for subjects treated with TYGACIL (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established [see WARNINGS AND PRECAUTIONS]. The most common treatment-emergent adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy. The majority of cases of nausea and vomiting associated with TYGACIL and comparators were either mild or moderate in severity. In patients treated with TYGACIL, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe). In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for TYGACIL and 9% for vancomycin/aztreonam; vomiting incidence was 20% for TYGACIL and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for TYGACIL and 21% for imipenem/cilastatin; vomiting incidence was 20% for TYGACIL and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for TYGACIL and 8% for levofloxacin; vomiting incidence was 16% for TYGACIL and 6% for levofloxacin. Discontinuation from tigecycline was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%). The following adverse reactions were reported infrequently (<2%) in patients receiving TYGACIL in clinical studies: Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis Cardiovascular System: thrombophlebitis Digestive System: anorexia, jaundice, abnormal stools Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia, hyponatremia Special Senses: taste perversion Hemic and Lymphatic System: partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia Skin and Appendages: pruritus Urogenital System: vaginal moniliasis, vaginitis, leukorrhea Post-Marketing Experience The following adverse reactions have been identified during postapproval use of TYGACIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Anaphylaxis/anaphylactoid reactions, acute pancreatitis, hepatic cholestasis, and jaundice. DRUG INTERACTIONS Warfarin Prothrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin [see CLINICAL PHARMACOLOGY (12.3) in full Prescribing Information]. Oral Contraceptives Concurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects—Pregnancy Category D [see WARNINGS AND PRECAUTIONS] Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with slight reductions in fetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively (28 mcg·hr/mL and 6 mcg·hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose. There are no adequate and well-controlled studies of tigecycline in pregnant women. TYGACIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers Results from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TYGACIL is administered to a nursing woman [see WARNINGS AND PRECAUTIONS]. Pediatric Use Safety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of effects on tooth development, use in patients under 8 years of age is not recommended [see WARNINGS AND PRECAUTIONS]. Geriatric Use Of the total number of subjects who received TYGACIL in Phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over. No unexpected overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out. No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg dose of tigecycline [see CLINICAL PHARMACOLOGY (12.3) in full Prescribing Information]. Hepatic Impairment No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response [see CLINICAL PHARMACOLOGY (12.3) and DOSAGE AND ADMINISTRATION (2.2) in full Prescribing Information]. OVERDOSAGE No specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of TYGACIL at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. In single-dose intravenous toxicity studies conducted with tigecycline in mice, the estimated median lethal dose (LD50) was 124 mg/kg in males and 98 mg/kg in females. In rats, the estimated LD50 was 106 mg/kg for both sexes. Tigecycline is not removed in significant quantities by hemodialysis. This Brief Summary is based on TYGACIL direction circular W10521C013 ET01, revised 09/09.

continued from page 12

showing a more consistent presence of therapeutic drug levels as a result of the texting program. As an additional aid, “we also can include an education and motivational component to the program and to the texts,” Mr. Loncar said. “When you explain to teens that their lives are at stake if they don’t take these medications, that’s a very powerful motivator to keep their cell phones charged and to respond honestly to the text prompts.”

What It Costs Mr. Loncar said the cost of the texting program varies, depending on the number and complexity of features included. Educational and motivational messages, for example, come at additional cost. “The basic systems start at about $1 per patient per month,” he said. “That compares pretty favorably to the $2 to $4 it can cost to send a traditional compliance letter to a patient via snail mail.” Plus, he added, multiple texts per day can be sent, versus only one letter per month. “A cell phone is the most personal accessory we carry everywhere. So it’s a much more efficient target for investment in a drug compliance tool.” Currently, hospitals pay for the texting service. But given the cost savings from preventing just one case of organ rejection, “it’s only logical that insurers take a look at this technology and consider paying for it themselves,” he said. As far as future clinical applications of the texting technology, several are in the works, Mr. Loncar noted. Collaborations are planned with “a major” diabetes hospital, for example, “and several other centers of excellence” are looking for help in boosting drug compliance in diabetes, asthma, HIV, congestive heart failure, kidney disease and others.

Hospital Pharmacists Can Help Asked to comment on the role hospital pharmacists might play in promoting use of text-based reminder systems, Mr. Loncar acknowledged that retail pharmacies have been more of a focus for his company. But told of the close-knit relationship between many organ transplant recipients and hospital pharmacists who specialize in transplant medicine, he replied, “That is a very exciting opportunity to pursue.” “Our goal is to connect all of the people in a patient’s circle of care into one seamless experience,” Mr. Loncar said. “If we can give tools such as texting to even more clinicians in that circle of care, whether it’s a hospital pharmacist or other provider, that’s very empowering and an important, ongoing goal.” —David Bronstein

Clinical 15

Pharmacy Practice News • October 2010

Educational Review

Anesthesia Information Management Systems Clinical and Operational Impact JESSE M. EHRENFELD, MD, MPH Department of Anesthesia and Critical Care Massachusetts General Hospital Boston, Massachusetts Dr. Ehrenfeld reports no relevant financial conflicts.

COMMENTARY: BETH SMITH, RPH Operating Room Pharmacy Supervisor Southeast Alabama Medical Center Dothan, Alabama

nesthesia information management systems (AIMS) are rapidly increasing in both their adoption and overall

functionality. This article discusses how AIMS can affect clinical practice in a variety of areas, including direct patient care, financial operations, and departmental management.

When considering how an AIMS can impact your practice, keep in mind that the technology has become much more than a simple automated record keeper. It has been shown to improve patient care and patient outcomes, and, in some cases, impact the financial health of a department.

AIMS in Operation AIMS are a specialized form of electronic health record (EHR) systems that facilitate the collection, storage, and presentation of patient data during the perioperative period. Multiple studies have found that AIMS can improve data collection relative to handwritten records, using a variety of metrics such as completeness and accuracy.2-6 In addition to providing basic record-keeping functions, most AIMS also simplify a variety of management, billing, and quality assurance functions. AIMS typically consist of a combination of hardware and software that interface with intraoperative monitors, and in many cases hospital clinical data repositories or EHRs. Although the primary role of an AIMS is to capture data during the intraoperative phase, most systems have expanded their functionality by also incorporating pre- and postoperative patient information. These data are housed in a robust

relational database that can be accessed simultaneously by multiple users in different locations. Although AIMS have existed in some form for the past 30 years, widespread adoption has been hindered by financial barriers and a perceived lack of value on the part of hospitals. As a result of these hurdles, only an estimated 5% of U.S. operating rooms (ORs) in 2006 had an AIMS.7 Adoption has accelerated recently (44% of academic centers have implemented or are currently planning to implement an AIMS), driven primarily by a need to address increased regulatory reporting requirements and a desire to improve routine clinical documentation.8 Today, AIMS have the potential to affect virtually every function within an anesthesiology department. These areas include clinical practice and patient care, financial operations, management of the OR suite and department, and quality assurance/quality improvement (Table 1).

Clinical Practice and Patient Care The most meaningful benefits of AIMS for both patients and frontline clinicians are likely to be the impact the technology can have on the provision of care. These benefits include opportunities to provide

clinical decision support, enhanced record keeping, better communication among providers, and improved availability of historical records. Clinical Decision Support Clinical decision support, or the provision of tools that allow end users to more effectively accomplish a particular task, is the fastest-growing area within AIMS product development. The overall objective is to assist the clinician in making the best decision possible for the patient, and in following the recommended practices throughout the course of treatment. Although the availability of this feature varies from vendor to vendor, decision support can facilitate both improvements in the quality, and reductions in the cost, of care. The most basic clinical decision support tools offer passive guidance. Examples include support around medication administration, such as providing drug-dosing calculations based on a patient’s weight, age, or creatinine clearance; checking for potential drug interactions based on a patient’s home or inpatient medication list; and reviewing the medical history for known drug allergies. More complex decision support features are designed to actively manage provider behavior by using on-screen pop-up displays or

integrated links to a hospital’s paging system. Examples include simple reminders to dose medications (ie, administer antibiotics prior to surgical incision) or re-dose medications (ie, cefazolin after 6 hours), apply physiologic monitors (ie, place a temperature probe when no temperature data are present), or measure finger-stick glucose values in diabetic patients with no blood sugar concentrations recorded. Much work has been done around enhancing the usability and efficacy of various notification systems, leading to vast improvements over first-generation alerts that often made the AIMS workstation unusable. Several studies in the peerreviewed literature have evaluated and shown the ability of AIMS clinical decision support systems to positively impact patient care in a variety of different areas. Specific examples include a workaround improving prophylactic antibiotic administration rates,9,10 adherence to prescribing guidelines for postoperative nausea prophylaxis,11 proper use of monitor alarm systems,12 and applying appropriate physiologic monitoring during surgery.13,14 A number of groups are developing advanced algorithms to provide point-of-care assistance during

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16 Clinical

Pharmacy Practice News • October 2010

Educational Review

AIMS

continued from page 15

critical intraoperative events. For example, in the event of a chaotic electrocardiogram or disappearance of a pulse oximeter waveform, one prototype system prompts the end user to consider ventricular fibrillation as a diagnostic possibility and then makes available on-screen the appropriate Advanced Cardiac Life Support algorithm. Other systems, which have been proposed but not yet implemented, aim to detect the presence of certain disease states, such as new-onset malignant hyperthermia, with a goal of helping the provider detect and respond to the event more quickly. Enhanced Record Keeping The core feature of all AIMS is their ability to accurately and reliably record intraoperative patient information, including vital signs and key events. This can allow an anesthesiologist to focus on the patient, rather than charting. Furthermore, because of their unflagging ability to faithfully capture physiologic events at high resolution, AIMS are able to facilitate more accurate recording of patient responses to anesthesia.4,15 For example, the minute-by-minute changes shown in the case of an air embolus depicted in Figure 1 would never have been recorded accurately on a handwritten record. Facilitate Communication Among Providers The ability of electronic systems to chart an anesthetic contemporaneously and legibly is another key feature that facilitates communication among providers. This ensures better communication among provider teams, and during transitions in care (ie, handoffs and breaks). Additionally, most AIMS allow end users to communicate with one another through built-in messaging functions that may be linked to hospital pagers, cell phones, and/or secure e-mail accounts. Improve Availability of Historical Records Because AIMS create electronic records that can be accessed simultaneously by different users at multiple locations, they have the ability to improve the availability of historical records. This can be helpful during a number of circumstances. For instance, with a paper system, the original record for a patient who returns to the OR after an initial procedure for a subsequent operation may still be in billing/coding—making

Table 1. Areas That May Be Impacted by Anesthesia Information Management Systems Clinical practice/patient care Clinical decision support Enhance record keeping Facilitate communication among providers Improve availability of historical records Financial operations Improve billing efficiency Enhance revenue capture Facilitate participation in P4P programs Operating room suite management Track operational throughput Manage drug/supply costs Controlled substance accounting Departmental management Case tracking/assignment Ensure compliance with regulatory guidelines Facilitate provider credentialing Staff recall in times of mass casualty/crises Quality assurance/quality improvement Track individual/aggregated provider performance Highlight occult problematic practice patterns Potential for enhanced legal protection P4P, pay-for-performance

that information inaccessible to clinicians in the OR. With an AIMS, historical records can be viewed across multiple workstations obviating the need to search for or borrow old charts. This can greatly improve access to key information, such as a patient’s prior airway management, or hemodynamic response to intraoperative agents.

Financial Operations Although perhaps less meaningful to patients or at the point-of-care in the OR, the impact of an AIMS on the financial operations of a department can be significant. Although the initial direct and ongoing support costs associated with an AIMS installation can easily reach six figures,1 even for

Figure 1. Physiologic events captured by an AIMS during an air embolus.

a small department, there are a number of significant financial opportunities brought about by the installation of AIMS. Depending on the baseline financial performance of a group or hospital, over time these financial advantages may compensate for— or in some cases exceed—the costs associated with maintaining an AIMS. The specific impact on financial operations are summarized in Table 2 and described in depth below. Improve Billing Efficiency There are several ways in which AIMS are able to improve billing efficiency. AIMS can ensure that electronic charts contain all of the necessary elements that are required for billing. This might include the necessary attending physician attestation statements, required billing times (start and end of anesthesia care), and elements needed to calculate base units (anesthesia type, ASA physical status classification, age, etc). This can be accomplished by requiring fields be completed at various points during the case or providing automatic notifications of missing/erroneous information after case completion. This method has been shown to decrease the time cases remain in accounts receivable and the number of unbillable cases.16 In addition to reducing charge lag, AIMS can facilitate the billing process by automatically extracting elements needed to generate a bill (personnel, surgical procedure, patient demographics, anesthetics given, and relevant modifiers such as central line insertions or deliberate hypotension). Because the effort required to prepare data for external processing can be diminished by an AIMS, labor costs are reduced,17 even in departments that contract

with a professional billing service. Furthermore, AIMS can provide automatic concurrency checking to ensure that charts are compliant with all local and national regulatory requirements. Enhance Revenue Capture Another way that AIMS can impact the financial operations of a department is through their ability to enhance revenue capture. This is possible when an AIMS reminds a clinician to complete documentation that allows for complete billing and maximization of revenue opportunities. For example, when one hospital developed an alert that prompted the clinician to sign an arterial line placement attestation statement 15 minutes after the appearance of an arterial waveform in the electronic record, they demonstrated an ability to increase their professional billing by in excess of $40,000 per year because a large number of arterial lines that were not previously being billed for suddenly joined the department’s revenue stream.18 Similar logic is available for central lines, regional blocks, spinal drains, intraoperative echocardiograms, and all other procedures for which a department can bill and obtain reimbursement. Facilitate Participation in Pay-for-Performance Programs In order to participate in various pay-for-performance programs, such as the Centers for Medicare & Medicaid Services (CMS) Physician Quality Reporting Initiative (PQRI), hospitals must provide insurers with the relevant data highlighting the metrics in question. Two such measures that impact the OR in many hospitals are “Timely Administration of Antibiotic Prophylaxis” and “Maintenance

Clinical 17

Pharmacy Practice News • October 2010

Educational Review of Perioperative Normothermia.” In order to participate in these programs, which provide additional reimbursement when certain criteria are met, one must indicate which cases meet the specific criteria associated with the specific metric. For the “Timely Administration of Antibiotic Prophylaxis” PQRI metric, one must report the “percentage of surgical patients aged 18 and older who have an order for a parenteral antibiotic to be given within one hour (if fluoroquinolone or vancomycin, two hours) prior to the surgical incision (or start of procedure when no incision is required) for whom administration of prophylactic antibiotic has been initiated within one hour (if fluoroquinolone or vancomycin, two hours) prior to the surgical incision (or start of procedure when no incision is required).”a An AIMS can greatly simplify obtaining these data, generating a list of compliant and noncompliant cases in a matter of a few minutes using little staff time. However, to gather these data from paper charts is an onerous task at best, and in many circumstances impossible. In addition to facilitating participation in pay-for-performance programs by allowing seamless data extraction, AIMS can help physicians improve their compliance with certain metrics. For example, reminders to provide prophylactic antibiotics can increase compliance with the “Timely Administration” metric.9,10 This is one example of how AIMS can provide the tools not only to track and measure performance, but also to allow clinicians to improve performance. Operating Room Suite Management In addition to serving as intraoperative record-keeping systems, AIMS have the potential to become useful tools to facilitate both OR workflow as well as management of the entire OR suite. A number of institutions have used AIMS to facilitate tracking of operational throughput and management of drug and supply costs, as well as accounting for controlled substances. Tracking Operational Throughput Many AIMS installations are accompanied by real-time status displays. Several different types of displays may be used, including passive status displays (eg, electronic whiteboards), active status displays (eg, notifications sent via text pager or short message service [SMS]), and command displays (eg, notifications that include automatic suggestions about how to proceed). Passive status displays often are located at

Table 2. Impact of AIMS on Financial Operations Allow for clinician improvement on various performance metrics Automatically extract data for billing Enhance revenue capture Ensure chart completion (required elements for billing) Extract and report on P4P metrics (PQRI, etc) Facilitate participation in P4P programs Highlight charting errors (time sequence problems) Improve billing efficiency Provide notifications around missing documentation Push data to third-party billing vendors

Figure 2. Real-time operating room status display.

Reduce charge lag/accounts receivable Reduce labor costs associated with billing operations P4P, pay-for-performance; PQRI, Physician Quality Reporting Initiative

OR control desks, but may also be placed in strategic locations around the OR (such as in anesthesia workrooms or physician lounges). In addition to providing continuously updated scheduling information, at least one study has shown that certain types of displays (command displays) are able to help managers make better decisions.19 At Massachusetts General Hospital (MGH), a custom display using AIMS data was designed and installed in the anesthesia workroom (Figure 2). This display allows anesthesia technicians to track the status of all 51 ORs, and has greatly helped facilitate a decrease in room turnover times. At MGH the technicians also receive automatic alert pages, generated by the AIMS, when cases are ending. Other hospitals have used their AIMS to send automatic notifications regarding patient flow to the OR team. Notifications have ranged from “patient arrived in holding area,” to “patient ready for surgery,” to “next scheduled case cancelled.”

systems also must have access to detailed pharmacy information systems that detail drug costs and vial sizes. This can allow the calculation of both case cost and wastage. When combined with the decision support capabilities of an AIMS, several centers have shown an ability to use AIMS as a cost-containment tool.20 At MGH, a number of AIMS-based efforts have been put into place to guide providers toward using lessexpensive intraoperative medications (eg, isoflurane instead of sevoflurane) with moderate success.21 Controlled Substance Accounting All anesthesia departments need to account for controlled substances, and AIMS are able to assist with those efforts. Although there have been reports of discrepancies between medication entries in AIMS and pharmacy records,22 at least one center has been able to develop a drug-diversion surveillance system that relies on AIMS data.23 This type of controlled substance monitoring is important for a variety of regulatory reasons, as well as because a number of observational studies indicate that death is one of the most common presentations of controlled substance abuse by a resident physician.

Managing Drug/Supply Costs

Departmental Management

Because AIMS have the ability to capture all of the drugs and supplies used for a case, they can be used to calculate the cost of an anesthetic. In order to calculate the costs associated with each case, however, these

Beyond the OR suite itself, AIMS also can impact management functions at the departmental level. One unique example is the managing of hospital staff in times of disaster or mass casualty. Despite the

widespread availability of e-mail, many departments still rely on traditional telephone trees to rapidly communicate mission-critical information—such as a mass casualty incident. At least one center has used its AIMS to create an electronic staff recall system. In this particular center, the AIMS is used as a source of contact information, allowing SMS text messaging to send urgent recall messages to the department.24

The Future of Information Technology in the Operating Room Anesthesia information management systems have the potential to impact individual patients, OR suites, and even entire anesthesia departments. They are rapidly increasing in market penetration, and will become more common across the country as hospitals and departments begin to understand the benefits of having an AIMS installation. The lack of interconnectivity and seamless integration among systems is still a barrier that is not unique to AIMS, but a problem across many types of EHR systems. Although there is a growing movement toward national standards for data sharing and interconnectivity, we are still years away from having plug-andplay systems that can easily share data across systems—either within or outside of a given institution. The provision of increasingly smart alarms will continue, as the

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Hem/Onc Pharmacy

Pharmacy Practice News • October 2010

In Focus

Medical Isotope Shortage Nearing End—For Now T he shortage of technetium-99m (Tc-99m) that has plagued nuclear medicine departments for the past year should be coming to an end soon, because two reactors that are the largest isotope producers in the world have both come back online as of early September. The shortage of Tc-99m, which is used in 80% of all diagnostic and therapeutic procedures that require medical isotopes in the United States, was precipitated by the unexpected shutdown in May

2009 of the National Research Universal Reactor (NRU) in Chalk River, Ontario, Canada, after a heavy water leak. The shortage was compounded last February when the High Flux Reactor (HFR) in Petten, Netherlands, was taken offline for repairs on a cooling water pipe. The NRU reactor went back online in August, and the HFR returned to production on Sept. 9. “The medical world has had to cope with serious shortages of isotopes and long waiting lists for

patients. I’m happy and relieved that this difficult period has come to an end and that we can now focus on working hard to develop new production capacity,” said Fred Verzijlbergen, chairman of the Dutch Association for Nuclear Medicine, in a statement. Tc-99m has two primary uses: bone scans for identifying metastases, and measuring the ejection fraction of the heart in patients who are receiving cardiotoxic chemotherapy.

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The return of the reactors to production does not, of course, ensure an immediate end to the shortage of Tc-99m. “If everything goes according to plan, we should be back to a normal supply of the isotope later this year,” said Kevin Crowley, PhD, director of the Nuclear and Radiation Studies Board at the National Academies. “But they just completed major repairs on these reactors, and it is not unusual to have startup problems.” Jeffrey Norenberg, PharmD, executive director of the National Association of Nuclear Pharmacists (NANP), struck an even more cautionary note. Having the reactors back online “may give us some short-term relief,” he said. “But as long as we’re dependent on nuclear reactors overseas for our radioisotope supply, rather than developing domestic production capacity, we’re just one reactor breakdown away from being right back in crisis mode.” Given the age of those overseas and Canadian reactors, future breakdowns are not just likely, “they’re pretty much guaranteed,” Dr. Norenberg said. He explained that the reactors were designed to last about 25 years, but are now more than 45 years old “and operating well beyond their projected life span.”

Pharmacies Lend Helping Hand Steven Larson, MD, chief of the nuclear medicine service at Memorial SloanKettering Cancer Center, in New York City, said he looked forward to the current shortage lifting. “It’s required a lot of creativity to make sure that patients were seen appropriately for imaging procedures,” he said. Dr. Larson praised the cooperation of commercial suppliers and hospitals to ensure that needed doses of technetium would be available during the shortage. “We have a network of radiopharmacies in the [United States] that supplies most hospital radioactive drugs, and they’re in competition, but they also work very effectively together in a time of shortage to ensure that patient care is not adversely affected,” he said. “If there is excess capacity at one pharmacy, they make it available for another area, even if it’s supplied by a competing pharmacy. It’s quite remarkable, and I think it’s in the nature of this particular modality, because of course you can’t store this stuff. There’s some incentive to use it, even if it’s to help your competitor, because you gain bargaining power for the next shortage.” Even with the cooperation of hospitals and the radiopharmacy network, however, adjustments had to be made in order to stretch the limited supplies of technetium. “Most hospitals, including

Hem/Onc Pharmacy 19

Pharmacy Practice News • October 2010

In Focus ours, took steps to reduce the impact of the shortage by lowering the dose of radiation used by about 15% to 20% for cardiac and bone scanning,” Dr. Larson said. “Also, our nuclear medicine physicians employed other tests instead, for example, thallium-201. Although Tc-99m is the best tracer in terms of giving high-quality images, these tracers [are good enough] so that patient care is not compromised.” A new reactor set to come online in France in 2014 may alleviate production pressures, Dr. Crowley said. (Three other existing reactors—in South Africa, Belgium and France—also produce Tc-99m, although the latter two do not produce at full capacity.) “When it’s up and running, the Jules Horowitz reactor will be producing molybdenum-99 [Tc-99m’s parent isotope], but opening a reactor is not like turning on a switch,” he said. “It takes time to establish production.” Another new reactor in Australia [the Open Pool Australian Lightwater reactor, or OPAL] is producing isotopes as well, “but they are only supplying domestic needs.”

In May 2009, the Chalk River reactor, a source of Tc-99m, was shut down due to safety concerns. It came back online this year, in August.

ing concerns that its provisions barring the export of enriched uranium overseas will potentially constrict an already small supply of Tc-99m.” In the meantime, pharmacies will have

to continue to help hospital colleagues use limited Tc-99m supplies judiciously. “And we’ve done a great job with that,” he stressed. “The supply of Tc-99m has trickled to less than 50% of pre-shortage

levels, yet we’ve been able to address, through efficiency models in the pharmacy—for example, reduced dosing, use of alternative isotopes, etc.—as much as 85% or more of the demand for nuclear medicine. That’s helped us limit any negative impact on patient care.” Nuclear pharmacy suppliers have also done their share, via just-in-time shipping of radioisotopes and other distributive efficiencies, he noted. “It’s really been a team effort.” —Gina Shaw, with additional reporting by David Bronstein

Ready to Use Wherever. Whenever.

Building Domestic Supplies A Crucial Part of the Solution As far as a more lasting solution, Dr. Larson echoed Dr. Norenberg’s call for a domestic supply of Tc-99m. No reactors in America currently make molybdenum-99. Rather, U.S. reactors produce enriched uranium which is then shipped overseas to foreign reactors. Those reactors then use the uranium to produce molybdenum-99 for sale in the United States and other countries. Legislative relief may be at hand. In 2009, the American Medical Isotopes Production Act was introduced. The bill authorizes $163 million for the establishment of a Department of Energy program to support industry and universities in the domestic production of molybdenum-99. It passed the House of Representatives overwhelmingly in December 2009, but has stalled in the Senate. “We, as a medical community, are very anxious to see Congress take effective action to encourage a domestic supply, because long-term we feel this is going to be our best insurance that we won’t have [this] kind of interruption in the future,” Dr. Larson said. “I’m very glad that these reactors have come back online, but they are both aging—nothing lasts forever.” Dr. Norenberg also applauded the bill, adding that efforts are under way to help the legislation gain more traction. “There’s a letter signed by 18 organizations, including the American Pharmacists Association and the NANP, trying to get this bill loose in the Senate,” he said. “Unfortunately, Sen. Kit Bond [R.-Mo.] has put a hold on the bill, cit-

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Hem/Onc Pharmacy

Pharmacy Practice News • October 2010

In Focus Q&A: Laura B. Michaud, PharmD

Weighing the ODAC and FDA Decisions on Avastin I

n late July, the Oncologic Drugs Advisory Committee (ODAC) voted 12 to 1 to recommend removing the advanced breast cancer indication for bevacizumab (Avastin, Genentech). The decision was based on several recent studies, including the AVADO, RIBBON-1 and RIBBON-2 trials, showing that the drug achieved only modest gains in progressionfree survival (PFS), and no increase in overall survival (OS). At press time, the FDA had not yet announced whether it would follow the ODAC’s recommendation to rescind Avastin’s indication as a first-line therapy for metastatic breast cancer. To analyze the issues that will likely impact that decision, Pharmacy Practice News editor David Bronstein interviewed Laura B. Michaud, PharmD, FASHP, BCOP, manager of clinical pharmacy services at The University of Texas M.D. Anderson Cancer Center in Houston.

PPN: How disappointing were the AVADO and RIBBON-1 and RIBBON-2 trial results? Dr. Michaud: Let’s put this in perspec-

tive. In the ECOG E2100 trial that led to bevacizumab’s accelerated approval, researchers reported a 5.5-month increase in PFS; no increase in overall survival was documented. My understanding is that the accelerated approval was conditional—the FDA wanted to see how AVADO, RIBBON-1 and RIBBON-2 panned out. The hope, at the least, was that the PFS gains from E2100 would be reproducible, and at best, that an actual OS increase would be seen. So it was very disappointing to have less than a one-month increase in PFS documented in the later trials, with yet again no increase in OS. Based on the new data, it really looks like E2100 was the outlier; those initial benefits just have not held up. PPN: Obviously, there’s concern over lack of efficacy. But what about adverse reactions?

Dr. Michaud: There again, E2100 has

proven to be an outlier. If you read the study—and remember, this was an openlabel, unblinded study—you’ll see that the investigators didn’t provide data on all side effects. Also, they deemed some deaths to be “unrelated to therapy,” despite the fact that those side effects clearly are known to be associated with bevacizumab (e.g., perforated bowel). As a result, their report underemphasizes the risks associated with this therapy. So I have some doubts about those side-effect results—they really skewed the risk–benefit equation, at least when E2100 was first released and used as the basis for the drug’s accelerated approval.

PPN: Has your clinical experience with bevacizumab supported this idea that the drug’s side effects have been downplayed in clinical trials? Dr. Michaud: In the case of hyperten-

sion, I’d say yes. While hypertension is fairly commonly reported in these trials (up to 22% in AVADO), they generally state that this was manageable by medical interventions (e.g., more drug therapy). The problem with these data is more of an issue with the criteria used to grade this toxicity, as the criteria do not match current national guidelines for treatment of hypertension. Nonetheless, a small percentage of our patients (probably less than 5%) have trouble with uncontrolled hypertension. We’ve had some very recalcitrant cases where we’ve had to give patients two or three different medications to get their elevated blood pressure under control. These added medications decrease the patients’ quality of life (increased numbers of medications, increased side effects, etc.), increase the complexity of their care and require additional time and resources to manage. Patients can also have symptoms and complications (e.g., cerebrovascular events) related to the hypertension when uncontrolled that can again lead to diminished quality of life. Granted, there may be some underlying disorders that contributed to their hypertension. And in many cases, our patients with advanced breast cancer already have elevated blood pressure— it’s a function of their age, as well as the increasing prevalence of heart disease in women. But that’s the reality in clinical practice: Such patients are far more representative than what you see in clinical trials. By giving them bevacizumab, you’re potentially adding to a risk for hypertension that is already elevated. And that’s a problem. So for those reasons, my enthusiasm over bevacizumab is somewhat tempered. But I also acknowledge that some women with advanced disease respond extremely well, and they continue to do well on the drug at a point in their disease process where there are not many other therapeutic options. That’s what makes the FDA’s decision whether to follow suit with ODAC and pull the

as PFS are used, is Laura B. Michaud, helpful. But I have PharmD, FASHP, BCOP to applaud the FDA for following up on bevacizumab, to ensure that the initial promise of the drug has been realized in more widespread clinical use. Because in the past, they’ve been criticized for not doing so. And in the case of bevacizumab, this is not an inexpensive drug. So ensuring that it is effective is critical. PPN: Just how much has cost shaped this debate? Dr. Michaud: Well, the FDA and its

breast cancer indication so difficult. PPN: If you were given a vote on this, which side would you come down on: to retain or rescind the indication? Dr. Michaud: It’s not cut-and-dried.

As I said, patients are benefiting. But there is also a significant proportion of patients in the published studies and in everyday practice who may have died due to bevacizumab toxicity; albeit, it is hard to tell from the studies. In the final analysis, I’d have to say that there isn’t a significant enough benefit from the more recent clinical trials to substantiate the initial results we saw in E2100, and to warrant the potential risks. Does that support the drug’s [advanced breast cancer] indication being rescinded? That’s FDA’s call. PPN: Has the FDA optimally defined valid end points for clinical trials? Dr. Michaud: It’s very much been a

moving target, and that’s part of the problem. The FDA tells pharmaceutical companies one thing: “You need to meet the end point of progression-free survival.” Then they add the caveat, “But it has to be clinically meaningful.” Well, the latter is somewhat subjective—and potentially confusing—to drug developers. And that’s borne out by the current debate over bevacizumab. I understand that OS is the gold standard. But that can be unrealistic, especially in breast cancer, where OS can take 10, 15 years to really play out. If we waited for those end points to be reached for every single new drug, I don’t know that we would get anywhere. That’s why I think the accelerated approval process, where surrogate end points such

advisory panels aren’t supposed to consider cost when evaluating a drug for approval. But there certainly has been lots of speculation about it as a factor in the case of bevacizumab. And it’s understandable: A year of bevacizumab therapy costs nearly $100,000 versus about $12K annually for conventional chemotherapy. How can that substantial differential not enter the minds of reviewers—especially in the current era of cost containment? It’s interesting to note, by the way, that some patient advocacy groups actually are not in favor of bevacizumab retaining its breast cancer approval. [Breast Cancer Action wrote a July 6 letter to ODAC, calling for the indication to be rescinded. The group stated in the letter that it was “deeply troubled by the prospect that Avastin has not been shown to improve survival of breast cancer patients, nor to improve their quality of life.”] By the same token, other advocacy groups are petitioning the FDA to retain the indication. So clinicians and policymakers are not the only ones debating this. This lack of consensus is nothing new: In December 2007, the ODAC recommended against bevacizumab being approved for this indication. In February 2008, the FDA chose not to follow that recommendation and granted the drug accelerated approval. So handicapping the next stage of this is anybody’s guess. But ODAC’s 12 to 1 vote in favor of rescinding the approval is going to be hard for the agency to go against, I would think. There’s another possibility here: The FDA can decide to leave the breast cancer indication intact, while asking for more time to study the data. It’s a hard situation to read, in part because while ODAC often makes very sound, scientific, objective recommendations, the FDA is in a more difficult position politically, and has to take into account all the different parties that would stand to benefit or be harmed by their final decision.

Hem/Onc Pharmacy

Pharmacy Practice News • October 2010

In Focus In Multiple Myeloma ...

Maintenance Therapy After Transplant Improves PFS sistency of the outcomes was mutually reinforcing. The expert invited by ASCO to discuss the studies, Dr. Giralt, concurred with the authors that the results support maintenance lenalidomide as a new standard after ASCT. In the IMF 2005-02 trial, 614 MM patients younger than age 65 years who had received ASCT within the previous six months and had nonprogressive disease were randomized to lenalidomide or placebo (abstract 8018). Those in the lenalidomide arm received a two-month consolidation course at 25 mg per day for 21 days for each of the two induction months, followed by 10 to 15 mg per day of maintenance lenalidomide until progression. In CALGB 100104, 568 MM patients younger than age 70 years were randomized to placebo or 10 mg per day of maintenance lenalidomide for three months, at which time the dose was escalated to 15 mg per day. At the end of 24 months of follow-up in the IMF trial, 68% of patients receiving lenalidomide maintenance had not progressed, compared with 35% of those on placebo, generating the 54% relative improvement (Figure 1). The overall survival estimated at three years was 88% in patients receiving lenalidomide maintenance compared with 80% for those given placebo, a relative 12% improvement that approached statistical significance (HR, 0.88; P=0.08). Compared with previous rates of PFS after ASCT, these outcomes were characterized as “unprecedented” by the senior author of the IMF 2005-02 trial, Michel Attal, MD, Department of Hematology and Biostatistics, Hôpital Purpan, Toulouse, France. However, he emphasized that the results were preliminary, that the survival figures are not meaningful with this amount of follow-up and a much more complete analysis will be presented at the Ameri-

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Chicago—Maintenance therapy with lenalidomide (Revlimid, Celgene) greatly improves progression-free survival (PFS) in patients with multiple myeloma (MM) after autologous stem cell transplantation (ASCT), according to two large, multicenter Phase III trials. The similarity of the outcomes, which are considered to have immediate relevance to clinical practice, was remarkable. In one study, investigators identified a 54% reduction in the risk for disease progression (hazard ratio [HR], 0.46; P<0.00000001). The other found a 58% improvement in time to progression (TTP; HR, 0.42; P<0.0001). “We have just heard two of the most practice-changing presentations that have happened in myeloma in the last couple of years,” said Sergio Giralt, MD, chief, Adult Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York City. Speaking at the 2010 meeting of the American Society of Clinical Oncology (ASCO), where these data had just been presented, Dr. Giralt emphasized that the benefit of maintenance therapy with lenalidomide after ASCT was observed regardless of β2 microglobulins, cytogenetics, type of induction or response to the initial therapy. The two studies had similar designs and asked the same question: Can a maintenance therapy after ASCT reduce or delay the high rates of relapse that are presumably due to residual disease? Lenalidomide, an oral therapy, was an attractive choice because it is reasonably well tolerated and has demonstrated substantial activity in MM in the past. There were a few design differences between the two studies, one conducted by the International Myeloma Foundation (IMF 2005-02) and the other by Cancer and Leukemia Group B (CALGB 100104), but the con-

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Figure 2. Comparison of grade 3 or higher neutropenia in CALGB 100104 Trial. can Society of Hematology meeting at the end of this year. In the CALGB 100104 study (abstract 8017), the median TTP was 25.5 months in patients receiving placebo but had not yet been reached in those randomized to receive lenalidomide. This

outcome, recorded after a median of 12 months of follow-up, generated the reported 58% risk reduction. There was no difference in overall survival between the arms, but the lead investigator, Philip L. McCarthy, MD, Roswell Park Cancer Institute, Buffalo, N.Y., explained that placebo patients were permitted to switch to lenalidomide at progression, diluting the ability to show a survival advantage. Lenalidomide was well tolerated in both studies. The major difference was the higher rate of hematologic toxicities, which were generally asymptomatic. In IMF 2005-02, grade 3 or 4 neutropenia was recorded in 7% of lenalidomide patients and 1% of patients randomized to placebo (P<0.001). There were no significant differences in any other grade 3 or 4 hematologic outcomes. In CALGB 100104, grade 3 or higher neutropenia was observed in 42% of lenalidomide patients and 7% of those on placebo (P<0.0001; Figure 2). Anemia (6% vs. 1%; P=0.0028) and thrombocytopenia (12% vs. 3%; P=0.01) also were significantly higher on lenalidomide. Grade 3 or 4 nonhematologic side effects, including neuropathy, were uncommon and relatively few patients dropped out of either study for adverse events. In his review of these data, Dr. Giralt expressed concern about the potential risks for significant hematologic toxicities among patients, indicating that some form of routine monitoring may be appropriate. Although he advocated lenalidomide maintenance, he said there is a new set of questions to answer, including how long patients should be maintained on treatment and whether a single ASCT before lenalidomide maintenance is the best approach. —Ted Bosworth

Novel Vincristine Formulation Improves Outcomes in ALL A liposomal formulation of vincristine (Marqibo, Hana Biosciences) is active in adult patients with refractory or relapsed Philadelphia chromosomenegative acute lymphoblastic leukemia (ALL), according to a Phase II trial presented at the American Society of Clinical Oncology meeting. Twenty percent of patients in the study achieved complete remission (CR) or CR with incomplete blood count recovery (CRi). Another 9% had a partial remission and 6% had bone marrow that normalized but without full recovery of blood counts.

“We have a significant response rate of 35% in a very heavily pretreated population of patients with ALL—poor performance status in 23%, almost 50% receiving four lines or greater of therapy, and all of whom had prior vincristine,” said Susan O’Brien, MD, professor, Department of Leukemia, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, at the ASCO meeting. “The CR/CRi rate of 20% compares favorably to historical experience of 4% CR with single agents. There were no unexpected toxicities.”

Patients were included in the openlabel trial if they were in their second relapse or had progressed after two or more prior lines of treatment. Data were available for 56 patients who received liposomal vincristine sulfate injection at a dose of 2.25 mg/m2 with no dose cap, IV weekly over one hour. The median age of patients was 32 years; 48% had received a prior stem cell transplant; 20% had extramedullary disease; 100% had prior vincristine exposure; and 82% had a history of neuropathy. The most common related adverse events of grade 3 or higher were neuropathy (22%),

febrile neutropenia (32%), constipation (2%) and diarrhea (5%). Dr. O’Brien said the liposomal formulation allows higher doses of vincristine to be delivered and prolongs the type of exposure. According to Richard Stone, MD, director of the Adult Leukemia Program at Dana-Farber Cancer Institute, Boston, the agent merits further study. “Packaging the old ‘standby’ vincristine in a liposomal matrix administered as a single agent yielded a better-than-expected 20% CR/CRi rate in a very poor prognosis group of [ALL] patients.” —Kate O’Rourke

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26 Clinical

Pharmacy Practice News • October 2010

Educational Review

AIMS

Commentary

continued from page 17

algorithms that provide real-time clinical decision support improve. This is the most exciting area of AIMS development and will be helped by the development of more robust algorithms, faster processing times, and the accumulating experience of a number of centers working in this area. With the increased reliance on clinical decision support comes the need for both redundancy and backup systems—as providers begin to rely more and more on AIMS for their daily workflow.

Summary AIMS clearly bring a number of benefits to anesthesiologists. These include the ability to provide clinical decision support, track and improve clinical performance, and potentially increase departmental revenue through the maximization of revenue opportunities. Although AIMS are not universally present in the OR, increasing pressure to provide more in-depth case-based details, such as to third-party payers or external quality improvement organizations, will continue to drive adoption nationwide. Key challenges include a lack of interoperability and a relatively immature market for these systems, with only a handful of vendors predominating.

References 1.

Ehrenfeld J. Anesthesia Information Management Systems: A guide to the successful installation and use of AIMS. Anesthesiology News. 2009;35(9):1-8.

2. Sandberg WS, Sandberg EH, Seim AR, et al. Real-time checking of electronic anesthesia records for documentation errors and automatically text messaging clinicians improves quality of documentation. Anesth Analg. 2008;106(1):192-201. 3. Reich DL, Wood RK Jr, Mattar R. Arterial blood pressure and heart rate discrepancies between handwritten and computerized anesthesia records. Anesth Analg. 2000;91(3):612-616. 4. Cook RI, McDonald JS, Nunziata E. Differences between handwritten and automatic blood pressure records. Anesthesiology. 1989;71(3):385-390. 5. Thrush DN. Are automated anesthesia records better? J Clin Anesth. 1992; 4(5):386-389. 6. Lerou JG, Dirksen R, van Daele M, Nijhuis GM, Crul JF. Automated charting of physiological variables in anesthesia: a quantitative comparison of automated versus handwritten anesthesia records. J Clin Monit. 1988;4(1):37-47. 7. Epstein RH, Vigoda MM, Feinstein DM. Anesthesia information management systems: a survey of current implementation policies and practices. Anesth Analg. 2007;105(2):405-411. 8. Egger Halbeis CB, Epstein RH, Macario A, Pearl RG, Grunwald Z. Adoption of anesthesia information management systems by academic departments in the

Beth Smith, RPh Operating Room Pharmacy Supervisor, Southeast Alabama Medical Center, Dothan, Alabama

his educational review offers an excellent overview of the main benefits one can expect to achieve after implementing an anesthesia information management system (AIMS). At Southeast Alabama Medical Center (SAMC), a nonprofit, 420-bed regional hospital with 25 operating rooms, we’ve had the DocuSys and DocuJect II (Merge Healthcare) AIMS components in place for about five years. During that time, we have seen many of the clinical and operational improvements detailed in Dr. Ehrenfeld’s review. For our hospital, the main impetus for installing an AIMS system was to move beyond our handwritten record keeping. Before implementing AIMS, we had to spend hours each day auditing every patient chart for key clinical and financial data. In the case of “charge capture”—that is, obtaining all the needed elements required for billing—we had to enter every single charge by hand in order to guarantee full reimbursement. Now, with AIMS, charges are automatically sent to our pharmacy computer system when a case is closed, appearing as one-time orders on the patient’s profile with exact time and date of administration. Narcotics tracking before the AIMS rollout was similarly arduous. Again, every chart had to be hand-audited by pharmacy—we had to take the anesthesia practitioner’s handwritten narcotic sheets and compare them with the handwritten anesthesia records. If discrepancies were found, then we had to investigate them, which was often difficult due to illegible handwriting and other flaws of manual record keeping. Now, all we have to do is access the AIMS program and print out an electronic report to check for discrepancies—it really is the final word in documenting narcotic use.

Staff Savings Regarding improved outcomes, I don’t think we’ve seen reductions in the misuse of narcotics after implementing AIMS. Similarly, our overall reimbursement for medications has not increased, despite the improved charge-capture process. But what we have seen are significant savings in staff time: We’ve gained at least one-half of a full-time equivalent (FTE) pharmacist after the rollout due to enhanced efficiencies and streamlining inherent in AIMS. Our ability to access and use key clinical patient information has also improved significantly since we implemented AIMS. This information is readily available to the pharmacy department through the “Pre-Anesthesia” component of DocuSys. This is particularly helpful with antibiotic dosing. Many of our patients are admitted on the same day that their surgery is scheduled. Before the AIMS was in place, we had no information on patient height, weight, renal function, drug allergies, etc. Now we can pull that information from the pre-anesthesia database and use it in calculating and preparing preoperative antibiotic doses. This capability has helped us meet the “Timely Administration of Antibiotic Prophylaxis” regulations set by the Centers for Medicare & Medicaid Services, which, if not met, results in reduced reimbursement to the hospital. During a case, the AIMS technology is also a huge help: Drug allergy alerts, drug interaction and contraindications, and antibiotic dosing time are automatically messaged to Anesthesia during a case. On-demand usage reports can be customized for combinations of drug, practitioner, case type or length, or time periods. This information has been useful in pinpointing opportunities for improvement in cost control, waste management, antibiotic use and quality assurance compliance. Hospitals considering implementing AIMS should, however, be ready to meet some challenges—many of which fall on the pharmacy department. For example, new labeling and drug storage systems will have to be ordered and integrated into the operating room pharmacy. The effort to make that work is certainly worth it: At SAMC, AIMS has simplified narcotic tracking in Anesthesia, improved and streamlined charge capture, and has helped improve the quality and breadth of clinical services that we can provide in the OR. It is an investment that has paid off for the hospital, physicians, pharmacists—and, most importantly, patients.

United States. Anesth Analg. 2008;107(4): 1323-1329. 9. O’Reilly M, Talsma A, VanRiper S, Kheterpal S, Burney R. An anesthesia information system designed to provide physicianspecific feedback improves timely administration of prophylactic antibiotics. Anesth Analg. 2006; 103(4):908-912. 10. Wax DB, Beilin Y, Levin M, Chadha N, Krol M, Reich DL. The effect of an interactive visual reminder in an anesthesia information management system on timeliness of prophylactic antibiotic administration. Anesth Analg. 2007;104(6):1462-1466. 11. Kooij FO, Klok T, Hollmann MW, Kal JE. Decision support increases guideline adherence for prescribing postoperative nausea and vomiting prophylaxis. Anesth Analg. 2008;106(3):893-898. 12. Eden A, Pizov R, Toderis L, Kantor G, Perel A. The impact of an electronic reminder on the use of alarms after separation from cardiopulmonary bypass. Anesth Analg. 2009;108(4):1203-1208. 13. Ehrenfeld J, Sandberg WS. Temperature monitoring and management practices in a large academic anesthesia department. Anesthesiology. 2007;107:A96. 14. Ehrenfeld JM, Sandberg WS. A novel method for creating alerts of intraoperative gaps in patient monitoring during anesthesia. Anesth Analg. 2008;106:S-110. 15. Devitt JH, Rapanos T, Kurrek M, Cohen MM, Shaw M. The anesthetic record: accuracy and completeness. Can J Anesth. 1999; 46(2):122-128. 16. Spring SF, Sandberg WS, Anupama S, Walsh JL, Driscoll WD, Raines DE. Automated documentation error detection and notification improves anesthesia billing performance. Anesthesiology. 2007; 106(1):157-163. 17. Reich DL, Kahn RA, Wax D, Palvia T, Galati M, Krol M. Development of a module for point-of-care charge capture and submission using an anesthesia information management system. Anesthesiology. 2006;105(1):179-186. 18. Kheterpal S, Gupta R, Blum JM, Tremper KK, O’Reilly M, Kazanjian PE. Electronic reminders improve procedure documentation compliance and professional fee reimbursement. Anesth Analg. 2007;104(3):592-597. 19. Dexter F, Willemsen-Dunlap A, Lee JD. Operating room managerial decisionmaking on the day of surgery with and without computer recommendations and status displays. Anesth Analg. 2007; 105(2):419-429. 20. Lubarsky DA, Sanderson IC, Gilbert WC, et al. Using an anesthesia information management system as a cost containment tool. Description and validation. Anesthesiology. 1997;86(5):1161-1169. 21. Sandberg WS, Spring FS, Xue F, Paul S, Ehrenfeld JM. Effective reduction of anesthesia drug costs: implementation & outcomes. Anesthesiology. 2009;109:27. 22. Vigoda MM, Gencorelli FJ, Lubarsky DA. Discrepancies in medication entries between anesthetic and pharmacy records using electronic databases. Anesth Analg. 2007;105(4):1061-1065. 23. Epstein RH, Gratch DM, Grunwald Z. Development of a scheduled drug diversion surveillance system based on an analysis of atypical drug transactions. Anesth Analg. 2007;105(4):1053-1060. 24. Epstein RH, Ekbatani A, Kaplan J, Shechter R, Grunwald Z. Development of a staff recall system for mass casualty incidents using cell phone text messaging. Anesth Analg. 2010;110(3):871-878.

28 Clinical

Pharmacy Practice News • October 2010

Cardiology

Colchicine Prevents Rare Heart Surgery Complication Stockholm—Colchicine is the first pharmacologic agent to show efficacy in preventing post-pericardotomy syndrome (PPS) after heart surgery, according to the first large-scale, double-blind, placebo-controlled trial to test the drug in this setting. “Colchicine halves the risk of postpericardotomy syndrome following cardiac surgery, and not only is it efficacious, but it is safe,” said the lead author of the study, Massimo Imazio, MD, of Maria

Vittoria Hospital, in Turin, Italy, who presented the findings at the European Society of Cardiology 2010 Congress. The research was published simultaneously in the online edition of the European Heart Journal (doi:10.1093/ eurheartj/ehq319). Occurring in 10% to 40% of patients, PPS is a relatively common complication that can cause life-threatening sequelae such as cardiac tamponade, as well as increase length of stay and health care

Immune Globulin Intravenous (Human) Flebogamma® 5% DIF For intravenous use only Rx only

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE Flebogamma® 5% DIF is indicated for replacement therapy in primary (inherited) humoral immunodeficiency disorders. DOSAGE AND ADMINISTRATION The usual dose of Flebogamma® 5% DIF for replacement therapy in primary humoral immunodeficiency diseases is 300 to 600 mg/kg body weight administered every 3 to 4 weeks. An in-line filter with a pore size of 15 to 20 microns is recommended for the infusion. Antibacterial filters (0.2 micron) may also be used. Discard unused contents and administration devices after use. The infusion of Flebogamma® 5% DIF should be initiated at a rate of 0.01 mL/kg body weight/minute (0.5 mg/kg/minute). If, during the first 30 minutes, the patient does not experience any discomfort, the rate may be gradually increased to a maximum of 0.10 mL/kg/minute (5 mg/kg/minute). For patients judged to be at risk for developing renal dysfunction or considered to be at increased risk of thombotic/thromboembolic events, it may be prudent to limit the infusion rate to a maximum rate less than 0.06 mL/kg body weight/minute (3 mg/ kg/minute). Reduction in dose, concentration, and/or rate of infusion in patients at risk of acute renal failure, which includes patients over 65, has been proposed in the literature in order to reduce the risk of acute renal failure. CONTRAINDICATIONS Flebogamma® 5% DIF should not be administered to individuals with a history of severe or anaphylactic reactions to blood or blood-derived products. Patients with severe selective IgA deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction. Anaphylaxis can occur using Flebogamma® 5% DIF even though it contains low amounts of IgA (typically < 50 μg/mL). Such patients should only receive intravenous immune globulin with utmost caution and in a setting where supportive care is available for treating life-threatening reactions. If patients are known to be intolerant to any component of Flebogamma® 5% DIF, such as sorbitol (i.e., intolerance to fructose), they should not receive the product. WARNINGS Immune Globulin Intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Flebogamma® 5% DIF does not contain sucrose. See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure. Flebogamma® 5% DIF is made from human plasma. As with all plasma derived products, the risk of transmission of infectious agents, including viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated. The risk that such products will transmit an infectious agent has been greatly reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Biologicals at 888-GRIFOLS (888-474-3657). All patients, but especially individuals receiving Flebogamma® 5% DIF for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks, may be at risk for the development of inflammatory reactions characterized by fever, chills, nausea, and vomiting. Careful monitoring of recipients and adherence to recommendations may reduce the risk of these types of events. Appropriate supportive care, including immediate access to epinephrine injection, should be available for the management of acute anaphylactic reactions.

costs. Until now, no prevention strategy has been successful, and the syndrome is usually managed with aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs), or with steroids if necessary. The COPPS (Colchicine for the Prevention of the Postpericardiotomy Syndrome) trial randomized 360 cardiac surgery patients to either colchicine or placebo on the third postoperative day. Patients in the active arm of the trial received 1 mg twice daily for the first day, followed by

PRECAUTIONS General: Any vial that has been entered should be used promptly. Partially used vials should be discarded and not saved for future use because the solution contains no preservative. Do not use if turbid. Solution that has been frozen should not be used. Ensure that patients are not volume-depleted before the initiation of the infusion of IGIV. Renal Function: Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma® 5% DIF and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. For patients judged to be at risk for developing renal dysfunction, it may be prudent to reduce the amount of product infused per unit time by infusing Flebogamma® 5% DIF at a maximum rate less than 0.06 mL/kg (3 mg/kg) body weight/minute. Aseptic Meningitis Syndrome: An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with IGIV treatment. The syndrome usually begins within several hours to 2 days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic milliliter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high-dose (e.g., > 1.0 g/kg body weight) and/or rapid-infusion IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. Hemolysis: Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration [See ADVERSE REACTIONS]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis [See PRECAUTIONS: Laboratory Tests]. Thrombotic Events: Thrombotic events have been reported in association with IGIV (See ADVERSE REACTIONS). Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [See PRECAUTIONS: Laboratory Tests]. Transfusion-Related Acute Lung Injury (TRALI): There have been reports of non-cardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1 to 6 hours after transfusion. Patients with TRALI may be managed by using oxygen therapy with adequate ventilatory support. IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum [See PRECAUTIONS: Laboratory Tests]. Information For Patients: Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (which may suggest kidney damage) to their physicians. It is recommended that the lot number of the vials used be recorded when Flebogamma® 5% DIF is administered. Laboratory Tests: Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma® 5% DIF in patients judged to have a potential increased risk for developing acute renal failure and again at appropriate intervals thereafter.

Clinical 29

Pharmacy Practice News • October 2010

Cardiology 0.5 mg twice daily for one month if they weighed 70 kg or more and half that dose if they weighed less than 70 kg or were intolerant to the higher dose. For the primary efficacy end point, the incidence of PPS at 12 months, the relative risk reduction with colchicine was 57.9% (P=0.002), which Dr. Imazio called “impressive.” The secondary end point, the combined rate of disease-related hospitalization, cardiac tamponade, constrictive pericarditis and relapses, was also reduced significantly, from nine cases (5%) in the placebo arm to one case (0.6%) in

the colchicine arm (P=0.024). The rate of side effects was minimal and comparable between the arms, the authors reported. Mainly related to gastrointestinal intolerance, side effects occurred in 8.9% of the colchicine group and 5% of the placebo group (P=0.212).

Good Study—With Caveats

‘Before this therapy could be said to be evidence-based, a determination of the balance of benefits to harms would be needed.’

Following infusion of Flebogamma® 5% DIF, there may be a transitory rise of various antibody titers that may result in misleading positive results in serological testing. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum. Pregnancy Category C: Animal reproduction studies have not been performed with Flebogamma® 5% DIF. It is also not known whether Flebogamma® 5% DIF can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Flebogamma® 5% DIF should be given to a pregnant woman only if clearly needed. Drug Interactions: Antibodies in Flebogamma® 5% DIF may interfere with the response to live viral vaccines, such as measles, mumps, and rubella. Physicians should be informed of recent therapy with Immune Globulin Intravenous (Human) so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months from the time of IGIV administration. Pediatric Use: The above mentioned clinical trial with Flebogamma® 5% DIF enrolled only a very limited number of children (0) and adolescents (3) with primary humoral immune deficiency, a number insufficient to fully characterize and establish the efficacy and safety in pediatric patients. Geriatric Use: Subjects over 65 are at increased risk of renal failure with IGIV treatment. For these subjects, and for any other subjects at risk of renal failure, the infusion rate of Flebogamma® 5% DIF should be limited to < 0.06 mL/kg/min (3 mg/kg/min). Adverse Reactions Increases of creatinine and blood urea nitrogen (BUN) have been observed as soon as 1 to 2 days following infusion of IGIV. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment. Types of severe renal adverse reactions that have been seen following IGIV therapy include: acute renal failure, acute tubular necrosis, proximal tubular nephropathy, and osmotic nephrosis. Certain severe adverse reactions may be related to the rate of infusion. The recommended infusion rate [See DOSAGE AND ADMINISTRATION] must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Adverse reactions may occur more frequently when a high infusion rate is used, the treatment is the initial exposure to immunoglobulin, the immunoglobulin product has been changed to that of a different manufacturer, or there has been a long interval (more than 8 weeks) since the previous infusion. Slowing or stopping an infusion usually results in the prompt disappearance of symptoms. Post-Marketing: The following adverse reactions have been identified and reported during the postapproval use of IGIV products. Respiratory

Cardiovascular Neurological Integumentary Hematologic General/Body as a Whole Musculoskeletal Gastrointestinal

Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiac arrest, thromboembolism, vascular collapse, hypotension Coma, loss of consciousness, seizures, tremor Stevens-Johnson Syndrome, epidermolysis, erythema multiformae, bullous dermatitis Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test Pyrexia, rigors Back pain Hepatic dysfunction, abdominal pain

Because post-marketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently. Adverse events were reported in a study of 46 individuals with primary humoral immunodeficiency diseases receiving infusions every 3 to 4 weeks of 300 to 600 mg/kg body weight. Forty-three (94%) subjects experienced at least 1 adverse event

—C. Michael White, PharmD

irrespective of the relationship with the product, and these subjects reported a total of 595 adverse events. None of the 46 subjects who participated in this study discontinued the study prematurely due to an adverse experience related to the study drug. One subject had treatment-emergent bronchiectasis, mild, ongoing, after infusion #10; and one subject had recurrent moderate leukopenia after the 7th and 12th infusions. No adverse events occurred with an incidence of > 2% on a per infusion basis. Table 1. Adverse Events Occurring with an Incidence of > 15% Adverse Event

Number of AEs

Combined Bronchitis Cough and productive cough Diarrhea NOSa Headache NOS and sinus headache Nasal congestion Injection site reaction NOS Pyrexia Arthralgia Sinusitis NOS Pharyngitis Upper respiratory tract infection Wheezing and asthma aggravated

19 10 14 46 11 13 27 11 38 9 24 24

Number of Subjects with AEs 14 10 9 16 7 7 17 7 20 8 15 10

Percent of Subjects with AEs 30 22 20 35 15 15 37 15 44 17 33 22

a. NOS = not otherwise specified The total number of AEs (regardless of attribution) reported whose onset was within 72 hours after the end of an infusion of Flebogamma® 5% DIF was 216. There were a total of 709 infusions, resulting in a rate of 0.305 (95% confidence interval 0.225 to 0.412) temporally associated AEs per infusion. There were 144 infusions (20.1%, 1-sided 95% upper bound confidence interval = 24.4%) associated with 1 or more AEs that began within 72 hours after the completion of an infusion. Table 2. Summary of Infusions with Mild, Moderate, and Severe TreatmentRelated Adverse Events Severity of AE Mild Moderate Severe

No. Infusions 58 25 1

Adjusted % a with AE 7.9 3.6 0.1

Confidence Intervalb 10.4 4.9 0.3

a. Adjusted % = average of the % of infusions with a treatment-related adverse event for each individual subject. b. The 95% upper bound for the adjusted % of infusions for which at least 1 treatmentrelated adverse event was reported was derived by using the t-statistic. The number and percent of subjects with treatment-emergent rises in AST or ALT are in Table 3. Table 3. Number (%) of Subjects with Treatment-Emergent Rises in AST or ALT (N = 46) Laboratory Test AST ALT

Assessment Criteria Above 3x the ULNa Above 3x the ULN

n 3 1

% 6.5 2.2

a. ULN = upper limit of normal. None of these subjects had a concomitant treatment-emergent rise in total bilirubin. Reported adverse reactions with Flebogamma® 5% DIF and other IGIV products include: headache, chills, fever, shaking, fatigue, malaise, anxiety, back pain, muscle cramps, abdominal cramps, blood pressure changes, chest tightness, palpitations, tachycardia, nausea, vomiting, cutaneous reactions, wheezing, rash, arthralgia, and edema, often beginning within 60 minutes of the start of the infusion. Rarely, Immune Globulin Intravenous (Human) can induce a severe fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with IGIV. In the case of shock, the current standard medical treatment for shock should be implemented. Manufactured by INSTITUTO GRIFOLS, S.A. Barcelona - Spain U.S. License No. 1181 Distributed by GRIFOLS BIOLOGICALS INC. Los Angeles - CA 90032 Phone: 888-GRIFOLS (888-474-3657)

“This is an interesting study with provocative results,” said C. Michael White, PharmD, professor of pharmacy at the University of Connecticut, in Storrs, and director of the UCONN/Hartford Hospital Evidence-Based Practice Center, in Hartford. But he noted that there are no commonly accepted definitions of post-pericardotomy syndrome. “Therefore, the clinical implications of the 59% reduction in syndrome formation in this trial cannot be extrapolated to clinical outcomes. However, in the secondary composite outcome, the incidence was reduced from 5% to 0.6%. This suggests that tangible reductions can be realized from colchicine therapy.” Whether the composite end point “was defined a priori or if it just represented the things that were reduced the most” is not clear, Dr. White added. “The individual components of the composite [end point] are not provided, so it’s hard to determine if the benefits are concentrated in one or two of them or dispersed throughout.” Dr. White noted that more information about the trial population, as well as other factors, would be helpful. “Were they having mostly CABG [coronary artery bypass graft] surgery or longer and more involved CABG and valve surgery? Were they using a cardiopulmonary pump known to increase inflammation? Did they cut a pericardial window posteriorly to allow blood to drain away from the heart? What other anti-inflammatory drugs (statins or vitamins) or delayed preconditioning medications (isoflurane and fentanyl) were the patients receiving?” Since postoperative atrial fibrillation can be related to inflammation, Dr. White also pointed out that the significantly higher incidence of postcardiac surgery atrial fibrillation found in large European cardiac trials compared with those done in the United States might suggest that less robust results would be found in a trial of colchicine here. Finally, he raised the question of side effects. “Although the incidence of gastrointestinal intolerance was reasonable in the trial given the modest colchicine dosing, it is not clear that they looked at any other adverse events, including those known to result from colchicine therapy. Before this therapy could be said to be evidence-based, a determination of the balance of benefits to harms would be needed.” —Gina Shaw

30 Clinical

Pharmacy Practice News • October 2010

Cardiology

Statin ‘Loading’ Cuts Post-op MI Risk Stockholm—Statins given before invasive procedures such as percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery and noncardiac surgery significantly reduce the risk for post-procedural myocardial infarction (MI), and also lower the risk for atrial fibrillation after CABG, a new meta-analysis has shown. The findings suggest that clinicians should consider using statins routinely before performing such procedures,

‘If I am seeing someone in clinic for evaluation of angina, I’ll start [him or her] on at least 40 mg of atorvastatin in anticipation of catheterization.’ —Anthony A. Bavry, MD, MPH according to the senior author, Anthony A. Bavry, MD, MPH, director of the Gainesville VA Medical Center cath-

eterization laboratory and assistant professor of medicine at the University of Florida, Gainesville. Dr. Bavry pre-

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sented the results of the meta-analysis at the 2010 European Society of Cardiology Congress in Stockholm. The study was published simultaneously online in the Journal of the American College of Cardiology (2010;56:doi:10.1016/j. jacc.2010.04.023). “There have been a number of individual studies that have been published examining the role of statin therapy before invasive procedures, but there has not been a comprehensive meta-analysis on the topic, so we wanted to gather together all of the individual studies and see what the benefit might be from this approach,” Dr. Bavry told Pharmacy Practice News. The meta-analysis, which comprised 21 trials and 4,805 patients, showed that use of pre-procedural statins reduced post-procedural MI (risk ratio [RR], 0.57; 95% confidence interval [CI], 0.46-0.70; P<0.0001). The benefit was seen after PCI (P<0.0001) and noncardiac surgical procedures (P=0.004), but not CABG (P=0.40). Post-procedural atrial fibrillation after CABG also was reduced (RR, 0.54; 95% CI, 0.43-0.68; P<0.0001). Statin therapy was also shown to reduce allcause mortality, albeit nonsignificantly (RR, 0.66; 95% CI, 0.37-1.17; P=0.15).

Questions Remain, But Results Still Practice-Changing “The optimal timing, dose and type of statin are unclear from these studies, because there was a lot of variability between the studies,” Dr. Bavry said. “However, we tried to distill down the common characteristics. For PCI, we found it was atorvastatin at a dose of 40 to 80 mg, one to seven days before the procedure. For the noncardiac surgical procedures, it was fluvastatin at a dose of 80 mg per day, given four weeks before the surgery.” Dr. Bavry said he is now incorporating the findings into his own practice. “If I am seeing someone in clinic for evaluation of angina, I’ll start [him or her] on at least 40 mg of atorvastatin in anticipation of catheterization,” he explained. “However, if I’m seeing [the patient] the day of or the day before the procedure, I’m going to start atorvastatin 80 mg. And for the other category of patients who come in already on statin therapy, we’ve begun giving them a booster dose

Clinical 31

Pharmacy Practice News • October 2010

Critical Care Finally, Dr. White said the use of statins to decrease post-CABG atrial fibrillation is very promising. But he pointed out that, by and large, the clinical trials evaluating the benefits of statins were not conducted in patients receiving prophylactic β-blockade and amiodarone. “These therapies are considered important first-line strategies since they [improve] health outcomes. Statins and a host of other agents reduce postoperative atrial fibrillation, but their impact on final health outcomes is not known.”

of 80 mg atorvastatin as well.” An editorial (doi:10.1016/j.jacc. 2010.04.022) that accompanied the article offered support for this strategy. “Given the strong biological rationale and the sum of the clinical data, no patient should undergo coronary procedures without statin therapy unless clear contraindications exist,” wrote Kim Eagle, MD, and Vineet Chopra, MD, from the University of Michigan, Ann Arbor. “Indeed, it is time to consider a new indication for an old friend.” The feedback from cardiologists attending the ESC Congress was also very good, Dr. Bavry stressed. “The audience received the news from our study very well, and I think [they] will apply it in their practice.”

—Fran Lowry

The commitment to

Pharmacist’s Perspective

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C. Michael White, PharmD, professor of pharmacy at the University of Connecticut, in Storrs, offered a more measured assessment of the study results. “This is a well-done meta-analysis. They used a random effects [statistical] model due to known differences in patient populations, had a large sample size to deal with, and used appropriate subgroup and meta-regression analyses,” he told Pharmacy Practice News. However, Dr. White added a word of caution about applying these data to noncardiac surgery.

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‘I am heartened that the impact on overall mortality was trending downward with statin therapy [in the ESC study], since β-blockers had a concerning trend toward an increase in mortality in our own meta-analysis.’

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32 Clinical

Pharmacy Practice News â&#x20AC;˘ October 2010

Educational Review

Managing GI Issues In the Rheumatology Patient on Chronic NSAID Therapy MARIA G. TANZI, PHARMD Clinical Assistant Professor College of Pharmacy University of Illinois at Chicago Chicago, Illinois

onsteroidal anti-inflammatory drugs (NSAIDs) are effective in controlling pain in patients with arthritis; however, these agents are associated with a variety of adverse effects,

with gastrointestinal (GI) toxicity being the most common.

NSAID-related Gastrointestinal Toxicity Epidemiology The adverse reactions associated with NSAIDs vary in both incidence and severity. Approximately 10% to 20% of patients taking NSAIDs will develop dyspepsia, although the prevalence of this adverse event has been reported to be as high as 50%.1 Data have shown that dyspepsia results in 5% to 15% of patients discontinuing therapy within a 6-month period of initiating therapy. In addition, patients receiving NSAID therapy are at a 2.5- to 5-fold increased risk for serious GI complications compared with patients not taking NSAIDs. An estimated 100,000 hospital admissions and 7,000 to 10,000 deaths annually in the United States have been attributed to NSAID-related GI toxicity.2 Complications Both upper and lower GI complications can occur with NSAID therapy.3,4 Upper GI problems can range from asymptomatic mucosal damage, mild dyspepsia, nausea/vomiting, and abdominal pain to more serious complications such as peptic ulcers and bleeding.4 The frequency of dyspepsia is estimated to be doubled in NSAID users compared with non-users; however, the presence of dyspeptic symptoms does not always correlate with the development of more serious GI complications.3 Many patients with bleeding peptic ulcers have few symptoms prior to the event. Lower GI complications include mucosal inflammation and increased mucosal permeability, ulcerations, strictures, hemorrhage, perforation, and exacerbation of

inflammatory bowel disease. Recent data have shown that lower GI adverse events are becoming more common in NSAID users, and these events are associated with higher mortality and more prolonged hospitalizations compared with upper GI events.4 Pathophysiology Injury to the GI tract by NSAIDs is thought to be multifactorial and related to the direct toxic effects of NSAIDs on the mucosa and to systemic effects resulting from inhibition of cyclooxygenase-1 (COX-1) and thromboxane A2.1,5 Direct topical toxicity occurs as a result of the acidic properties of aspirin and many other NSAIDs.1 These agents are ingested and remain in their non-ionized, lipo-

inhibit thromboxane A2, which reduces platelet function and results in a higher risk for bleeding.1,5 Data also suggest that NSAIDs impair angiogenesis, which is the growth of new capillary blood vessels and an important natural process in healing and reproduction, and this interference may affect ulcer healing.1 Risk Factors Numerous risk factors have been identified that place patients at increased risk for NSAID-related GI complications.2,6 A publication by the Practice Parameters Committee of the American College of Gastroenterology (ACG), Guide-

Pharmacists should strive to educate physicians on the risk factors for NSAID-induced gastroduodenal ulcers and the role of prophylactic therapies. philic form in the highly acidic gastric lumen, which enables NSAIDs to penetrate through the gastric mucus, across plasma membranes, and into epithelial cells. Once in epithelial cells, NSAIDs are dissociated to their ionized state, resulting in trapping of hydrogen ions and, ultimately, damage to the GI mucosa. By inhibiting COX-1, nonselective NSAID use results in decreased synthesis of protective mucosal prostaglandins.1,5 This is the reason why selective COX-2 inhibitors seem to be associated with a lower risk for peptic ulcers.1 In addition, NSAIDs

lines on the Prevention of NSAIDrelated Ulcer Complications, states that risk factors for NSAID-related GI complications include a previous GI event, especially if the event was a previous complicated ulcer; older age; concomitant use of anticoagulants, corticosteroids, or other NSAIDs including low-dose aspirin; use of high-dose NSAIDs; and chronic debilitating disorders.2 The risk for GI complications appears to increase linearly with age, with patients over 70 years old having a risk similar to those with a previous history of an ulcer.1 The guidelines

also state that the presence of Helicobacter pylori is an independent and additive risk factor for NSAIDrelated GI toxicity.2 Other risk factors for GI toxicity include alcohol use and smoking.6 The guidelines classify patients as being at high, moderate, or low risk for NSAID-related GI complications (Table 1). Preventive strategies are tailored to the individual patientâ&#x20AC;&#x2122;s GI risk and will be discussed below. FDA Warning The occurrence of NSAID-related GI toxicity prompted the FDA to review postmarketing adverse event reports to determine if new labeling requirements were needed for over-the-counter (OTC) NSAID products.7,8 Based on the data, the FDA concluded that serious stomach bleeding events can occur when NSAIDs are used according to the current warnings and directions on the OTC label. The review noted the various risk factors for NSAID-related GI toxicity discussed above and determined that these risk factors should be prominently displayed on the packaging of OTC NSAIDs. In April 2009, the FDA published a

Clinical 33

Pharmacy Practice News • October 2010

Table 1. Risk Factors for NSAID-related GI Toxicitya final rule requiring manufacturers of OTC NSAIDs (including but not limited to aspirin, carbaspirin calcium, choline salicylate, ibuprofen, ketoprofen, magnesium salicylate, naproxen, and sodium salicylate) to revise their labeling to contain new GI warnings so that patients are aware of the potential risks associated with use of these medications.8 An overview of the GI-related labeling changes for OTC NSAIDs is provided in Table 2.

High risk

• History of a previously complicated ulcer, especially a recent flare-up • More than 2 risk factors

Moderate risk (1 to 2 risk factors)

• • • •

Low risk

No risk factors

Age >65 y High-dose NSAID therapy History of uncomplicated ulcer Concurrent use of aspirin (including low dose), corticosteroids, or anticoagulants

H. pylori is an independent risk factor and needs to be addressed separately.

NSAID, nonsteroidal anti-inflammatory drug

Guidelines for Prevention The ACG guidelines on the prevention of NSAID-related ulcer complications discuss 2 methods that are commonly used to prevent the development of peptic ulceration and mucosal injury in patients taking NSAIDs: 1) cotherapy with misoprostol, a high-dose histamine-2-receptor antagonist (H2RA), or a proton-pump inhibitor (PPI); or 2) use of a COX2-selective NSAID instead of a traditional, nonselective NSAID.2 The guidelines specifically state that use of enteric-coated or buffered NSAIDs or cotherapy with sucralfate have not been shown to be effective in preventing NSAID-related GI toxicity.

Adapted from reference 2.

Table 2. GI-related Labeling Changes for OTC NSAIDs • The ingredient name and the term NSAID must be highlighted or in bold type and in a prominent print size on the principal display panel. • The following warnings must be present for products indicated for adultsa: • Stomach bleeding warning (in bold): This product contains a nonsteroidal anti-inflammatory drug (NSAID), which may cause severe stomach bleeding. The chance is higher if you are age 60 or older, have had stomach ulcers or bleeding problems, take a blood thinning (anticoagulant) or steroid drug, take other drugs containing prescription or nonprescription NSAIDs (aspirin, ibuprofen, naproxen, or others), have 3 or more alcoholic drinks every day while using this product, or take more or for a longer time than directed.”

Misoprostol Cotherapy Misoprostol, a synthetic prostaglandin E1 analog, was one of the first agents approved for the prevention of NSAID-related ulceration.2 Data from a large randomized, 6-month trial involving 8,843 patients receiving continuous NSAID therapy for the treatment of rheumatoid arthritis showed that use of misoprostol 200 mcg 4 times daily reduced the risk for serious upper GI complications by 40% compared with placebo.9 A 2002 Cochrane review of 41 randomized controlled trials evaluating the prevention of NSAID-induced gastroduodenal ulcers concluded that misoprostol significantly reduced the risk for endoscopic gastric and duodenal ulcers, with an 800-mcg per day dose being more effective than a 400-mcg per day dose.10 Misoprostol 800 mcg per day was associated with a relative risk (RR) for endoscopic ulcers of 0.18 (95% confidence interval [CI], 0.12-0.27) compared with placebo, and the 400 mcg per day dose was associated with a RR of endoscopic ulcers of 0.43 (95% CI, 0.28-0.67) compared with placebo. However, use of this agent was associated with diarrhea at both doses (800 mcg per day: RR, 3.16 [95% CI, 2.33-4.29] and 400 mcg per day: RR, 1.76 [95% CI, 1.37-2.26]). The guidelines state that misoprostol, when given in full doses (800 mcg per day), is very effective in preventing ulcers and ulcer complications

• Ask a doctor before use if stomach bleeding warning applies to you, you have a history of stomach problems such as heartburn, you have high blood pressure, heart disease, liver cirrhosis, or kidney disease, or you are taking a diuretic.” • Stop use and ask a doctor if you experience any of the following signs of stomach bleeding: feel faint, vomit blood, have bloody or black stools, or have a stomach pain that does not get better.” a

Slightly different labeling requirements apply to products only labeled for children under 12 years of age and those for both adults and children.

Adapted from references 7, 8.

Combination Therapy in patients taking NSAIDs; however, the usefulness of this agent is limited by adverse effects such as diarrhea (occurring in 13% of patients) and abdominal pain (occurring in 7% of patients), and adherence issues related to the 4-times-daily dosing requirement.2,11 High-dose H2RA is defined as a double dose of therapy (eg, famotidine 40 mg twice daily) and has been shown to be effective in reducing the risk for NSAID-induced ulcers.2 The 2002 Cochrane review concluded that high-dose H2RA therapy was associated with a significant reduction in the risk for both duodenal (RR, 0.26; 95% CI, 0.11-0.65) and gastric (RR, 0.44; 95% CI, 0.26-0.74) ulcers compared with placebo.10 The guidelines state that high-dose H2RA therapy is superior to placebo in reducing the risk for NSAID-induced endoscopic peptic ulcers; however, it is significantly less effective than combination therapy with PPIs.2

Combination therapy with an NSAID and PPI for NSAID-related upper GI injury prophylaxis and treatment has skyrocketed in recent years.2 The increased use of this combination has been attributed to a multitude of published literature supporting the efficacy and safety of this combination. Data from 2 large randomized, 6-month controlled trials performed in patients with osteoarthritis and rheumatoid arthritis who had ulcers that exceeded 3 mm in diameter or more than 10 erosions showed that omeprazole cotherapy resulted in better treatment outcomes compared with ranitidine and misoprostol.12,13 One study showed that after 8 weeks of treatment, 80% of patients given omeprazole 20 mg per day and 79% of patients given omeprazole 40 mg per day were classified as having successful treatment, defined as the resolution of ulcer and the presence

Educational Review of fewer than 5 erosions in the stomach and duodenum, compared with 63% of patients given ranitidine (P<0.001 for omeprazole 20 mg per day; P=0.001 for omeprazole 40 mg per day).12 The second study showed that after 8 weeks of treatment, healing of gastric ulcers was significantly more common among patients given omeprazole 20 mg per day (87%) compared with those given misoprostol (73%; P=0.004).13 The guidelines state that PPIs significantly reduce gastric and duodenal ulcers and their complications in patients taking nonselective NSAIDs or COX-2 inhibitors.2 Although the efficacy of PPIs has been established, these agents have been associated with some key adverse events and drug–drug interactions.14 Data suggest that PPIs may increase the risk for Clostridium difficile–associated disease, and long-term PPI use may increase the risk for hip fracture.15,16 Data from a retrospective case-control study of 188 hospitalized patients reported that patients using PPIs were 3.6 times more likely to develop C. difficile–associated diarrhea.15 Another case-control study reported that exposure to PPIs for 7 years or more increased the risk for an osteoporosis-related fracture by 1.92 times, with the risk for hip fracture increasing 4.55 times after 7 years of exposure.16 In addition, PPI use has been linked to community-acquired pneumonia (CAP).17 A nested case-control study reported that PPI therapy started within 30 days was associated with an increased risk for CAP. Unfortunately, the incidence of these 3 adverse events is difficult to quantify, because the occurrence varies between studies.18 Recently, there has been concern over whether PPIs given in combination with clopidogrel decrease the antiplatelet efficacy of the drug.1921 Data from a nested case-control study of 13,636 patients prescribed clopidogrel following an acute myocardial infarction showed that concomitant therapy with a PPI, other than pantoprazole, was associated with loss of the beneficial effects of clopidogrel.20 Another study confirmed that pantoprazole does not appear to alter the effectiveness of clopidogrel compared with other PPIs such as omeprazole or esomeprazole.21 The FDA issued an alert in November 2009 warning clinicians that the combination of omeprazole and clopidogrel should be avoided because omeprazole inhibits cytochrome P450 (CYP) 2C19, which is responsible for the conversion of

•

see GI ISSUES, page 34

34 Clinical

Educational Review

Pharmacy Practice News • October 2010

Table 3. Recommendations for Prevention of NSAID-related Ulcer Complications

GI ISSUES

Gastrointestinal Risk

continued from page 33

clopidogrel to its active form.19 The FDA went on to recommend avoidance of esomeprazole and clopidogrel as well, and stated that separating the intake of these PPIs from clopidogrel would not decrease the likelihood of this interaction. Acid-suppressing agents such as ranitidine, famotidine, nizatidine, and antacids do not appear to interfere with clopidogrel’s metabolism and are good alternatives for these patients. When considering use of a COX-2 inhibitor, the ACG guidelines state that these agents are associated with a significantly lower incidence of gastric and duodenal ulcers compared with nonselective NSAIDs; however, this beneficial effect is lost in patients who are concomitantly taking low-dose aspirin therapy.2 In addition, COX-2 inhibitors have been linked to serious cardiovascular adverse events, which limits their usefulness. However, ACG acknowledges that emerging evidence suggests that both COX-2 inhibitors and nonselective NSAIDs, with the possible exception of naproxen, increase the risk for cardiovascular adverse events. The ACG guidelines state that the lowest possible dose of celecoxib should be used to minimize potential cardiovascular adverse events. Based on a patient’s GI and cardiovascular risk factors, ACG has published specific recommendations for the prevention of NSAID-related ulcer complications (Table 3).2 The guidelines state that all patients who are about to start long-term nonselective NSAID therapy should be considered for testing for H. pylori and treated if it is present.

New Combination Agents In April 2010, the FDA approved a new combination extended-release tablet that contains enteric-coated naproxen and esomeprazole (Vimovo, AstraZeneca and POZEN) for the relief of signs and symptoms of osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, and to decrease the risk for gastric ulcers in patients at risk for NSAID-associated gastric ulcers.22 The tablets will be marketed in 2 strengths of 375 mg/20 mg and 500 mg/20 mg of naproxen/esomeprazole, and the dose is 1 tablet twice daily taken 30 minutes before meals. The tablet has a unique release mechanism and is considered delayed-release. The core of the tablet contains enteric-coated naproxen, which is surrounded by immediate-release esomeprazole;

Low

Moderate

High

Low CV risk

NSAID alone

NSAID + PPI or misoprostol

Alternative therapy if possible OR COX-2 inhibitor + PPI or misoprostol

High CV riska

Naproxen + PPI or misoprostol

Avoid NSAIDs or COX-2 inhibitors Use alternative therapy

Arbitrarily defined as the requirement for low-dose aspirin for prevention of serious CV events.

COX-2, cyclooxygenase-2; CV, cardiovascular; NSAID, nonsteroidal anti-inflammatory drug; PPI, proton pump inhibitor Adapted from reference 2.

Table 4. Tips for Counseling Patients Using NSAIDs • Give patients examples of drugs that are NSAIDs and tell them that these agents are also found in a variety of medications, so read labels carefully. • Tell patients that taking a higher dose than recommended of an NSAID can cause stomach bleeding, and the risk for this adverse event is increased in specific patients. • Educate patients about potential signs and symptoms of stomach bleeding. • Tell patients that taking a higher dose of an NSAID than recommended can also cause reversible kidney damage, and the risk for this adverse event is increased in patients who are over 60 years old; those with hypertension, heart disease, or pre-existing kidney disease; and those taking a diuretic. Adapted from reference 32.

because of the release mechanism, the tablet must be swallowed whole and cannot be crushed or chewed. Data from 2 studies which compared naproxen/esomeprazole 500 mg/20 mg with enteric-coated naproxen 500 mg have been published together in Alimentary Pharmacology and Therapeutics.23 Both Phase III trials had identical methods: randomized, controlled, double-blind, parallel-group, multicenter studies conducted in the United States. The objective was to determine if the combination of esomeprazole and naproxen (Vimovo) reduced the risk for gastric ulcers at 6 months compared with enteric-coated naproxen without gastroprotection. To participate in the studies, patients had to require at least 6 months of daily NSAID therapy and have a risk factor for a GI complication.23 Qualifying risk factors included age 50 years or older or at least 18 years old with a history of an uncomplicated gastric or duodenal ulcer within the previous 5 years. Before randomization, patients were stratified according to the use of

low-dose aspirin; treatment regimens for both trials included naproxen 500 mg (n=216, n=210) or naproxen/ esomeprazole 500 mg/20 mg (n=218, n=210). Naproxen was enteric-coated, and treatments were given twice daily for 6 months or until development of a gastric ulcer. Patients were allowed to take acetaminophen as needed for pain and an antacid for GI discomfort. The primary end point was cumulative incidence of gastric ulcers at months 1, 3, and 6 as assessed by endoscopy. Secondary end points included onset of duodenal ulcer, NSAID-associated upper GI events, number of patients discontinuing treatment due to a GI event, and discontinuation due to an adverse event. A variety of symptom questionnaires were also administered. Demographic data revealed that a majority of patients were female with a mean age of 61 years.23 The most common indication for NSAID therapy was osteoarthritis (80%), and less than one-fourth of patients were receiving low-dose aspirin therapy. The cumulative incidence

of gastric ulcers over 6 months in the intent-to-treat population was significantly lower with combination therapy (4.1% vs 23.1% and 7.1% vs 24.3% for study 1 and study 2, respectively; P<0.001 for both). Patients taking low-dose aspirin at baseline had results that were similar to the overall population, with 3% of those who received combination therapy experiencing an ulcer compared with 28.4% of those receiving naproxen (P<0.001). The cumulative incidence of duodenal ulcers was also significantly lower with combination therapy (0.5% vs 5.1% in study 1 [P=0.003] and 1% vs 5.7% in study 2 [P=0.007]). The most common NSAID-associated upper GI events were erosive gastritis, gastritis, dyspepsia, and erosive duodenitis; these events occurred more frequently in naproxen recipients (69% vs. 52.3% and 71.9% vs 54.3% for study 1 and study 2, respectively; P<0.001 for both).23 More patients receiving naproxen alone discontinued therapy due to these events (12% vs 3.2% in study 1 [P<0.001] and 11.9% vs 4.8% in study 2 [P=0.009]). Patient-reported upper GI tolerability (as assessed by surveys) was better with combination therapy. No significant differences were found between regimens in terms of adverse effects. The authors concluded that the combination of naproxen and esomeprazole was superior to enteric-coated naproxen alone for reducing the incidence of gastric ulcers in at-risk patients requiring long-term NSAID therapy. A second combination agent (HZT-501) containing ibuprofen 800 mg and famotidine 26.6 mg is under investigation by Horizon Therapeutics.24 A decision on approval by the FDA is anticipated in the first quarter of 2011. Efficacy of HZT-501 was demonstrated in 2 identically designed Phase III trials known as Registration Endoscopic Study to Determine Ulcer Formation of HZT501 Compared to Ibuprofen: Efficacy and Safety Study (REDUCE-1 and REDUCE-2).25 The trials have not been published as of June 2010; however, some details are available. The randomized, double-blind, controlled trials were designed to compare the efficacy of the combination product given 3 times daily for 24 weeks in reducing the incidence of gastric ulcers compared with ibuprofen 800 mg given 3 times daily. The second trial, REDUCE-2, expanded the primary outcome to include the incidence of duodenal ulcers. A total of 1,382 patients participated in the trials. Results revealed that

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Built on data

36 Clinical

Pharmacy Practice News • October 2010

Educational Review

GI ISSUES continued from page 34

the combination product was superior to ibuprofen in reducing the incidence of gastric ulcers (REDUCE-1: 12.9% vs 25.3%; P<0.05) and the incidence of gastric and duodenal ulcers (REDUCE-2: 13.8% vs 22.6%; P<0.05). In addition to the Phase III data, an open-label safety study of the agent is currently recruiting.26 Publication of these trials will provide insight into the role of combination ibuprofen and famotidine in therapy.

Poor Prescribing Patterns Although concomitant use of gastroprotective agents is recommended for patients taking NSAIDs who are at moderate to high risk for GI events, a multitude of data have shown that few patients are prescribed these agents.27-29 A prospective drug utilization study conducted at an orthopedic outpatient unit showed that out of 884 NSAID prescriptions, only 288 (32.6%) were co-prescribed with gastroprotective agents.27 Another study assessing time trends in preventive strategies among 50,126 NSAID users,

of which 43.3% had at least 1 risk factor for an NSAID-related GI complication, showed that approximately 60% of new NSAID users with at least 1 risk factor and 52% of patients with a medical history of an upper GI event were not prescribed a proper preventive strategy.28 A 3-month, retrospective study of 338 patients discharged from an urban hospital on NSAID therapy showed that only 45.6% received any form of gastroprotection.29 These data show that prescribing patterns for gastroprotective agents are poor, and that the use

of cotherapy in patients on NSAIDs needs improvement.

Physician, Patient Education Needed Both prescribers of NSAID therapy and patients need to be educated about the GI risks associated with use of these agents. Physician education is needed to improve the poor prescribing rates for recommended gastroprotective cotherapies. Data have shown that physician education in combination with an electronic computer alert system informing

CSL Behring BRIEF SUMMARY OF PRESCRIBING INFORMATION

Some viruses, such as Parvovirus B19 virus (B19V) or hepatitis A (HAV), are particularly difﬁcult to remove or inactivate. B19V may most seriously affect pregnant women and immune-compromised individuals.

Humate-P® Antihemophilic Factor/von Willebrand Factor Complex (Human)

Although the overwhelming number of B19V and HAV cases are community acquired, reports of these infections have been associated with the use of some plasma-derived products. Therefore, physicians should be alert to the potential symptoms of B19V and HAV infections (see Patient Counseling Information [17.1]). Symptoms of B19V may include low-grade fever, rash, arthralgias, and transient symmetric, nondestructive arthritis. Diagnosis is often established by measuring B19V-speciﬁc IgM and IgG antibodies. Symptoms of HAV include low-grade fever, anorexia, nausea, vomiting, fatigue, and jaundice. A diagnosis may be established by measuring speciﬁc IgM antibodies.

Before prescribing, please consult full prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information. 1 INDICATIONS AND USAGE 1.1 Hemophilia A Humate-P, Antihemophilic Factor/von Willebrand Factor Complex (Human), is indicated for treatment and prevention of bleeding in adults with hemophilia A (classical hemophilia). 1.2 Von Willebrand Disease (VWD) Humate-P is also indicated in adult and pediatric patients with von Willebrand disease (VWD) for: (1) treatment of spontaneous and trauma-induced bleeding episodes, and (2) prevention of excessive bleeding during and after surgery. This applies to patients with severe VWD as well as patients with mild to moderate VWD where use of desmopressin (DDAVP) is known or suspected to be inadequate. Controlled clinical trials to evaluate the safety and efﬁcacy of prophylactic dosing with Humate-P to prevent spontaneous bleeding have not been conducted in VWD subjects (see Clinical Studies [14]). 3 DOSAGE FORMS AND STRENGTHS Humate-P is a sterile, lyophilized powder for intravenous administration. Each vial of Humate-P contains the labeled amount of VWF:RCo and FVIII activity expressed in International Units (IU). The average ratio of VWF:RCo to FVIII is 2.4:1. Approximate potencies are shown below; check each carton/vial for the actual potency prior to reconstitution: VWF:RCo/vial 600 IU 1200 IU 2400 IU

FVIII/vial 250 IU 500 IU 1000 IU

Diluent 5 mL 10 mL 15 mL

IU = International Units.

4 CONTRAINDICATIONS Humate-P is contraindicated in individuals who have had an anaphylactic or severe systemic reaction to antihemophilic factor or von Willebrand factor preparations. 5 WARNINGS AND PRECAUTIONS 5.1 Thromboembolic Events (VWD Patients) Thromboembolic events have been reported in VWD patients receiving Antihemophilic Factor/von Willebrand Factor Complex replacement therapy, especially in the setting of known risk factors for thrombosis.3,4 Early reports indicate a higher incidence may occur in females. Endogenous high levels of FVIII have also been associated with thrombosis, but no causal relationship has been established. Exercise caution and consider antithrombotic measures in all at-risk VWD patients who are receiving coagulation factor replacement therapy. 5.2 Monitoring for Intravascular Hemolysis Humate-P contains blood group isoagglutinins (anti-A and anti-B). When doses are very large or need to be repeated frequently (for example, when inhibitors are present or when pre- and post-surgical care is involved), monitor patients of blood groups A, B, and AB for signs of intravascular hemolysis and decreasing hematocrit values and treat appropriately. 5.3 Monitoring VWF:RCo and FVIII Levels Monitor the VWF:RCo and FVIII levels of VWD patients receiving Humate-P using standard coagulation tests, especially in cases of surgery. It is advisable to monitor trough VWF:RCo and FVIII:C levels at least once a day in order to adjust the dosage of Humate-P as needed to avoid excessive accumulation of coagulation factors (see Dosage and Administration [2.2, 2.3]). 5.4 Transmission of Infectious Agents Humate-P is made from human plasma. Products made from human plasma may contain infectious agents (e.g., viruses and theoretically, the Creutzfeldt-Jakob disease [CJD] agent) that can cause disease (see Description [11] and Patient Counseling Information [17.1]). The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacturing (see Description [11.1] for virus reduction measures). Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Thus the risk of transmission of infectious agents cannot be eliminated completely. Report all infections thought by a physician possibly to have been transmitted by this product to CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800FDA-1088 or www.fda.gov/medwatch.

Physicians should strongly consider administration of hepatitis A and hepatitis B vaccines to individuals receiving plasma derivatives. Potential risks and benefits of vaccination should be weighed by the physician and discussed with the patient. 6 ADVERSE REACTIONS The most serious adverse reaction observed in patients receiving Humate-P is anaphylaxis. Thromboembolic events have also been observed in patients receiving Humate-P for the treatment of VWD (see Warnings and Precautions [5.1]). Reports of thromboembolic events in VWD patients with other thrombotic risk factors receiving coagulation factor replacement therapy have been obtained from spontaneous reports, published literature, and a European clinical study. In some cases, inhibitors to coagulation factors may occur. However, no inhibitor formation was observed in any of the clinical studies. In patients receiving Humate-P in clinical studies for treatment of VWD, the most commonly reported adverse reactions observed by >5% of subjects are allergic-anaphylactic reactions (including urticaria, chest tightness, rash, pruritus, and edema. For patients undergoing surgery, the most common adverse reactions are postoperative wound and injection-site bleeding, and epistaxis. 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. Treatment of Bleeding Episodes in VWD Allergic symptoms, including allergic reaction, urticaria, chest tightness, rash, pruritus, and edema, were reported in 6 of 97 (6%) subjects in a Canadian retrospective study (see Clinical Studies [14.1]). Four of 97 (4%) subjects experienced seven adverse events that were considered to have a possible or probable relationship to Humate-P. These included chills, phlebitis, vasodilation, paresthesia, pruritus, rash, and urticaria. All were mild in intensity with the exception of a moderate case of pruritus. In a prospective, open-label safety and efficacy study of Humate-P in VWD subjects with serious life- or limb-threatening bleeding or undergoing emergency surgery, seven of 71 (10%) subjects experienced nine adverse reactions. These were one occurrence each of mild vasodilation and mild pruritis; two occurrences of mild paresthesia; and one occurrence each of moderate peripheral edema and extremity pain and severe pseudothrombocytopenia (platelet clumping with a false low reading). Humate-P was discontinued in the subject who experienced the peripheral edema and extremity pain. Prevention of Excessive Bleeding During and After Surgery in VWD Among the 63 VWD subjects who received Humate-P for prevention of excessive bleeding during and after surgery, including one subject who underwent colonoscopy without the planned polypectomy, the most common adverse events were postoperative hemorrhage (35 events in 19 subjects with five subjects experiencing bleeding at up to three different sites), postoperative nausea (15 subjects), and postoperative pain (11 subjects). Table 5 presents the postoperative hemorrhagic adverse events. Table 5: Hemorrhagic Adverse Events in 63 Surgical Subjects Adverse Event

Wound/injection site bleeding Epistaxis Cerebral hemorrhage/ subdural hematoma Gastrointestinal bleeding Menorrhagia Groin bleed

Surgical Procedure Category

Number of Subjects/ Events

Major Minor Oral Major Minor

8/11 2/2 2/6 4/4 1/1

Major

1/2

Major

1/3

Major Oral

1/1 1/1

Onset* Severity (Number of (Number of Events) Events) On Post Mild Mod Severe 7 4 9 – 2 2 – 1 1 – – 6 3 3 – 2 2 3 1 – 1 – 1 – – 2† 3‡ 1 –

–

– 1

1 –

– –

Clinical 37

Pharmacy Practice News • October 2010

Educational Review prescribers about the current recommended preventive strategies increases the use of gastroprotection among NSAID users.30 A study showed that use of gastroprotection increased from 43% to 61% when an electronic computer alert and physician education were implemented at a hospital (P<0.001), and this rate increased even more in PPI-naive patients (from 26% to 55%; P<0.0001). Physicians need to be educated about the safety and effectiveness of gastroprotective therapies in patients receiving chronic NSAID

Adverse Event Ear bleed Hemoptysis Hematuria Shoulder bleed * † ‡ §

Surgical Procedure Category Major Major Major Major

Number of Subjects/ Events 1/1 1/1 1/1 1/1

Onset* (Number of Events) 1 – 1 – 1 – 1 –

therapy. It has been estimated that patients with one or more risk factors for upper GI complications receive no gastroprotection regimen 70% to 80% of the time.30 Therefore, pharmacists should strive to educate physicians on the risk factors for NSAID-induced gastroduodenal ulcers and the role of prophylactic therapies. In addition, pharmacists should educate physicians about the availability of new agents that have combined a nonselective NSAID with a PPI or H2RA, because these agents may offer a more convenient dosing

1 1 1 1

Severity (Number of Events) – – – – – – – –

On = on-therapy; onset while receiving Humate-P or within 1 day of completing Humate-P administration. Post = post-therapy; onset at least one day after completing Humate-P administration. Reported as serious adverse events following intracranial surgery. Two of these events were reported as serious adverse events following gastrojejunal bypass. Reported as a serious adverse event requiring hysterectomy following hysteroscopy and dilation and curettage.

Table 6 lists the non-hemorrhagic adverse events reported in at least two subjects, regardless of causality, and the adverse events that were possibly related to Humate-P. Pulmonary embolus considered possibly related to Humate-P occurred in one elderly subject who underwent bilateral knee replacement. Table 6: Non-Hemorrhagic and Possibly Related Adverse Events in 63 Surgical Subjects

Body System

Body as a whole

Cardiovascular

Digestive Hemic and lymphatic system Metabolic/ nutritional Nervous Skin and appendages Urogenital * †

Adverse Event (AE)

Pain Fever Abdominal pain Infection Surgery Back pain Facial edema Chest pain Pulmonary embolus† Thrombophlebitis† Nausea Constipation Vomiting Sore throat Anemia / decreased hemoglobin

Number of Subjects With an AE Possibly Related to Humate-P – – – – – – – –

Number of Subjects With an AE Regardless of Causality* 11 4 3 3 3 2 2 3

1 1 – 1 –

1 15 7 3 2

–

Increased SGPT

Dizziness Headache Increased sweating Insomnia Pruritus Rash Urinary retention Urinary tract infection

1 1 – – – 1 –

5 4 3 2 3 1 4

–

Events occurring in two or more subjects. Events occurring in separate subjects.

Eight subjects experienced 10 postoperative serious adverse events: one with subdural hematoma and intracerebral bleeding following intracranial surgery related to an underlying cerebrovascular abnormality; one with two occurrences of gastrointestinal bleeding following gastrojejunal bypass; and one each with sepsis, facial edema, infection, menorrhagia requiring hysterectomy following hysteroscopy and dilation and curettage, pyelonephritis, and pulmonary embolus. 6.2 Postmarketing Experience The following adverse reactions have been identiﬁed during postapproval use of Humate-P. Because these reactions are reported voluntarily from a

option for patients. For patients, the American Gastroenterological Association Institute and Horizon Therapeutics have partnered and developed a Web site known as Connect to Protect (www. connecttoprotect.com), which educates patients about the GI risks associated with NSAIDs and how to manage those risks.31 Specific patient-related materials on the Web site include a discussion guide to help patients track their potential risks and prepare to discuss those risks with their physician, a dictionary

of terms commonly used in diagnosing and treating NSAID-induced GI issues, and a patient narrative detailing firsthand experience of complications from chronic NSAID use. The Web site also contains tools for physicians such as a discussion guide, references on this topic, and a webinar program. The FDA has also published Guide to Safe Use of Pain Medicine, which is available on the agency’s consumer health information Web page (www. fda.gov/ForConsumers).32 The document includes numerous tips for counseling patients to safely use NSAIDs (Table 4).

population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Humate-P exposure.

Conclusion

Adverse reactions reported in patients receiving Humate-P for treatment of VWD or hemophilia A are allergic-anaphylactic reactions (including urticaria, chest tightness, rash, pruritus, edema, and shock), development of inhibitors to FVIII, and hemolysis. Additional adverse reactions reported for VWD are thromboembolic complications, chills and fever, and hypervolemia. 7 DRUG INTERACTIONS None reported.

NSAID-related GI toxicity is an increasing problem and results in 100,000 hospital admissions and 7,000 to 10,000 deaths annually in the United States.2 The 2009 ACG guidelines on the prevention of NSAID-related ulcer complications were designed to give clinicians specific recommendations on the use of appropriate gastroprotective agents in patients receiving NSAIDs, with the goal of reducing the substantial burden associated with NSAID-related GI effects. Unfortunately, many studies have shown that clinicians are failing to follow these recommendations, and many patients at risk for NSAID-related GI effects are not receiving appropriate gastroprotective agents.27-29 Therefore, prescribers need to be educated about the occurrence of NSAID-related GI complications, which patients are at the greatest risk for these potential adverse events, and about the availability of new agents that have combined a nonselective NSAID with a PPI or H2RA. In addition, patients need to understand their potential risks for NSAID-related GI adverse events, signs and symptoms of these events, and the proper steps to take if these events occur. Pharmacists can educate patients about the Connect to Protect Web site and the availability of materials on this topic on the FDA consumer Web site.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Humate-P. It is also not known whether Humate-P can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Humate-P should be given to a pregnant woman only if clearly needed. 8.2 Labor and Delivery It is not known whether Humate-P can cause harm to the mother or the fetus when administered during labor and delivery. Humate-P should be given during labor and delivery only if clearly needed. 8.3 Nursing Mothers It is not know whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Humate-P is administered to a nursing woman. 8.4 Pediatric Use Hemophilia A Adequate and well-controlled studies with long-term evaluation of joint damage have not been done in pediatric subjects. Joint damage may result from suboptimal treatment of hemarthroses. VWD The safety and effectiveness of Humate-P for the treatment of VWD was demonstrated in 26 pediatric subjects, including infants, children, and adolescents, but have not been evaluated in neonates. The safety of Humate-P for the prevention of excessive bleeding during and after surgery was demonstrated in eight pediatric subjects (ages 3 to 15) with VWD. Of the 34 pediatric subjects studied for either treatment of bleeding episodes in VWD or prevention of excessive bleeding during and after surgery, four were infants (1 month to under 2 years of age), 23 were children (2 through 12 years), and seven were adolescents (13 through 15 years). As in adults, pediatric patients should be dosed based on body weight (kg) (see Dosage and Administration [2.2, 2.3]). 8.5 Geriatric Use Clinical studies of Humate-P did not include sufﬁcient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects. As for all patients, dosing for geriatric patients should be appropriate to their overall situation. 15 REFERENCES 3. Mannucci, PM. Venous Thromboembolism in Von Willebrand Disease. Thromb Haemostas. 2002;88:378-379. 4. Markis M, Colvin B, Gupta V, Shields ML, Smith MP. Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand’s disease. Thromb Haemostas. 2002;88:387-388.

Manufactured by: CSL Behring GmbH 35041 Marburg, Germany US License No. 1765

Distributed by: CSL Behring LLC Kankakee, IL 60901 USA

References 1.

Based on January 2010 revision.

Mix2Vial is a trademark of West Pharmaceuticals Services, Inc.

Arroyo M, Lanas A. NSAIDs-induced gastrointestinal damage. Minerva Gastroenterol Dietol. 2006;52(3):249-259.

2. Lanza FL, Chan FK, Quigley EM; Practice Parameters Committee of the American College of Gastroenterology. Guidelines for prevention of NSAID-related ulcer complications. Am J Gastroenterol. 2009;104(3):728-738. 3. Vakil N. The prevention of gastropathy and upper abdominal symptoms caused by nonsteroidal anti-inflammatory drugs. Rev Gastroenterol Disord. 2006;6 (4):221-226.

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4. Bijlsma JW. Patient benefit-risk in arthritis—a rheumatologist’s perspective. Rheumatology (Oxford). 2010;49(Suppl 2): ii11-ii17. 5. Pilotto A, Sancarlo D, Addante F, Scarcelli C, Franceschi M. Non-steroidal anti-inflammatory drug use in the elderly. Surg Oncol. 2010;19(3):167-172. 6. Bardou M, Barkun AN. Preventing the gastrointestinal adverse effects of nonsteroidal anti-inflammatory drugs: from risk factor identification to risk factor intervention. Joint Bone Spine. 2010;77(1):6-12.

11. Cytotec [package insert]. Phoenix, AZ: Apotheca; 2010. 12. Yeomans ND, Tulassay Z, Juhász L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med. 1998;338(11):719-726. 13. Hawkey CJ, Karrasch JA, Szczepañski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal antiinflammatory drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. N Engl J Med.1998;338(11):727-734.

7. Food and Drug Administration. Questions and answers on final rule for labeling changes to over-the-counter pain relievers. www.fda.gov/Drugs/NewsEvents/ ucm144068.htm. Accessed June 18, 2010.

14. Arora G, Singh G, Triadafilopoulos G. Proton pump inhibitors for gastroduodenal damage related to nonsteroidal anti-inflammatory drugs or aspirin: twelve important questions for clinical practice. Clin Gastroenterol Hepatol. 2009;7(7):725-735.

8. Food and Drug Administration. Organspecific warnings; internal analgesic, antipyretic, and antirheumatic drug products for over-the-counter human use; final monograph. Fed Regist. 2009;74(81): 19385-19409.

15. Aseeri M, Schroeder T, Kramer J, Zackula R. Gastric acid suppression by proton pump inhibitors as a risk factor for Clostridium difficile-associated diarrhea in hospitalized patients. Am J Gastroenterol. 2008;103(9):2308-2313.

9. Silverstein FE, Graham DY, Senior JR, et al. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving nonsteroidal antiinflammatory drugs. A randomized, doubleblind, placebo-controlled trial. Ann Intern Med. 1995;123(4):241-249.

16. Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ. 2008;179(4):319-326.

10. Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced gastroduodenal ulcers. Cochrane Database Syst Rev. 2002;(4):CD002296.

17. Sarkar M, Hennessy S, Yang YX. Protonpump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med. 2008;149(6):391-398. 18. Thomson ABR, Sauve MD, Kassam N, Kamitakahara H. Safety of the long-term use of proton pump inhibitors. World J

Gastroenterol. 2010;16(19):2323-2330. 19. Food and Drug Administration. Information for healthcare professionals: update to the labeling of clopidogrel bisulfate (marketed as Plavix) to alert healthcare professionals about a drug interaction with omeprazole (marketed as Prilosec and Prilosec OTC). www.fda.gov/Drugs/DrugSafety/ PostmarketDrugSafetyInformationfor PatientsandProviders/DrugSafety InformationforHeathcareProfessionals/ ucm190787.htm. Accessed June 21, 2010. 20. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009;180(7):713-718. 21. Neubauer H, Engelhardt A, Kruger JC, et al. Pantoprazole does not influence the antiplatelet effect of clopidogrel: a whole blood aggregometry study after coronary stenting. J Cardiovasc Pharmacol. 2010;56(1):91-97. 22. Vimovo [package insert]. Wilmington, DE: AstraZeneca; 2010. 23. Goldstein JL, Hochberg MC, Fort JG, Zhang Y, Hwang C, Sostek M. Clinical trial: incidence of NSAID-associated endoscopic gastric ulcers in patients treated with PN 400 (naproxen plus esomeprazole magnesium) vs. enteric-coated naproxen alone. Aliment Pharmacol Ther. 2010;32(3):401-413.. 24. Horizon Pharma. Horizon Pharma announces FDA acceptance of HZN-501 new drug application filing. www. horizontherapeutics.com/ArticleDetail. asp?tid=156. Accessed June 18, 2010. 25. Birk JW, Myers M. A fixed dose combination of ibuprofen and famotidine. Expert Opin

Investig Drugs. 2009;18(9):1358-1391. 26. U.S. National Institutes of Health. ClinicalTrials.gov. Safety study of HZT-501 in patients who require long-term daily nonsteroidal anti-inflammatory drug (NSAID) treatment. http://clinicaltrials.gov/ct2/show/ NCT00984815. Accessed June 18, 2010. 27. Raghavendra B, Narendranath S, Ullal SD, et al. Trends in prescribing gastroprotective agents with non steroidal anti-inflammatory drugs in an orthopedic outpatient unit of a tertiary care hospital. JCDR. 2009;3(3):1553-1556. 28. Valkhoff VE, van Soest EM, Sturkenboom MC, Kuipers EJ. Time-trends in gastroprotection with nonsteroidal antiinflammatory drugs (NSAIDs). Aliment Pharmacol Ther. 2010;31(11):1218-1228. 29. Coté GA, Norvell JP, Rice JP, Bulsiewicz WJ, Howden CW. Use of gastroprotection in patients discharged from hospital on nonsteroidal anti-inflammatory drugs. Am J Ther. 2008;15(5):444-449. 30. Coté GA, Rice JP, Bulsiewicz W, et al. Use of physician education and computer alert to improve targeted use of gastroprotection among NSAID users. Am J Gastroenterol. 2008;103(5):1097-1103. 31. Horizon Pharma. AGA Institute and Horizon Therapeutics expand CONNECT to protect program to educate consumers on NSAID risk. www.horizontherapeutics.com/Article Detail.asp?tid=128. Accessed June 22, 2010. 32. Food and Drug Administration. A guide to safe use of pain medicine. www.fda.gov/ downloads/ForConsumers/Consumer Updates/ucm095742.pdf. Accessed June 22, 2010.

OPERATIONS & MANAGEMENT

Practice Pearl

RECONCILIATION continued from page 10

nurse reconciliation that was observed during the study. The hospital is a highstress environment for a patient and it is difficult to collect accurate medication information from patients in this setting. The nursing staff often is juggling multiple patients, which can make it difficult for them to contact physicians, community pharmacies, and family members to gain the medication history of a new patient. Pharmacists, who are the medication experts, have more experience with what questions to ask patients to gain a more complete history and are also able to ask the physicians and community pharmacies more direct questions regarding the medication history when the patient is unable to provide the information. It also can be difficult to obtain information from other institutions due to HIPAA regulations, occasionally turning the information-garnering process into a time-consuming affair. Nursing time constraints due to patient care, medication administration, and charting may make it difficult for both the ED nurse and floor nurse to access this information. Pharmacists also are more familiar with medication dosing and frequency of medication administration, preventing some of the

common errors made by the nursing staff that can occur when they try to reconcile medications with which they are not familiar. This pharmacist familiarity leads to a decrease in errors when they enter the patient’s medication history into the chart for physician review.

Conclusion There are many opportunities for improvement in medication reconciliation. Including pharmacists in the medication reconciliation process improves success. Pharmacists are medication experts and have insight about target questions to ask patients when they review their chart for the medical history. Implementing a program that involves pharmacists is ideal; however, this is not always possible given budgeting and staffing constraints. Therefore, increasing nursing education about medication reconciliation would be beneficial. Providing a reference list of questions for the nurse to ask patients may increase the completeness of the history. Also, educating the nursing staff on the importance of all medications, including overthe-counter medications and vitamins, is important because these medications can account for a significant amount of interactions. An environment of open communication between patients, nurs-

es, pharmacists, and physicians is ideal for medication reconciliation. Increasing staff awareness of the importance of the medication reconciliation process ultimately will improve overall patient care and safety. The authors have no potential conflicts of interest to disclose. At the time of the study, Dr. Hysan was affiliated with The Medical Center of Aurora. She is currently affiliated with Lawnwood Regional Medical Center and Heart Institute in Fort Pierce, Florida.

References

Goals. http://www.JointCommission.org/ PatientSafety/NationalPatientSafetyGoals/. Accessed August 2, 2010.

Suggested Reading Agency for Healthcare Research and Quality. Medication Reconciliation. Patient safety primer. http://www.psnet.ahrq.gov/primer. aspx?primerID=1 Accessed August 2, 2010.

New Product Advertisement Bedford Labs Now Shipping Sumatriptan Succinate in Pre-filled Syringes

1. The Institute for Healthcare Improvement. Protecting 5 million lives from harm. http:// www.ihi.org/IHI/Programs/Campaign/Campaign.htm?TabId=1. Accessed August 2, 2010. 2. The Institute for Healthcare Improvement. Errors from unreconciled medications per 100 admissions. http://www.ihi.org/IHI/Topics/PatientSafety/MedicationSystems/Measures/Errors+Related+to+Unreconciled+ Medications+per+100+Admissions.htm. Accessed August 2, 2010. 3. American Society of Health-System Pharmacists. ASHP Medication Reconciliation (Med Rec) Toolkit. http://www.ashp.org/Import/ PRACTICEANDPOLICY/PracticeResourceCenters/PatientSafety/ASHPMedicationReconciliationToolkit_1.aspx. Accessed August 2, 2010. 4. American Medical Association. Medication Reconciliation. http://www.ama-assn.org/ama/ no-index/physician-resources/medication-reconciliation.shtml. Accessed August 2, 2010. 5. The Joint Commission. National Patient Safety

edford Laboratories, a division of Ben Venue Laboratories, Inc announced that Sumatriptan Succinate Injection, 6 mg (base)/0.5 mL pre-filled syringes are now shipping. Sumatriptan Succinate Injection is indicated for the acute treatment of migraine attacks with or without aura, and the acute treatment of cluster headache episodes. The product is AP-rated to Imitrex, according to the company.

For more information, call 800.521.5169, or visit the company’s web site, www.bedfordlabs.com

Gelfoam + Human Thrombin In one kit. ®

Gelfoam Plus...

• Provides cost savings compared to items purchased separately1 • Provides up to 20 mL of volume to saturate the GELFOAM sterile sponge • Allows easy management of thrombin use • Helps consolidate inventory of multiple products

And FLOSEAL [Hemostatic Matrix] are part of a complete hemostasis product line from Baxter. For more information please contact your local Baxter BioSurgery Representative or call 1-800-423-2090.

www.baxterbiosurgery.com

GELFOAM PLUS Hemostasis Kit Indications GELFOAM PLUS is intended as a hemostatic device for surgical procedures when control of capillary, venous, and arteriolar bleeding by pressure, ligature, and other conventional procedures is either ineffective or impractical. Thrombin (Human) used without the Gelfoam Sterile Sponge is not indicated for hemostasis. Important Safety Information GELFOAM PLUS should not be used in closure of skin incisions, because it may interfere with the healing of the skin edges. GELFOAM PLUS should not be placed intravascularly, because of the risk of embolization. GELFOAM PLUS is not recommended for use other than an adjunct for hemostasis. GELFOAM PLUS contains thrombin, which is made from human plasma. It may carry the risk of transmitting infectious agents, e.g., viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent. While packing a cavity for hemostasis is sometimes surgically indicated, GELFOAM PLUS should not be used in this manner unless excess product not needed to maintain hemostasis is removed. Whenever possible, GELFOAM PLUS should be removed after use in laminectomy procedures and from foramina in bone, once hemostasis is achieved. This is because GELFOAM Plus may swell to its original size on absorbing ﬂuids, and produce nerve damage by pressure within conﬁned bony spaces. GELFOAM PLUS is not recommended in the presence of infection. There have been reports of fever associated with the use of Gelfoam Sterile Sponge, without demonstrable infection.

FLOSEAL [Hemostatic Matrix] Indications FLOSEAL is indicated in surgical procedures (other than ophthalmic) as an adjunct to hemostasis when control of bleeding by ligature or conventional procedures is ineffective or impractical. Important Safety Information FLOSEAL must not be injected into blood vessels, or allowed to enter blood vessels. Do not apply in the absence of active bleeding. Extensive intravascular clotting and even death may result. Do not use FLOSEAL in the closure of skin incisions because it may interfere with the healing of the skin edges. Do not use FLOSEAL in patients with known allergies to materials of bovine origin. FLOSEAL is made from human plasma. It may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The maximum swell volume of approximately 20% is achieved within about 10 minutes. Excess FLOSEAL (material not incorporated in the hemostatic clot) should be removed from the site of application using gentle irrigation. RX only: For safe and proper use of these devices, please refer to full device Instructions For Use.

1. 2006 IMS Hemostat and Sealant Revenue, Unit, and ASP Sales Data. Baxter, FLOSEAL and ADVANCING SURGERY,ENHANCING LIFE are trademarks of Baxter International Inc. Gelfoam is a registered trademark of Pharmacia & Upjohn Company LLC., used under license. BS1889 4/2008

40 Clinical

Pharmacy Practice News • October 2010

Infectious Disease

Catheter-Tip Cultures for Bloodstream Infections Questioned Study too small to alter current practice? Las Vegas—Researchers from Detroit are calling into question the longstanding practice of obtaining catheter-tip cultures in order to diagnose and manage catheter-related bloodstream infections. “It’s been our experience that catheter-tip cultures rarely change therapy when bacteremia has been identified, suggesting that routine vascular catheter cultures in the management of suspected catheter-related bloodstream infection [CR-BSI] in the ICU setting may not be required,” said the study’s lead author, Steven D. Tennenberg, MD, associate professor of surgery at Wayne State University School of Medicine and director of the surgical intensive care unit at Harper University Hospital.

were not associated with a case of CR-BSI. Overall, only one in 10 catheter-tip cultures was associated with a case of CR-BSI. The majority of CR-BSI cases were diagnosed based on blood cultures obtained before or at the time of catheter removal. Ninety-eight percent (47 of 48) of the CR-BSIs were identified by bacteremia. It was the bacteremia that dictated

antimicrobial therapy. Patients received appropriate antibiotics based on the blood culture in 94% of cases (45 of 48). In 6% of cases (n=3), the antibiotic therapy was considered inadequate. “The data from this study leads us to seriously question the longstanding dogma that catheter-tip cultures are necessary in the clinical diagnosis,

and more importantly, the management of criti-cally ill patients with th suspected CR-BSI,”” said id Dr. Rose. The investigators now do not seek regular catheter-tip cultures for suspected cases of CR-BSI. The study met with mixed reviews

Guidelines Unclear The report comes at a time when guidelines regarding catheter-tip cultures are somewhat unclear, despite recent revisions. This year, the Centers for Disease Control and Prevention (CDC) modified its epidemiologic definition of CR-BSI to only require bacteremia with the absence of an identified noncatheter source. In the past, the CDC required blood and catheter-tip cultures with the same organism to diagnose CR-BSI. Other organizations still advise physicians to obtain tip cultures. The Infectious Diseases Society of America recommends that catheter cultures be performed when a catheter is removed for suspected CR-BSI. The society also advocates cultures to check for Staphylococcus aureus colonization in the absence of bacteremia. At the 2010 annual meeting of the Surgical Infection Society (SIS), coinvestigator Alexander Rose, MD, a surgical resident at Wayne State, reported results from his group’s retrospective review of all CR-BSI in a 40-bed, mixed medical-surgical ICU. Of the 474 catheter-tip cultures obtained between Sept. 1, 2006, and mid-November 2009, 132 (28%) were positive. Most positive cultures (64%)

What’s Your View?

Humulin N is now available in a smaller vial.*

Indication, continued

Lilly also offers Humalog and Humulin R U-100 in a smaller vial size.*

Humalog should be used with longer-acting insulin, except when used in combination with sulfonylureas in patients with type 2 diabetes.

The smaller vials are designed to give hospitals ﬂexibility when evaluating insulin storage and distribution (ﬂoor stock vs individual patient supply), in addition to the 10 mL vial and Humalog® KwikPen™. Same bar-coding technique, same color-differentiating system, smaller size. • Humalog® (insulin lispro injection [rDNA origin]) NDC Number - 0002-7510-17 • Humulin® N (NPH human insulin [rDNA origin] isophane suspension) NDC Number - 0002-8315-17 • Humulin® R U-100 (regular insulin human injection, USP [rDNA origin]) NDC Number - 0002-8215-17 * Smaller vials contain 3 mL of insulin in a 5 mL vial.

=?6;A

@5.?2

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Humalog Indication Should staff stop obtaining catheter-tip cultures as a guide for diagnosing and managing catheterrelated bloodstream infections?

Humalog (insulin lispro injection [rDNA origin]) is for use in patients with diabetes mellitus for the control of hyperglycemia.

Send replies to

ppneditor@mcmahonmed.com HI65435

0710 PRINTED IN USA

Humalog Important Safety Information Contraindications Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or one of its excipients. Warnings Humalog differs from regular human insulin by its rapid onset of action as well as a shorter duration of action. Therefore, when used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Due to the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an insulin pump). Glucose monitoring is recommended for all patients with diabetes. The safety and effectiveness of Humalog in patients less than 3 years of age have not been established.

Clinical 41

Pharmacy Practice News • October 2010

Infectious Disease from attendees at the SIS annual meeting. Some said the study illustrates that the th practice of routine catheter-tip cultures is ca outdated and unnecessary. Critics said the study was too small and provided too few details to warrant pracde tice changes. “It’s a pilot study ti h for them to examine their data and practice patterns. It’s not a study to globally change our practice paradigm,” said Lewis Kaplan, MD, associate professor of surgery at Yale University School of

The report comes at a time when guidelines regarding catheter-tip cultures are somewhat unclear, despite recent revisions. Medicine, in New Haven, Conn. Dr. Kaplan said he removes catheters and cultures the tips in all suspected cases of bacteremia, catheter-site infec-

tions or CR-BSI. He does not plan to change his practice, he added. The surgeons at Wayne State believe that S. aureus cases rarely will be missed even if catheter-tip cultures are not obtained regularly. In their study, they identified five cases of S. aureus catheter colonization in the absence of bacteremia. However, in four of the five cases, the patients were started on vancomycin prior to the catheter removal. “The clinical relevance of isolated S. aureus-positive catheter-tip cultures was very small,” Dr. Rose said. The investigators pointed out that

Introducing our newest small vial for an even larger range of options.

Important Safety Information, continued

Warnings, continued There are no adequate and well-controlled clinical studies of the use of Humalog in pregnant or nursing women.

Other Side Effects, continued Because of the difference in action of Humalog, care should be taken in patients in whom hypoglycemia or hypokalemia may be clinically relevant (eg, those who are fasting, have autonomic neuropathy or renal impairment, are using potassium-lowering drugs, or taking drugs sensitive to serum potassium level).

Starting or changing insulin therapy should be done cautiously and only under medical supervision. Hypoglycemia Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. Hypoglycemia can happen suddenly, and symptoms may be different for each person and may change from time to time. Severe hypoglycemia can cause seizures and may be life-threatening. Other Side Effects Other potential side effects associated with the use of insulins include: hypokalemia, weight gain, lipodystrophy, and hypersensitivity. Systemic allergy is less common, but may be life-threatening.

Please see reverse side for Brief Summary of full Prescribing Information. Please see full user manual that accompanies the pen. Humalog® and Humalog® KwikPen™ are registered trademarks of Eli Lilly and Company and are available by prescription only. Humulin® is a registered trademark of Eli Lilly and Company.

cultures waste precious dollars and technician time. They calculated that, in their hospital, the costs for culture tips equalled approximately $20,000 and required 205 microbiology technician-hours. “If we were to translate this to the national incidence of just ICU cases of CR-BSI and the costs associated with culturing all the catheters,” Dr. Rose said, “it would be in the neighborhood of $33 million per year and a significant amount of technician hours.” —Christina Frangou

42 Clinical

Pharmacy Practice News • October 2010

Critical Care

OR DRUG SAFETY continued from page 1

“Anesthesia providers, at the head of the table in the OR, are going to need to surrender some of their traditional, wellprotected autonomy,” said John Eichhorn, MD, professor of anesthesiology at the University of Kentucky College of Medicine, in Lexington, and consultant to the executive committee of the APSF board of directors. “The only way to really help prevent some of these errors is for other people and other systems to be involved in the process. There has to be a

significant departure from traditions, and traditions are very hard to change.” The recommendations come from a conference, held in January in Phoenix, that included 100 stakeholders from various ends of the health care spectrum. The participants proposed a new paradigm for improving medication safety in the OR, including four specific parts: standardization, technology, pharmacy/ prefilled/premixed and culture. Dr. Eichhorn, who wrote the report on the conference, said a video likely will be produced for educational purposes on some of the recommendations.

The next steps toward implementation largely involve getting the message out on which areas of medication practice in the OR need improvement. If anesthesia and pharmacy directors, along with OR administrators, collectively approach hospital administration with the call for improvements, it could help the push to improve patient care, he said.

Putting Pharmacists in the OR Among the recommendations is one that hospital pharmacists should become more involved with dispensing medications in the OR. Satellite pharma-

HUMALOG® INSULIN LISPRO INJECTION (rDNA ORIGIN) BRIEF SUMMARY: Consult package insert for complete prescribing information. INDICATIONS AND USAGE: Humalog is an insulin analog that is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Humalog has a more rapid onset and a shorter duration of action than regular human insulin. Therefore, in patients with type 1 diabetes, Humalog should be used in regimens that include a longer-acting insulin. However, in patients with type 2 diabetes, Humalog may be used without a longer-acting insulin when used in combination therapy with sulfonylurea agents. Humalog may be used in an external insulin pump, but should not be diluted or mixed with any other insulin when used in the pump. Humalog administration in insulin pumps has not been studied in patients with type 2 diabetes. CONTRAINDICATIONS: Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or any of its excipients. WARNINGS: This human insulin analog differs from regular human insulin by its rapid onset of action as well as a shorter duration of activity. When used as a mealtime insulin, the dose of Humalog should be given within 15 minutes before or immediately after the meal. Because of the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an external insulin pump). External Insulin Pumps: When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin. Patients should carefully read and follow the external insulin pump manufacturer’s instructions and the “PATIENT INFORMATION” leaflet before using Humalog. Physicians should carefully evaluate information on external insulin pump use in the Humalog physician package insert and in the external insulin pump manufacturer’s instructions. If unexplained hyperglycemia or ketosis occurs during external insulin pump use, prompt identification and correction of the cause is necessary. The patient may require interim therapy with subcutaneous insulin injections (see PRECAUTIONS, For Patients Using External Insulin Pumps, and DOSAGE AND ADMINISTRATION). Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using an external insulin pump. Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (eg, regular, NPH, analog), species, or method of manufacture may result in the need for a change in dosage. PRECAUTIONS: General—Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the use of all insulins. Because of differences in the action of Humalog and other insulins, care should be taken in patients in whom such potential side effects might be clinically relevant (eg, patients who are fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to serum potassium level). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins. As with all insulin preparations, the time course of Humalog action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity. Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stress. Hypoglycemia—As with all insulin preparations, hypoglycemic reactions may be associated with the administration of Humalog. Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control. Renal Impairment—The requirements for insulin may be reduced in patients with renal impairment. Hepatic Impairment—Although impaired hepatic function does not affect the absorption or disposition of Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary. Allergy—Local Allergy—As with any insulin therapy, patients may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Systemic Allergy—Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life-threatening. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient. In Humalog-controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving Humulin R® (N=2969) and 30 patients receiving Humalog (N=2944) (P=.053). Antibody Production—In large clinical trials, antibodies that cross-react with human insulin and insulin lispro were observed in both Humulin R- and Humalog-treatment groups. As expected, the largest increase in the antibody levels during the 12-month clinical trials was observed with patients new to insulin therapy. Usage of Humalog in External Insulin Pumps—The infusion set (reservoir syringe, tubing, and catheter), Disetronic® D-TRON®2,3 or D-TRONplus®2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced and a new infusion site selected every 48 hours or less. Humalog in the external insulin pump should not be exposed to temperatures above 37°C (98.6°F). In the D-TRON ®2,3 or D-TRONplus ®2,3 pump, Humalog 3 mL cartridges may be used for up to 7 days. However, as with other external insulin pumps, the infusion set should be replaced and a new infusion site should be selected every 48 hours or less. When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin (see INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, For Patients Using External Insulin Pumps, Mixing of Insulins, DOSAGE AND ADMINISTRATION, and Storage). Information for Patients—Patients should be informed of the potential risks and advantages of Humalog and alternative therapies. Patients should also be informed about the importance of proper insulin storage, injection technique, timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose monitoring, periodic hemoglobin A1C testing, recognition and management of hypoglycemia and hyperglycemia, and periodic assessment for diabetes complications. Patients should be advised to inform their physician if they are pregnant or intend to become pregnant. Refer patients to the “PATIENT INFORMATION” leaflet for timing of Humalog dosing (< _15 minutes before or immediately after a meal), storing insulin, and common adverse effects. For Patients Using Insulin Pen Delivery Devices: Before starting therapy, patients should read the “PATIENT INFORMATION” leaflet that accompanies the drug product and the User Manual that accompanies the delivery device. They should also reread these materials each time the prescription is renewed. Patients should be instructed on how to properly use the delivery device, prime the Pen to a stream of insulin, and properly dispose of needles. Patients should be advised not to share their Pens with others. For Patients Using External Insulin Pumps: Patients using an external infusion pump should be trained in intensive insulin therapy and in the function of their external insulin pump and pump accessories. Humalog was tested in the MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested in the Disetronic ®2 H-TRONplus ® V100 insulin pump (with plastic 3.15 mL insulin reservoir), and the Disetronic D-TRON ®2,3 and D-TRONplus ®2,3 insulin pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets. The infusion set (reservoir syringe, tubing, catheter), D-TRON®2,3 or D-TRONplus ®2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced, and a new infusion site selected every 48 hours or less. Humalog in the external pump should not be exposed to temperatures above 37°C (98.6°F). A Humalog 3 mL cartridge used in the D-TRON ®2,3 or D-TRONplus ®2,3 pump should be discarded after 7 days, even if it still contains Humalog. Infusion sites that are erythematous, pruritic, or thickened should be reported to medical personnel, and a new site selected. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. Laboratory Tests—As with all insulins, the therapeutic response to Humalog should be monitored by periodic blood glucose tests. Periodic measurement of hemoglobin A1C is recommended for the monitoring of long-term glycemic control. Drug Interactions—Insulin requirements may be increased by medications with hyperglycemic activity, such as corticosteroids, isoniazid, certain lipid-lowering drugs (eg, niacin), estrogens, oral contraceptives, phenothiazines, and thyroid replacement therapy (see CLINICAL PHARMACOLOGY). Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity or have hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors), angiotensin-converting-enzyme inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (eg, octreotide), and alcohol. Beta-adrenergic blockers may mask the symptoms of hypoglycemia in some patients. Mixing of Insulins—Care should be taken when mixing all insulins as a change in peak action may occur. The American Diabetes Association warns in its Position Statement on Insulin Administration, “On mixing, physiochemical changes in the mixture may occur (either immediately or over time). As a result, the physiological response to the insulin mixture may differ from that of the injection of the insulins separately.” Mixing Humalog with Humulin® N or Humulin® U does not decrease the absorption rate or the total bioavailability of Humalog. Given alone or mixed with Humulin N, Humalog results in a more rapid absorption and glucose-lowering effect compared with regular human insulin. Pregnancy—Teratogenic Effects—Pregnancy Category B—Reproduction studies with insulin lispro have been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the average human dose (40 units/day) based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to Humalog. There are, however, no adequate and well-controlled studies with Humalog in pregnant women. Because

animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Although there are limited clinical studies of the use of Humalog in pregnancy, published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Careful monitoring of the patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to mothers with diabetes is warranted. Nursing Mothers—It is unknown whether Humalog is excreted in significant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Humalog is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog dose, meal plan, or both. Pediatric Use—In a 9-month, crossover study of prepubescent children (n=60), aged 3 to 11 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 minutes before meals 8.4%, Humalog immediately before meals 8.4%, and Humalog immediately after meals 8.5%. In an 8-month, crossover study of adolescents (n=463), aged 9 to 19 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 to 45 minutes before meals 8.7% and Humalog immediately before meals 8.7%. The incidence of hypoglycemia was similar for all 3 treatment regimens. Adjustment of basal insulin may be required. To improve accuracy in dosing in pediatric patients, a diluent may be used. If the diluent is added directly to the Humalog vial, the shelf life may be reduced (see DOSAGE AND ADMINISTRATION). Geriatric Use—Of the total number of subjects (n=2834) in 8 clinical studies of Humalog, 12% (n=338) were 65 years of age or over. The majority of these were patients with type 2 diabetes. A1C values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Humalog action have not been performed. ADVERSE REACTIONS: Clinical studies comparing Humalog with regular human insulin did not demonstrate a difference in frequency of adverse events between the 2 treatments. Adverse events commonly associated with human insulin therapy include the following: Body as a Whole—allergic reactions (see PRECAUTIONS). Skin and Appendages—injection site reaction, lipodystrophy, pruritus, rash. Other—hypoglycemia (see WARNINGS and PRECAUTIONS). OVERDOSAGE: Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. DOSAGE AND ADMINISTRATION: Humalog is intended for subcutaneous administration, including use in select external insulin pumps (see DOSAGE AND ADMINISTRATION, External Insulin Pumps). Dosage regimens of Humalog will vary among patients and should be determined by the healthcare provider familiar with the patient’s metabolic needs, eating habits, and other lifestyle variables. Pharmacokinetic and pharmacodynamic studies showed Humalog to be equipotent to regular human insulin (ie, one unit of Humalog has the same glucose-lowering effect as one unit of regular human insulin), but with more rapid activity. The quicker glucose-lowering effect of Humalog is related to the more rapid absorption rate from subcutaneous tissue. An adjustment of dose or schedule of basal insulin may be needed when a patient changes from other insulins to Humalog, particularly to prevent premeal hyperglycemia. When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Regular human insulin is best given 30 to 60 minutes before a meal. To achieve optimal glucose control, the amount of longer-acting insulin being given may need to be adjusted when using Humalog. The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables. Humalog was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 U/kg regular human insulin or Humalog at abdominal, deltoid, or femoral sites, the 3 sites often used by patients with diabetes. When not mixed in the same syringe with other insulins, Humalog maintains its rapid onset of action and has less variability in its onset of action among injection sites compared with regular human insulin (see PRECAUTIONS). After abdominal administration, Humalog concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of Humalog is slightly shorter following abdominal injection, compared with deltoid and femoral injections. As with all insulin preparations, the time course of action of Humalog may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques. Humalog in a vial may be diluted with STERILE DILUENT for Humalog, Humulin N, Humulin R, Humulin 70/30, and Humulin® R U-500 to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50). Diluted Humalog may remain in patient use for 28 days when stored at 5°C (41°F) and for 14 days when stored at 30°C (86°F). Do not dilute Humalog contained in a cartridge or Humalog used in an external insulin pump. Parenteral drug products should be inspected visually before use whenever the solution and the container permit. If the solution is cloudy, contains particulate matter, is thickened, or is discolored, the contents must not be injected. Humalog should not be used after its expiration date. The cartridge containing Humalog is not designed to allow any other insulin to be mixed in the cartridge or for the cartridge to be refilled with insulin. External Insulin Pumps—Humalog was tested in MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested in the Disetronic ®2 H-TRONplus ® V100 insulin pump (with plastic 3.15 mL insulin reservoir) and the Disetronic D-TRON ®2,3 and D-TRONplus ®2,3 pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. HOW SUPPLIED: Humalog (insulin lispro injection, USP [rDNA origin]) is available in the following package sizes (with each presentation containing 100 units insulin lispro per mL [U-100]): 10 mL vials NDC 0002-7510-01 (VL-7510) 3 mL vials NDC 0002-7510-17 (VL-7533) NDC 0002-7516-59 (VL-7516) 5 x 3 mL cartridges 3 5 x 3 mL prefilled insulin delivery devices (Pen) NDC 0002-8725-59 (HP-8725) 5 x 3 mL prefilled insulin delivery devices (Humalog® KwikPen™ ) NDC 0002-8799-59 (HP-8799)

1 2 3

MiniMed® and Polyﬁn® are registered trademarks of MiniMed, Inc. Disetronic®, H-TRONplus®, D-TRON®, and Rapid® are registered trademarks of Roche Diagnostics GMBH. 3 mL cartridge is for use in Eli Lilly and Company’s HumaPen® MEMOIR™ and HumaPen® LUXURA™ HD insulin delivery devices, Owen Mumford, Ltd.’s Autopen® 3 mL insulin delivery device, and Disetronic D-TRON ® and D-TRONplus ® pumps. Autopen® is a registered trademark of Owen Mumford, Ltd. HumaPen®, HumaPen® MEMOIR™ and HumaPen® LUXURA™ HD are trademarks of Eli Lilly and Company. Other product and company names may be the trademarks of their respective owners.

Storage —Unopened Humalog should be stored in a refrigerator (2° to 8°C [36° to 46°F]), but not in the freezer. Do not use Humalog if it has been frozen. Unrefrigerated (below 30°C [86°F]) 12 vials, cartridges, Pens, and KwikPens must be used within 28 days or be discarded, even if they still contain Humalog. Protect from direct heat and light. Use in an External Insulin Pump—A Humalog 3mL cartridge used in the D-TRON®2,3 or D-TRONplus®2,3 should be discarded after 7 days, even if it still contains Humalog. Infusion sets, D-TRON ®2,3 and D-TRONplus ®2,3 cartridge adapters, and Humalog in the external insulin pump reservoir should be discarded every 48 hours or less. Literature revised December 7, 2009 KwikPens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA. Pens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Lilly France, F-67640 Fegersheim, France. Vials manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Hospira, Inc., Lake Forest, IL 60045, USA or Lilly France, F-67640 Fegersheim, France. Cartridges manufactured by Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company, Indianapolis, IN 46285, USA. www.humalog.com Copyright © 1996, 2008, Eli Lilly and Company. All rights reserved.

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cies with presences in the OR have already begun to med errors spring up in larger institutions, but practices are not standardized, and most smaller hospitals do not use are fatal this approach. To change this, the report suggested that enhanced training of pharmacists who work exclusively 1,000 deaths in ORs as “perioperative consultants” would provide an additional layer of checks and balances to anesthesia practice. “Anesthesiology is genuinely unique in that we’re the only health care professionals who prescribe, compound, dispense and administer medications all in one continuous process, in real time, and sometimes in a matter of less than a minute,” Dr. Eichhorn said. By putting more people such as pharmacists in the OR, who are responsible for parts of that process and who can double-check doses and medications and other factors, the potential for error is reduced, he noted.

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Pharmacist Responds Tricia A. Meyer, PharmD, MS, director of the Department of Pharmacy and assistant professor of anesthesiology at Scott and White Hospital at Texas A&M Health Science Center, in Temple, said she is encouraged that the APSF is urging that pharmacists play a more active role in ensuring OR drug safety. “But they’re not the first professional society to do so,” she stressed. In 2006, Dr. Meyer pointed out, the United States Pharmacopeia (USP) published “A Chartbook on Medication Error Findings from the Perioperative Setting.” The report reviewed errors from 1998 to 2005 across the perioperative continuum. The highest percentage of medication errors that resulted in harm occurred in the OR (7.2%). “Because of the rate of errors,” Dr. Meyer said, “the recommendations from this group emphasized the need for dedicated pharmacy satellites in the OR when possible, in addition to other medication safety initiatives.” Dr. Meyer added that the clinical value of pharmacists is certainly not limited to the OR. “The involvement of pharmacists in other practice settings has also been shown to reduce preventable adverse drug events, resolve medication-related problems and provide oversight for the most appropriate and cost-effective medication use,” she said. Noting that the OR “is one of the most medication-intensive areas of the hospital, and with both [the USP and the APSF] endorsing increased pharmacy involvement in the operating room, it only seems reasonable that administrators, anesthesia providers and pharmacy directors collaborate to strongly consider this service for the OR.” A potential obstacle to the addition of OR pharmacists, however, is the culture

Clinical 43

Pharmacy Practice News • October 2010

Critical Care that anesthesia professionals have developed over many years. “People do things the way they do them for a reason; it’s their comfort zone,” said Philip J. Schneider, RPh, associate dean of the University of Arizona College of Pharmacy, in Phoenix. “This [proposed change] adds additional steps into the system. It may result in loss of autonomy and professional judgment, so I’m quite certain that it will be challenging to do.” Jerry Cohen, MD, of the University of Florida College of Medicine, in Gainesville, and the first vice president of the American Society of Anesthesiologists, who participated in the conference and supports its conclusions, said that the cultural barrier will not be the primary obstacle to change. “Any group of specialists tends to resist change,” Dr. Cohen said. “But when objective evidence that [there is] a better way of doing things comes along, we’re going to do it. We don’t really spend a lot of time figuring out ways not to change.”

Standardization and Technology Aside from adding layers of human checks and balances to OR anesthesia, the recommendations call for standardizing practices to reduce errors. For example, high-alert drugs, including phenylephrine and epinephrine, should be readily available in pharmacy-prepared concentrations. The increased use of technology also has a role in these situations, with electronically controlled devices used to manage infusions. Other ways of standardizing safety include keeping any concentrated versions of potentially lethal drugs out of the OR entirely; placing drugs in an OR at set locations; implementing consistent infusion libraries and protocols throughout individual institutions; and having standard route-specific tubing connectors. The key technology recommendation involves bar coding all medications, and having each anesthesia location carry a bar-code reader to ensure proper drug and dosing for patients. Technology training and device education could also be built in, with the possibility of requiring formal certification for users. “We can’t afford to have old-style thinking anymore, and it’s time to bring this—like so many other things—into the modern era,” Dr. Eichhorn told Phar-

macy Practice News.

‘With both [the USP and the APSF] endorsing increased pharmacy involvement in the operating room, it only seems reasonable that administrators, anesthesia providers and pharmacy directors collaborate to strongly consider this service for the OR.’ —Tricia A. Meyer, PharmD, MS “Unless they have personally experienced it, they don’t believe you—that years’ worth of incremental costs to do this is less than a single event that leads to a lawsuit,” Dr. Eichhorn said. “Why does it have to take these accidents to provoke change?”

Although it may be intuitive that measures like adding a pharmacist to the OR would reduce errors and therefore long-term costs, Dr. Cohen said, the real impetus for changing practices will be data on those costs. “It is possible that it’s a cost; it’s pos-

—Dave Levitan, with additional reporting by David Bronstein

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Assessing the Costs Aside from the obstacles related to tradition and culture that may arise, Dr. Eichhorn said costs—in terms of workforce and technology—may cause some hospitals to balk at implementing the recommendations. Unfortunately, he said, it often takes a catastrophic error to make institutions take measures to improve safety.

sible that it’s a savings,” Dr. Cohen said. “The only way we’re going to figure that out is with massive amounts of aggregated data. It is unlikely we will have randomized controlled trials on this [question].” Dr. Cohen noted that databases like those maintained by the Anesthesia Quality Institute will soon start to provide the kind of data that could point health care professionals toward true cost-saving measures and safety improvements.

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44 Clinical

Pharmacy Practice News â&#x20AC;˘ October 2010

Infectious Disease

CEFTAROLINE continued from page 1

in CABPâ&#x20AC;&#x201D;FOCUS I and FOCUS IIâ&#x20AC;&#x201D;and two Phase III trials in cSSSIâ&#x20AC;&#x201D;CANVAS I and CANVAS II. The proposed dosing regimen is 600 mg IV every 12 hours in a one-hour infusion for five to seven days for the treatment of CABP, and five to 14 days for the treatment of cSSSI, with a reduction to 400 mg IV every 12 hours in patients with moderate renal impairment. Ceftaroline has antibacterial activity against aerobic and anaerobic gram-

positive and aerobic gram-negative bacteria that are associated with skin and respiratory infections. Its bactericidal action results from inhibition of cell wall synthesis by high-affinity binding to penicillin-binding proteins (PBPs). In addition to its activity against MRSA because of its high affinity for PBP2a, it also is active against S. pneumoniae due to its high affinity for PBP2x. According to in vitro studies, ceftaroline is not an inhibitor or inducer of major cytochrome P450 (CYP) isoenzymes and thus unlikely to cause clinically significant drug interactions with

known CYP substrates. Members of the advisory panel said they found it very easy to answer in the affirmative to the questions posed to them by the FDA as to whether the sponsor had demonstrated safety and efficacy in the two proposed indications. They also congratulated Cerexa for coming forward with ceftaroline and lauded the quality of its data. Diane Cappelletty, PharmD, associate professor of pharmacy practice at the University of Toledo College of Pharmacy, in Ohio, and the sole PharmD on the panel, said that the demonstrated safety

with ceftaroline was solid, and so was the efficacy. â&#x20AC;&#x153;I think we do have a pretty good agent here and I look forward to using it,â&#x20AC;? she said during the advisory panel meeting. Erica Brittain, PhD, a mathematical statistician from the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institutes of Health (NIH) in Bethesda, Md., said she was very impressed with the data, adding â&#x20AC;&#x153;there were hints of superiority all over the placeâ&#x20AC;? for ceftaroline. Her colleague at the NIH, John E. Bennett, MD, head of the clinical mycology section at the NIAID, congratulated Cerexa for doing â&#x20AC;&#x153;well-designed, carefully conducted and conservatively analyzed studiesâ&#x20AC;? and added that he was also impressed by the quality of the data.

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â&#x20AC;&#x153;It appears the [FDA] is going to give approval for the new anti-MRSA cephalosporin, ceftaroline, for the two indications under consideration, namely community-acquired bacterial pneumonia and complicated skin infections,â&#x20AC;? Robert P. Rapp, PharmD, FCCP, professor of pharmacy and surgery emeritus at the University of Kentucky Medical Center, Lexington, told Pharmacy Practice News. â&#x20AC;&#x153;Ceftaroline will be marketed as an injectable prodrug that must be converted to the active antibiotic ceftaroline after IV administration. It will be the first Î˛-lactam antibiotic with activity against Î˛-lactamâ&#x20AC;&#x201C;resistant Staph aureus [MRSA] by virtue of high affinity for penicillin-binding protein 2a. In the era of â&#x20AC;&#x2DC;no new antimicrobials,â&#x20AC;&#x2122; [ceftaroline] is indeed a welcome addition to our antimicrobial formulary. In my opinion, anytime we can replace combination therapy with a single agent, there is virtue in doing so, and with ceftaroline the addition of an anti-MRSA second agent will apparently not be necessary,â&#x20AC;? he said. However, Dr. Rapp pointed out that certain â&#x20AC;&#x153;collateral damage issuesâ&#x20AC;? will need to be addressed after the drug is marketed. â&#x20AC;&#x153;Questions include the induction of the ampC Î˛-lactamase leading to resistance in certain gram-negative bacteria, selection for vancomycin-resistant enterococci, promotion of extendedspectrum Î˛-lactamases and potential for Clostridium difficile infection,â&#x20AC;? he said. â&#x20AC;&#x153;All of this will take time to sort out after marketing. Meanwhile, congratulations to Forest Laboratories for doing what appear to be high-quality clinical trials and for getting a promising new antibiotic approved by the FDA.â&#x20AC;? A complete report on the development, in vitro activity and results of ceftaroline clinical trials for the NDA is available on the FDA Web site at www.fda.gov. â&#x20AC;&#x201D;Fran Lowry

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46 Policy

Pharmacy Practice News • October 2010

Reimbursement

OUTPATIENT continued from page 1

four and a half years on the [CMSappointed] Ambulatory Payment Classification [APC] Advisory Panel making recommendations and feeling like a lone wolf crying in the wilderness,” Dr. Tyler said, “it’s refreshing to see that CMS is finally acknowledging that there is such a thing as pharmacy overhead, that it’s not an insignificant cost and that it really isn’t fully captured in our current reimbursement strategy.” The apparent gain could be shortlived, however, according to Ernie Anderson Jr., MS, RPh, FASHP, system vice president of pharmacy at Caritas Christi Health Care in Boston. “We have found historically that often by the time the final rule comes out [the proposed payment rate] may have slipped by a percentage point, and sometimes two.” There are several reasons for the slippage. The main one is that the complex, two-step process that CMS uses to compute an OPPS rate sufficient to cover drug costs plus pharmacy overhead relies on average drug manufacturer prices and hospital charge data that often are outdated by the time the final rule for the following year is issued in November. Mr. Anderson would like to see that

‘It’s refreshing to see that CMS is finally acknowledging that there is such a thing as pharmacy overhead, that it’s not an insignificant cost and that it really isn’t fully captured in our current reimbursement strategy.’ —Timothy Tyler, PharmD

slippage end. Testifying for the Association of Community Cancer Centers (ACCC) at a late August hearing of the APC Advisory Panel, he urged that CMS stipulate in its final rule that separately payable drug reimbursements be set at “no less than” ASP plus 6%. OPPS rate levels can have a particularly

strong impact on the financial viability of outpatient cancer centers, where the cost of complex therapies plus pharmacy services required to prepare, administer and monitor them often outstrips Medicare payments. Mr. Anderson calls this being “upside down” in the cost-to-payment ratio. “Last year when I did the calculation, I was ‘upside down’ on about onethird of drugs,” he said. “This year, it is approaching 50%.” Dr. Tyler agreed with the analysis. “Assuming that the ASP plus 6% rates hold—which is a crapshoot,” he said it would be better if CMS had to go down from there rather than from ASP plus 4% or less. “At ASP plus 4%,” he added, “most of the ambulatory outpatient facilities have said, ‘We’re underwater on half of what we do if they take it down any further. It begs the question of whether we can stay solvent.’” In addition to keeping the reimbursement formula for separately payable drugs at ASP plus 6%, Mr. Anderson said ACCC would like to see all outpatient drugs with Healthcare Common Procedure Coding System codes given separately payable status, rather than having those below a specific cost threshold bundled into prospective payments. CMS is proposing to raise the 2011 threshold to $70 from the current $65. ACCC’s fallback position is to keep the level at $65. “If you continue to increase the threshold and bundle more and more drugs, eventually you will get to a place where you come up with ASP minus a percentage,” Mr. Anderson said. “How could that possibly make any sense?”

CMS’ Flawed Calculations ACCC also believes the methodology CMS uses to calculate OPPS reimbursement rates has inherent flaws that often result in inadequate payments.

One is the difference in time between reports of ASP data and those of hospital claims and costs. In a letter to Donald Berwick, MD, CMS administrator, the organization noted that CMS is using hospital costs derived from 2009 claims data and comparing them with the ASP file from April 2010. “CMS proposed to use the ASP file from July 2010 in the final rule,” the letter added, “and the agency acknowledges that use of updated data could produce lower estimates of aggregated costs. “This effect is due to the use of misaligned data that fail to recognize the effects of inflation on hospitals’ costs of drugs,” the letter continued. Another flaw, according to ACCC, is failure of the agency to account for what is known as “charge compression” in determining rates. Charge compression describes the practice of some hospitals to use a lower percentage markup for expensive drugs and a higher percentage for the less costly ones. A third flaw is the inclusion of 340B hospital data in CMS calculations. Drugs are sold to 340B-eligible hospitals at steep discounts, Mr. Anderson pointed out. By including those drug pricing data in its calculations, CMS is getting an artificially lower estimate of the drug costs incurred by non-340B hospitals. Each factor, Mr. Anderson said, “skews the results and puts us at a deficit.” Mr. Anderson said he remains “very pragmatic about what CMS will do. I’m hoping that the best that we can get out of this year is to stay at ASP plus 6%. I don’t think they will keep the threshold at $65, as we have recommended, and I don’t think they will back out 340B from their calculations.”

Medicaid Cuts Also Eased In a separate issue, CMS has proposed eliminating certain provisions of the Medicaid drug payment formula that would have resulted in significant reimbursement cuts for generic drugs dispensed to Medicaid patients. The provisions, which cover how Medicaid payments for multisource drugs are calculated using average manufacturer prices (AMPs), would have had a severe impact on retail pharmacies, but according to Mr. Anderson, hospital outpatient pharmacies that fill Medicaid prescriptions would also have been affected. In a joint statement, the National Association of Chain Drug Stores and the National Community Pharmacists Association said the result of the CMS proposed rule was “not an increase in reimbursement to pharmacy, but rather the lessening of cuts that previously would have involved pharmacies selling most generic drugs at a loss, thereby threatening their long-term ability to provide patient care.”

—Bruce Buckley