Page 1

Un

Co

Su

ve

m

ra

m

ge

,p

it

ag

e

c

pharmacypracticenews.com

The Pharmacist’s News Source Hematology/Oncology Pharmacy Edition

Volume 38 • Number 6 • June 2011

20

22

c

Printer-friendly versions available online

Part 1 of a two-part series

Tainted TPN Cases Put Focus on <797> Rules

T

hree years after the U.S. Pharmacopeia (USP) issued a major revision to General Chapter <797> concerning pharmaceutical compounding of sterile preparations, questions and concerns continue to be raised about proper procedures to clean and disinfect equipment, sample and monitor air and surfaces, and train and evaluate personnel. Many of the concerns stem from several wellpublicized incidents of patient infections and deaths tied to contaminated products prepared at compounding pharmacies. Most recently, in March, nine patients at six Alabama hospitals died from Serratia marcescens-associated infections from contaminated total parenteral nutrition (TPN) admixtures prepared at one pharmacy. According to the Alabama Department of Public Health, the source of the bacteria was traced to Meds IV, an outsource compounding

see TAINTED TPN, page 7

Can Patients, Caregivers Shoulder the Rising Cost of Cancer Therapy?

T

hanks to improving survival, changing practice patterns and an aging and growing population, the total cost of cancer care in the United States may surpass $200 billion by 2020, according to new projections from the National Cancer Institute (NCI; JNCI J Natl Cancer Inst 2011;103:117-128). That is 66% higher than total cancer care costs today. “There is a continuing ratcheting up of what is a socially acceptable price for chemotherapy,” said David H. Howard, PhD, associate professor of health policy and management at Emory University in Atlanta. “Every few months, another new treatment comes out with an eye-popping price,” added Dr. Howard, who was not involved in the NCI study. “Many of these drugs do increase survival time but it’s

see NCI REPORT, page 17

in this issue Policy

Quality Improvement Accountable care organization initiatives gain momentum.

4

ASHP House of Delegates vote may yield more direction

A

Technology

Bar Coding The clinical and business case for BCMA.

22

Operations & Mgmt

Drug Costs Helping patients benefit from pharmaceutical assistance programs.

24

Leadership in Action Listening: the first step on road to success.

30

Clinical

Practice Pearl Dietary supplements: a teaching opportunity for pharmacists.

33

Hem/Onc Pharmacy When drugs are dispensed from oncology offices, do patients benefit?

Pharmacists’ Role in Medical Marijuana Remains a Bit Hazy

44

Is it ever safe to stop premedicating paclitaxel patients?

46

Educational Reviews

Managing Anemia in CKD Patients Insert after page

Evolving Treatment Paradigms In NSCLC Insert after page

s more states legalize marijuana, pharmacists and other clinicians are left somewhat stranded on the front lines, trying to navigate a path between conflicting legal requirements and effectively treating their patients. Fifteen states and the District of Columbia have approved medical usage of marijuana and at least a dozen more are considering various stages of legislation, according to the Marijuana Policy Project, a Washington, D.C.-based lobbying organization. Meanwhile, pharmacists say they are facing more questions than answers. Among their concerns: what to do if a hospital patient brings in marijuana; what about medication reconciliation and potential clinical interactions; and how to verify the safety of the product itself. “In some ways this is an instance where the legality has gotten ahead of how we know how to use it,” said Cynthia Reilly, RPh, director of the Practice Development Division at the American Society of Health-System Pharmacists (ASHP). “There are so many unknowns, but clinicians are being faced with patients who are using it.” This month, ASHP’s House of Delegates is scheduled to vote on a medical marijuana policy during the group’s Summer Meeting. The policy was developed in

New Reporting Tool May Provide Better Measure of Hospital Safety

T

8

16

see MARIJUANA, page 9

he standard methods for detecting adverse events in hospitalized patients could be underreporting the true incidence of such episodes by a factor of 10, a new study has found. Hospitals typically use either voluntary reporting systems or patient safety indicators designed by the Agency for Healthcare Research and

Quality. But the new study showed that these two measures detect only 1% and 9% of adverse events, respectively. In contrast, a relatively new technique, called the Global Trigger Tool, identified 90% of adverse events, according to the researchers. Developed in 2003 by the Institute for Healthcare Improvement (IHI), a

see REPORTING TOOL, page 36

New Products American Health Packaging launches three new unit-dose products, including Donepezil 5 and 10 mg tablets.

FIRST® “Magic Mouthwash” Compounding Kits from Cutis Pharma. See page

19

11


Now Available from Sandoz

Argatroban Injection in 0.9% Sodium Chloride

Available in 125 mg/125 mL vials ▲ ▲ ▲ ▲ ▲

Each pack contains 2 vials Ready for IV infusion, dilution not required Vial labels contain ring sling for hanging from IV pole Latex free NDC bar coded on the individual vial

Choose the full potential of generics. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

www.us.sandoz.com a Novartis company © 2011 Sandoz Inc. SDZ0095


Pharmacy Practice News • June 2011

Up Front 3

Capsules

surf

FDA Issues Final Guidance for Boosting Liquid OTC Drug Safety

JUNE 2011

watch

T

The five most-viewed articles last month on pharmacypracticenews.com: 1. As Pain Rx Databases Gain Transparency, Are Pharmacists at Risk? 2. The Power of Checklists Applied to Medication Storage 3. Medication Errors: A Year in Review 4. Elderly ICU Patients Often Given Inappropriate Drugs at Discharge 5. Not Keeping Patients at Home Post-Discharge Looms as Big Cost Factor Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here first

‘Not only are our patients faced with the high cost of

immunosuppressive medications, many also have chronic medical conditions, such

as diabetes and hypertension, adding to the cost of their prescription drugs.’ See article, page 24

—Marie Chisholm-Burns, PharmD

To Scan 2-D Bar Codes in PPN: 1.

Download the FREE Microsoft Tag Reader application through your smartphone browser.

2.

Open the Tag Reader and let it focus on the bar-code image to instantly access related materials and/or Web sites.

he FDA has released its final guidance to companies that manufacture, market or distribute over-thecounter (OTC) liquid drug products packaged with cups, droppers, syringes and spoons to measure and dispense the doses of medication. The guidance, titled “Dosage Delivery Devices for Orally Ingested OTC Liquid Drug Products,” describes how easy-to-use dosage delivery devices and devices that minimize the risk for accidental overdose in children can be supplied for OTC medicines such as liquid pain relievers, cold medicine, 10 Safety Tips cough syrups and digestion aids. To Pass on to Patients The FDA issued the guidance because of continuing concerns about the 1. Always read and follow the Drug Facts potential unintended drug overdoses that label on your OTC medicine. can result from dosage delivery devices 2. Know the “active ingredient” in your with markings that are confusing, unclear child’s medicine. or inconsistent with the labeled dosage 3. Give the right medicine, in the right directions. Key recommendations in the amount, to your child. guidance include: 4. Talk to your doctor, pharmacist or • Dosage delivery devices should be nurse to find out what mixes well and what doesn’t. included for all orally ingested OTC liquid drug products. 5. Use the dosing tool that comes with the medicine, such as a dropper or a • Devices should be marked with dosing cup. calibrated units of measurement for 6. Know the difference between a liquids (e.g., teaspoon, tablespoon tablespoon and a teaspoon. or milliliter) that are the same as the 7. Know your child’s weight. units of liquid measure specified in the directions for the product; there should 8. Prevent a poison emergency by always using a child-resistant cap. not be any unnecessary markings. 9. Store all medicines in a safe place. • Manufacturers should ensure that dosage delivery devices are used only 10. Check the medicine three times. with the products with which they are Source: FDA packaged. • Liquid measure markings on dosage delivery devices should be clearly visible and not obscured when the liquid product is added to the device. The FDA recommends that anyone who has questions about dosage delivery devices or how to measure liquid OTC medicines should contact a physician, pharmacist or other health care professional. —Staff

EDITORIAL BOARD

ART/PRODUCTION STAFF

Administration

Michele McMahon Velle, MAX Graphics/Creative Director

Robert Adamson, PharmD, Livingston, NJ

Frank Tagarello, Senior Art Director/Managing Director, MAX Graphics

Ernest R. Anderson Jr., MS, RPh, Boston, MA

Volume 38 • Number 6 • June 2011 • pharmacypracticenews.com

Anesthesiology/Pain Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY

Internal Medicine

EDITORIAL STAFF

David S. Craig, PharmD, BCPS, Tampa, FL

Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP, Des Moines, IA

Biotechnology

NUCLEAR PHARMACY

David Bronstein, Editorial Director davidb@mcmahonmed.com

Indu Lew, PharmD, Livingston, NJ

Jeffrey Norenberg, PharmD, Albuquerque, NM

Cardiology

Oncology

C. Michael White, PharmD, Storrs, CT CNS/Psychiatry Charles F. Caley, PharmD, Storrs, CT Lawrence Cohen, PharmD, BCPP, FASHP, FCCP, Spokane, WA

James O’Neill, Senior Systems Manager Dan Radebaugh, Director of Production and Technical Operations Marty Barbieri, Production Manager Brandy Wilson, Circulation Coordinator

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

McMAHON PUBLISHING

Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Kate O’Rourke, Contributing Editors

Raymond E. McMahon, Publisher and CEO, Managing Partner

Robert T. Dorr, PhD, RPh, Tucson, AZ Robert Ignoffo, PharmD, San Francisco, CA

James Prudden, Group Editorial Director

Philip E. Johnson, MS, RPh, FASHP, Tampa, FL

Robin B. Weisberg, Manager, Editorial Services

Larry Ereshefsky, PharmD, San Antonio, TX

Cindy O’Bryant, PharmD, Aurora, CO

Elizabeth Zhong, Associate Copy Chief

Complementary and Alternative Medicine

Ali McBride, PharmD, MS, BCPS, St. Louis, MO

SALES

Cathy Rosenbaum, PharmD, Cincinnati, OH

Sara S. Kim, PharmD, BCOP, New York, NY

Critical Care

Pediatrics

David Kaplan, Group Publication Director dkaplan@mcmahonmed.com

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Gretchen Brummel, PharmD, BCPS, Hudson, OH

Matt Spoto, Account Manager mspoto@mcmahonmed.com

Van Velle, President, Partner Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

McMahon Publishing mcmahonmed.com Sales, Production and Editorial Offices: 545 West 45th Street, 8th Floor, New York, NY 10036. Telephone: (212) 957-5300.

David P. Nicolau, PharmD, Hartford, CT

Technology

Robert P. Rapp, PharmD, Lexington, KY

Thomas Van Hassel, RPh, Yuma, AZ

David Nathanson, Account Manager dnathanson@mcmahonmed.com

Copyright © 2011 McMahon Publishing, New York, NY 10036. All rights reserved. Pharmacy Practice News (ISSN 0886-988x) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Send address changes to Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036.

Want to subscribe? Change your address? Here’s How All U.S. hospital pharmacists should re­ceive Pharmacy Practice News free of charge. If you are a hospital pharmacist and do not receive the publication, you must add your professional address or make your address change directly

with Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036. You can also fax your request to (212) 977-3645, or send it via e-mail, circulation@mcmahonmed.com. If you are not a hospital pharmacist but would like to re­ceive Pharmacy Practice News, please send a check for $70.00 (U.S.) or $90.00 (outside U.S.) for a year’s

subscription pay­­able to Pharmacy Practice News to ­McMahon Pub­lish­ing, 545 West 45th St., 8th Floor, New York, NY 10036. Please allow 8 to 12 weeks for delivery of the first issue. In­dividual issues are $7.00 (U.S.) or $10.00 (outside U.S.). McMahon Publishing is a 38-year-old, first-generation, ­family-owned publishing company dedicated to providing

medical professionals with essential, up-to-date news. As the second largest publisher of medical newspapers, McMahon produces Anesthesiology News, Clinical Oncology News, Gastroenterology & Endos­copy News, General Surgery News, Infectious Disease Special Edition, Pain Medicine News, Phar­macy Practice News and Rheumatology Practice News.

Infectious Diseases Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH Peggy McKinnon, PharmD, Detroit, MI

Reimbursement Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO

A family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers and several annual or semiannual Special Editions.

Nancy Parker, Executive Manager, Classified Advertising nparker@mcmahonmed.com


4 Policy

Pharmacy Practice News • June 2011

Quality Improvement

ACO Concept Is Gaining Traction A

ccountable care organizations, or ACOs, are finally gaining momentum. In late March, the Centers for Medicare & Medicaid Services (CMS) released its proposed rule for ACOs, and several health-systems already have begun testing initiatives that may help them achieve improvements in the cost and quality of care that are at the heart of the ACO program. With a networking session on ACOs slated to convene during the Summer Meeting of the American Society of Health-System Pharmacists (ASHP), the time appears ripe for the profession to embrace the ACO concept. Whatever role pharmacists may end up playing in the ACO model, it will be based on a program that aims to improve quality and lower costs of care for Medicare’s nearly 47 million participants. CMS is counting on ACOs and other innovative health care delivery models arising from the Patient Protection and Affordable Care Act of 2010, to help fix what it says is the often-fragmented nature and inefficiency of health care delivery in the United States. Varying in size and structure, ACOs will be charged with taking on the total health care needs of groups of at least 5,000 Medicare patients that are assigned to them based on the patients’ primary care use patterns. Healthsystems and primary care physician groups that form ACOs will continue to be reimbursed on a fee-for-service basis, and patients will be allowed to seek medical attention outside of their ACO networks. CMS intends to share potential cost savings with ACOs that deliver on the quality measures published in the final rule, which is due out later this year. The program’s emphasis on balancing cost and quality makes it an ideal fit for the profession of pharmacy, according to Joseph M. Hill, ASHP’s director of federal legislative affairs. “Pharmacists can play an integral role in ACOs through medication and chronic disease management,” he said. “In addition, pharmacists can help reduce costs in areas such as preventing hospital readmissions by performing medication reconciliation and patient follow-up after discharge.”

The Early Innovators With the first ACOs set to launch in January, hospitals and primary care physician groups across the country have been scrambling to design coordinated care models that will satisfy ACO quality standards. Steward Health Care System in Massachusetts, for example, is considering an early 2012 kickoff for its entry into the ACO arena. Ernest R. Anderson Jr.,

MS, FASHP, Steward’s system vice president of pharmacy, said the eight-hospital group is testing various quality and cost strategies to determine the best ones to implement system-wide when the ACO goes live. Steward also has 123 physician groups set to take part in the ACO. A central goal for Steward will be to prevent expensive hospital readmissions. And because appropriate medication use is crucial to this objective, Mr. Anderson

wants to see pharmacists taking a greater part in medication reconciliation across the transitions of care, particularly at discharge and after patients return home. “We want to make sure that patients go home on the appropriate medications and that they understand how to take them,” he said. “We’re talking now about how to follow up at home with patients who we think are at high risk” for

Take IV iron therapy to a proven place:

Responsewith toleration!

IMPORTANT SAFETY INFORMATION: Venofer® is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia not caused by iron deficiency. Serious hypersensitivity reactions have been reported in patients receiving Venofer®. In clinical studies, several patients experienced hypersensitivity reactions presenting with wheezing, dyspnea, hypotension, rashes, or pruritus. The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse, bronchospasm with dyspnea, or convulsion) associated with Venofer® administration. Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving IV iron. Hypotension following administration of Venofer® may be related to rate of administration and total dose delivered. In a multi-dose efficacy study in NDD-CKD patients (N=91), the most frequent adverse events ( 5%) whether or not related to Venofer® administration, were taste disturbance (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). In an additional study of Venofer® with varying erythropoietin doses in 96 treated NDD-CKD patients, adverse events, whether or not related to Venofer® reported by 5% of Venofer® exposed patients are as follows: diarrhea (16.5%), edema (16.5%), nausea (13.2%), vomiting (12.1%), arthralgia (7.7%), back pain (7.7%), headache (7.7%), hypertension (7.7%), taste disturbance (7.7%), dizziness (6.6%), extremity pain (5.5%), and injection site burning (5.5%).

Leading anemia management.™


Pharmacy Practice News • June 2011

Policy 5

Quality Improvement readmission, including those with heart failure or chronic obstructive pulmonary disease or those who have had an acute myocardial infarction or pneumonia. Steward already has experience with an ACO-type model. In January 2010, Mr. Anderson said, the health care system signed an Alternative Quality Contract with Blue Cross Blue Shield of Massachusetts. The agreement promises performance-based incentives for meeting nationally recognized measures of quality, efficiency and patient experience. Mr. Anderson said the first-year

‘The way we’re really going to make accountable care succeed is by paying particularly close attention to efficiencies. Embracing health information technology is essential.’ —Gloria P. Sachdev, PharmD results of the program will not be reconciled until later this summer. Other CMS pilot programs have shown that ACO-style provider–hospital net-

works can work for Medicare beneficiaries, mainly by eliminating unnecessary or duplicative tests and treatments and preventing readmissions. The five-year

12

Over 9 million patients treated with 180 million units* 1

240

First-line IV iron for adult pre-dialysis CKD patients... In treatment of iron deficiency anemia • Raises hemoglobin levels and improves iron stores 2 • Effective with or without erythropoietin

With a demonstrated safety profile • Contains no dextran or modified dextran • No test dose required; no black box warning • Greater tolerability than oral iron with fewer gastrointestinal symptoms

For treatment of iron deficiency anemia in adult non-dialysis dependent-chronic kidney disease patients whether or not receiving an erythropoietin. Contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer ® or any of its inactive components, and in patients with anemia not caused by iron deficiency. Serious hypersensitivity reactions have been reported in patients receiving Venofer ®.

Millions prescribed. Millions treated.

*100 mg vials and ampules worldwide from 1992 to February 2010.

Please see brief prescribing information and references on following pages. Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2010 American Regent, Inc. • Reimbursement and Patient Assistance Program Hotline: 800-282-7712 • Orders or information: 800-645-1706 • venofer.com

Medicare Physician Group Practice Demonstration, for example, found that all 10 of the large practices involved in the initiative were able to meet most quality goals, and six of the 10 produced savings totaling $78 million (N Engl J Med 2011;364:e32). The CMS proposed rule would require ACOs to satisfy quality standards in several key areas, including care coordination; patient–caregiver experiences; patient safety; preventive health; and care for the frail, elderly population. The

see ACO CONCEPT, page 15


Reference: 1. Data on file. American Regent, Inc., Shirley, NY. 2. Van Wyck DB, Roppolo M, Martinez CO, Mazey RM, McMurray S, for the United States Iron Sucrose (Venofer®) Clinical Trials Group. A randomized, controlled trial comparing IV iron sucrose to oral iron in anemic patients with nondialysis-dependent CKD. Kidney Int. 2005;68:2846-2856.

(Table 2 continued)

Brief Summary (See Package Insert For Full Prescribing Information) Therapeutic Class: Hematinic CLINICAL INDICATIONS AND USAGE Venofer® (iron sucrose injection,USP) is indicated in the treatment of iron deficiency anemia in the following patients: • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving an erythropoietin CONTRAINDICATIONS The use of Venofer® is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia not caused by iron deficiency. WARNINGS Hypersensitivity reactions have been reported with injectable iron products.See PRECAUTIONS and ADVERSE REACTIONS. PRECAUTIONS General: Because body iron excretion is limited and excess tissue iron can be hazardous, caution should be exercised to withhold iron administration in the presence of evidence of tissue iron overload.Patients receiving Venofer® require periodic monitoring of hematologic and hematinic parameters (hemoglobin,hematocrit,serum ferritin and transferrin saturation). Iron therapy should be withheld in patients with evidence of iron overload. Transferrin saturation values increase rapidly after IV administration of iron sucrose; thus, serum iron values may be reliably obtained 48 hours after IV dosing.See DOSAGE AND ADMINISTRATION and OVERDOSAGE. Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving Venofer®. No life-threatening hypersensitivity reactions were observed in the clinical studies. Several cases of mild or moderate hypersensitivity reactions were observed in these studies. There are post-marketing spontaneous reports of life-threatening hypersensitivity reactions in patients receiving Venofer.See ADVERSE REACTIONS. Hypotension: Hypotension has been reported frequently in hemodialysis dependent chronic kidney disease patients receiving intravenous iron. Hypotension also has been reported in non-dialysis dependent and peritoneal dialysis dependent-chronic kidney disease patients receiving intravenous iron. Hypotension following administration of Venofer® may be related to rate of administration and total dose administered. Caution should be taken to administer Venofer® according to recommended guidelines. See DOSAGE AND ADMINISTRATION. Carcinogenesis,Mutagenesis,and Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of Venofer®. Venofer® was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test. Venofer® at IV doses up to 15 mg iron/kg/day (about 1.2 times the recommended maximum human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats. Pregnancy Category B: Teratology studies have been performed in rats at IV doses up to 13 mg iron/kg/day (about 0.5 times the recommended maximum human dose on a body surface area basis) and rabbits at IV doses up to 13 mg iron/kg/day (about 1 times the recommended maximum human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Venofer®. There are, however, no adequate and well controlled studies 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. Nursing Mothers: Venofer® is excreted in milk of rats.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 Venofer® is administered to a nursing woman. Pediatric Use: Safety and effectiveness of Venofer® in pediatric patients have not been established. In a country where Venofer® is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five expired during or following a period when they received Venofer®, several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer® or any other drugs could be established. Geriatric Use:The five pivotal clinical trials did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients,but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS Adverse Events observed in all treated populations The frequency of adverse events associated with the use of Venofer® has been documented in six randomized clinical trials involving 231 hemodialysis dependent, 139 non-dialysis dependent and 75 peritoneal dialysis dependent-CKD patients; and in two post-marketing safety studies involving 1,051 hemodialysis dependent-CKD patients for a total of 1,496 patients. In addition,over 2,000 patients treated with Venofer® have been reported in the medical literature. Treatment-emergent adverse events reported by 2% of treated patients with NDDCKD in the randomized clinical trials, whether or not related to Venofer® administration, are listed by indication in Table 2. Table 2. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Clinical Indication (Multidose Safety Population) NDD-CKD Oral Iron Adverse Events Venofer® (Preferred Term) (N=139) (N=139) % % Subjects with any adverse event 76.3 73.4 Ear and Labyrinth Disorders Ear Pain 2.2 0.7 Eye Disorders Conjunctivitis 0 0 Gastrointestinal Disorders Abdominal pain NOS* 1.4 2.9 Constipation 4.3 12.9 Diarrhea NOS 7.2 10.1 Dysgeusia 7.9 0 Nausea 8.6 12.2 Vomiting NOS 5.0 8.6 General Disorders and Administration Site Conditions Asthenia 0.7 2.2 Chest pain 1.4 0 Edema NOS 6.5 6.5 Fatigue 3.6 5.8 Feeling abnormal 0 0 Infusion site burning 3.6 0 Injection site extravasation 2.2 0 Injection site pain 2.2 0 Peripheral edema 7.2 5.0 Pyrexia 0.7 0.7 Infections and Infestations Catheter site infection 0 0 Nasopharyngitis 0.7 2.2 Peritoneal infection 0 0 Sinusitis NOS 0.7 0.7 Upper respiratory tract infection NOS 0.7 1.4 Urinary tract infection NOS 0.7 5.0 Injury, Poisoning and Procedural Complications Graft complication 1.4 0 Investigations Cardiac murmur NOS 2.2 2.2 Fecal occult blood positive 1.4 3.6 Metabolism and Nutrition Disorders Fluid overload 1.4 0.7 Gout 2.9 1.4 Hyperglycemia NOS 2.9 0 Hypoglycemia NOS 0.7 0.7 Musculoskeletal and Connective Tissue Disorders Arthralgia 1.4 2.2 Arthritis NOS 0 0

Treatment-emergent adverse events reported in 2% of patients by dose group are shown in Table 3. Table 3. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)

Adverse Events (Preferred Term) Subjects with any adverse event Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain NOS* Constipation Diarrhea NOS Dysgeusia Nausea Vomiting NOS General Disorders and Administration Site Conditions Asthenia Chest pain Edema NOS Fatigue Feeling abnormal Infusion site burning Injection site pain Peripheral edema Pyrexia Infections and Infestations Catheter site infection Nasopharyngitis Peritoneal infection Sinusitis NOS Upper respiratory tract infection NOS Injury, Poisoning and Procedural Complications Graft complication Investigations Cardiac murmur NOS Fecal occult blood positive Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia NOS Hypoglycemia NOS Musculoskeletal and Connective Tissue Disorders Arthralgia Back pain Muscle cramp 0 Myalgia

NDD-CKD 200 mg 500 mg (N=109) (N=30) % % 75.2 80.0 0.9

6.7

0

0

1.8 3.7 6.4 9.2 9.2 5.5

0 6.7 10.0 3.3 6.7 3.3

0.9 0.9 7.3 4.6 0 3.7 2.8 5.5 0.9

0 3.3 3.3 0 0 3.3 0 13.3 0

0 0.9 0 0 0.9

0 0 0 3.3 0

1.8

0

2.8 1.8

0 0

1.8 1.8 3.7 0.9

0 6.7 0 0

0.9 1.8

3.3 3.3

2.8

3.3

6.7

(Table 3 continued)

NDD-CKD Venofer® Oral Iron (N=139) (N=139) % %

Adverse Events (Preferred Term) Musculoskeletal and Connective Tissue Disorders Back pain Muscle cramp0.7 Myalgia Pain in extremity Nervous System Disorders Dizziness Headache Hypoesthesia Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Dyspnea exacerbated Nasal congestion Pharyngitis Rhinitis allergic NOS Skin and Subcutaneous Tissue Disorders Pruritus Rash NOS Vascular Disorders Hypertension NOS Hypotension NOS *NOS=Not otherwise specified

2.2 3.6 4.3

0.7

3.6 0 0

6.5 2.9 0.7

1.4 0.7 0.7

2.2 3.6 2.2 1.4 0 0.7

0.7 0.7 0.7 2.2 0 2.2

2.2 1.4

4.3 2.2

6.5 2.2

4.3 0.7

Adverse Events (Preferred Term) Musculoskeletal and Connective Tissue Disorders Pain in extremity Nervous System Disorders Dizziness Headache Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Pharyngitis Skin and Subcutaneous Tissue Disorders Pruritus Vascular Disorders Hypertension NOS Hypotension NOS

NDD-CKD 200 mg 500 mg (N=109) (N=30) % % 4.6

3.3

5.5 3.7

10.0 0

0.9 1.8 0

6.7 10.0 0

0.9

6.7

6.4 0.9

6.7 6.7

*NOS=Not otherwise specified

Drug related adverse events reported by 2% of Venofer® (iron sucrose injection, USP) treated patients are shown by dose group in Table 4. Table 4. Most Common Adverse Events Related to Study Drug Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)

Adverse Events (Preferred Term) Subjects with any adverse event Gastrointestinal Disorders Diarrhea NOS* Dysgeusia Nausea General Disorders and Administration Site Conditions Infusion site burning Injection site pain Peripheral edema Nervous System Disorders Dizziness Headache Vascular Disorders Hypotension NOS

200 mg (N=109) % 23.9

NDD-CKD

500 mg (N=30) % 20.0

0 7.3 2.8

0 3.3 0

3.7 2.8 1.8

0 0 6.7

2.8 2.8

6.7 0

0

6.7

*NOS=Not otherwise specified Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients In a multi-dose efficacy study in non-dialysis dependent-CKD patients (N=91), the most frequent adverse events ( 5%) whether or not related to Venofer® administration, were taste disturbance (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). In an additional study of Venofer® with varying erythropoietin doses in 96 treated NDD-CKD patients, adverse events, whether or not related to Venofer® reported by 5% of Venofer® exposed patients are as follows: diarrhea (16.5%), edema (16.5%), nausea (13.2%), vomiting (12.1%), arthralgia (7.7%), back pain (7.7%), headache (7.7%), hypertension (7.7%), taste disturbance (7.7%), dizziness (6.6%),extremity pain (5.5%),and injection site burning (5.5%). Hypersensitivity Reactions: See WARNINGS and PRECAUTIONS. In clinical studies,several patients experienced hypersensitivity reactions presenting with wheezing,dyspnea,hypotension,rashes,or pruritus. Serious episodes of hypotension occurred in 2 patients treated with Venofer® at a dose of 500 mg. The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse,bronchospasm with dyspnea,or convulsion) associated with Venofer® administration. OVERDOSAGE Dosages of Venofer® (iron sucrose injection,USP) in excess of iron needs may lead to accumulation of iron in storage sites leading to hemosiderosis.Periodic monitoring of iron parameters such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation.Venofer® should not be administered to patients with iron overload and should be discontinued when serum ferritin levels equal or exceed established guidelines [1]. Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment has been incorrectly diagnosed as iron deficiency anemia. Symptoms associated with overdosage or infusing Venofer® too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most symptoms have been successfully treated with IV fluids, hydrocortisone, and/or antihistamines. Infusing the solution as recommended or at a slower rate may also alleviate symptoms. Preclinical Data: Single IV doses of Venofer® at 150 mg iron/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and 100 mg iron/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal. The symptoms of acute toxicity were sedation,hypoactivity,pale eyes,and bleeding in the gastrointestinal tract and lungs. DOSAGE AND ADMINISTRATION The dosage of Venofer® is expressed in terms of mg of elemental iron.Each mL contains 20 mg of elemental iron. Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron,administered over sequential sessions,to achieve a favorable hemoglobin response and to replenish iron stores (ferritin,TSAT). Administration:Venofer® must only be administered intravenously either by slow injection or by infusion. Recommended Adult Dosage: Non-Dialysis Dependent-Chronic Kidney Disease Patients (NDD-CKD): Venofer® is administered as a total cumulative dose of 1,000 mg over a 14 day period as a 200 mg slow IV injection undiluted over 2 to 5 minutes on 5 different occasions within the 14 day period.There is limited experience with administration of an infusion of 500 mg of Venofer®,diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5-4 hours on day 1 and day 14; hypotension occurred in 2 of 30 patients treated. (See CLINICAL TRIALS,Study D: Non-Dialysis DependentChronic Kidney Disease (NDD-CKD) Patients and ADVERSE REACTIONS, Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients sections.) HOW SUPPLIED Venofer® is supplied in 5 mL and 10 mL single dose vials. Each 5 mL vial contains 100 mg elemental iron (20 mg/mL) and each 10 mL vial contains 200 mg elemental iron (20 mg/mL).Contains no preservatives.Store in original carton at 25°C (77°F).Excursions permitted to 15°-30°C (59°-86°F).[See the USP controlled room temperature]. Do not freeze. Sterile NDC-0517-2340-01 100 mg/5 mL Single Dose Vial Individually Boxed NDC-0517-2310-01 200 mg/10 mL Single Dose Vial Individually Boxed NDC-0517-2340-10 100 mg/5 mL Single Dose Vial Packages of 10 NDC-0517-2310-05 200 mg/10 mL Single Dose Vial Packages of 5 NDC-0517-2340-25 100 mg/5 mL Single Dose Vial Packages of 25 NDC-0517-2310-10 200 mg/10 mL Single Dose Vial Packages of 10 Rx Only REFERENCE: [1] National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000. Am J Kidney Dis. 37:S182-S238,(suppl 1) 2001.

BS2340 Rev.5/10 Venofer® is manufactured under license from Vifor (International) Inc.,Switzerland.

VENJA Rev.5/2010 © 2010 American Regent,Inc


Pharmacy Practice News • June 2011

Policy 7

Chapter <797> Compliance

TAINTED TPN

Table. CFU Identification and Sources

continued from page 1

pharmacy in Birmingham, Ala., that used a tap water spigot to rinse a mixing container and stirrer. A failure in the sterilization process and improper filtering allowed the bacteria to get into the final TPN product, authorities said. “We can’t let down our guard, and vigilance is absolutely important” to keep mistakes such as this from happening, said Eric S. Kastango, MBA, RPh, a member of the 2010-2015 USP Compounding Expert Committee and president of Clinical IQ, a pharmacy consultancy in Florham Park, N.J. During a recent webinar on Chapter <797> environmental sampling requirements, Mr. Kastango reviewed the Alabama incident and seven other cases in which patients became infected with Serratia and other pathogens. He cited a recent survey in which 34% of pharmacy directors at more than 400 health systems nationwide reported experiencing at least one patient incident due to compounding errors during the previous five years. “That’s a terrifying statistic,” Mr. Kastango said. “There are lots of systems and processes in <797> designed to prevent this from happening,” he said during the webinar, which was hosted by Pharmacy OneSource.

Focus on Environmental Sampling The revised USP Chapter <797> is included in the second supplement to USP 31–NF 26 and the second edition of the USP Pharmacists’ Pharmacopeia, published in March 2008. The revised standards became effective June 2008. Environmental sampling is “probably the most contentious part of the revised chapter,” Mr. Kastango said. Its importance lies in allowing for early detection of contamination from personnel, work surfaces, supplies, equipment or failure of engineering controls. The revised chapter separates sampling into facility- and personnelrelated metrics. In the former, viable (microbial) air testing via volumetric (impaction) methods must occur as part of the commissioning and certification of facilities and equipment; following any servicing or major change, such as when a hood or isolator is installed or moved; and as part of the semiannual recertification process. Personnel fingertip sampling should be done during initial training and also accompanying media fills to assess employee competency, another chapter

Microorganisms

Indication

Staphylococcus/ Micrococcus

Personnel habits or gowning problems

Gram-negative rods

Water condensation, leaking, aerosols

Bacillus species

Dust, dirt, floor traffic, possible air handling

Molds

Influx of unfiltered air, mold from street clothing or mold-contaminated cardboard, water reservoir, i.e., incubator humidification system

Yeast

Possible outdoor air influx; clothingborne, especially in late summer/fall; possible human contaminant

Diphtheroids/ coryneforms

Poor air conditioning (leading to sweating and personnel discharge from gowns)

CFU, colony-forming unit Source: Microbiological Environments (www.microbioenv.com)

requirement. “We know that personnel are the dirtiest thing in the room,” Mr. Kastango said. “We are generating and releasing microorganisms, and our behavior and work practices can have a significant impact on the quality of the CS [compounded sterile] preparations.” Gloved fingertip sampling is another misunderstood component of Chapter <797>, Mr. Kastango said. All employees must successfully don sterile gloves three times with zero colonyforming units. The test is done for new employees as part of initial training assessment, annually for all employees at low- and medium-risk compounding operations, and semiannually for all employees at high-risk compounding operations, and during any media fills. “If people can’t successfully garb or don a pair of sterile gloves without contaminating them, what chance do you think they’ll have of evaluating and preventing touch contamination during compounding?” Mr. Kastango asked. Surface sampling for microorganisms assesses the effectiveness of disinfection, another competency requirement. Growth media for bacteria include soybean-casein digest media (trypticase soy broth/agar); fungi can be cultured via malt extract agar or other media.

T

C

S

see TAINTED TPN, page 8

‘If people can’t successfully garb or don a pair of sterile gloves without contaminating them, what chance do you think they’ll have of evaluating and preventing touch contamination during compounding?’

—Eric S. Kastango, MBA, RPh

A re tota com

A recent outbreak of Serratia marcescens-associated infections from contaminated total parenteral nutrition has led many hospitals to take another look at their sterile compounding practices.


8 Policy

Pharmacy Practice News • June 2011

Chapter <797> Compliance

TAINTED TPN continued from page 7

One pending change to Chapter <797> would require use of both bacterial and fungal growth-supporting media in all compounding environments, regardless of risk level. “We have to be concerned about fungus, molds and yeast, because they tend to be pathogenic,” Mr. Kastango said. Volumetric air sampling should be performed at locations that are prone to contamination during compounding or staging of supplies, labeling, gowning and cleaning. Sampling is required during initial facility commissioning and then semiannually for all risk levels. Doing it more frequently will provide earlier detection of problems. “Environmental sampling is a snapshot in time, so the frequencies in the chapter are inadequate to capture trends,” Mr. Kastango said. “If you are concerned and want to demonstrate more control, [sampling] more frequently will allow you to do that.”

Problems With Paddles Settling plates and paddles are commonly used for air sampling, but they have limitations: They are not qualitative and particle settling is influenced by the size of the particle and by air movement.

“I am not a fan of paddles,” said Alice S. Weissfeld, PhD, president and laboratory director at Microbiology Specialists Inc., a reference laboratory she cofounded in Houston. “There is not enough surface area and they are not manufactured with the same media formulation as are used in the round surface plates,” Dr. Weissfeld said during the webinar. She was a presenter along with Mr. Kastango. Both presenters noted limitations of isopropyl alcohol (ISA) for use in cleaning. “Isopropyl alcohol is not the end-all, be-all,” Mr. Kastango said. ISA is disinfectant, but it doesn’t remove dirt and it doesn’t kill spores, he noted. Simply spraying a laminar-flow hood or engineering controls with alcohol, or wiping with an alcohol pad, is insufficient. “You have to get the spill or residue off the surface first before you can disinfect it,” said Luci A. Power, MS, RPh, senior pharmacy consultant, Power Enterprises, San Francisco. Ms. Power, whose background is in handling chemotherapy and hazardous drugs, recommends newer, more-effective cleaners formulated with accelerated hydrogen peroxide. Even the old standby, sodium hypochlorite bleach, is still one of the primary appropriate cleaners because it inactivates many pathogens, including spores, and is effective in deactivating some hazardous drugs.

Surface sampling and gloved fingertip sampling can be effective methods for assessing sterile compounding conditions in the pharmacy.

“But even with bleach, you need a surfactant—something that removes dirt, dextrose and drug residues from the surfaces you are trying to clean,” Ms. Power told Pharmacy Practice News. But she also noted that bleach is an eye and respiratory hazard, depending on the concentration. The choice to use it in primary engineering controls that have no containment can be problematic. Bleach also can cause stainless steel surfaces to pit and rust, so it needs to be neutralized or rinsed off thoroughly. Cleaners also should be low residue. “You just cleaned up the residue of the drug; you don’t want to leave behind residue from the cleaner. It’s not appropriate to get into your IV products. It’s not an easy situation to deal with,” Ms. Power said. She agreed with Mr. Kastango that,

in the end, much relies on pharmacy personnel. “People are the cause of the problems, not equipment. They need to be taught what to do, understand what they are doing, and they need to be monitored so they continue to do it properly.” —Ted Agres Next Month: ISMP urges more oversight of sterile compounding. How will FDA, state boards of pharmacy respond? Ms. Power disclosed that she is on the Scientific Advisory Board of Intelligent Hospital Systems and has been a speaker for and has accepted honoraria from ProCE. Ms. Power also disclosed that she has a royalty agreement with Covidien. Mr. Kastango disclosed that he has received fees from ITW Texwipe. Ms. Weissfeld disclosed that her laboratory provides USP Chapter <797> services to approximately 30 hospitals in Texas.

Virtual Clean Room Boosts USP <797> Learning P urdue University’s College of Pharmacy has developed a three-dimensional (3-D) virtual clean room to teach its students how to comply with USP Chapter <797> requirements for sterile IV preparations. The primary goal of the program—the first of its kind in pharmacy education, according to the instructors—was to enhance the students’ ability to confidently follow the sterile-compounding requirements. Another important aim was for students to gain a better understanding of the extent to which a typical hospital is at risk for making errors during IV drug preparation. The teaching program succeeded on both counts, according to Sheetal Patel, PharmD, first author of a report in the American Journal of Pharmaceutical Education (2011;75:7). Students’ mean scores on sterile compounding written exams improved significantly as a result of the virtual clean room teaching initiative (89.6% in year 0 vs. 96.1% in year 2). And nearly 10% more students who completed the program said they disagreed with the notion that the risk for a highly skilled pharmacist making a sterile compounding error was low, compared with a baseline pre-assessment.

The virtual clean room learning option was offered as a voluntary addon to a conventional, classroom-based course on parenteral products, Dr. Patel noted. She explained that although students were happy with that course, which includes some hands-on lab sessions on IV admixtures, many of them expressed concerns about the prospect of actually preparing IV medications in a real-world setting—for example, during the Advanced Pharmacy Practice Experience (APPE). To ease those concerns, two sessions in a “virtual laboratory” were created, geared toward helping students gain confidence with the layout and special procedures associated with a clean-

room environment. The developers used various methods for ensuring that the lab replicated real-world conditions, such as visiting various hospital sites in Indiana and merging aspects of the IV clean rooms they observed (e.g., equipment and medications) into the virtual laboratory design. The clean room was made interactive via images that are projected on several wall-sized panels and computer screens. Students used 3-D eyeglasses and a wireless controller to navigate throughout the room. The system also featured a head-tracking device that adjusted the students’ view and allowed the image on the wall-sized panels to change based on the direction that the students face. The head tracker also enabled the students to view very detailed information, such as labels printed on a small medication vial. Several key components of sterile IV preparation were taught during the virtual sessions, including product verification, how to handle patient cases requiring high-alert medications and how to follow safe medication safety practices. In the latter category, for example, students were taught how to identify the expiration date of each

product. They also were given experience in handling look-alike/soundalike medication names or unapproved abbreviations.

Other Markers for Success In addition to the improvements seen in written exams and awareness of safety risks, several other markers of successful learning emerged. For example, 92% of the participating students who went on to an APPE program said the virtual classroom helped prepare them for that real-world experience by enhancing their understanding of how sterile IV compounding is performed. Additionally, 88% of the students said they “strongly agreed” or “agreed” that the virtual clean-room experience met their expectations. Dr. Patel and her colleagues said the results underscore the effectiveness of the program. “The ability to bring the clean-room environment into the classroom increased student confidence when working in an IV room, and fostered a greater appreciation for the role pharmacists have in promoting safe IV product preparation.” —David Bronstein


PRINTER-FRIENDLY VERSION AT PHARMACYPRACTICENEWS.COM

Managing Anemia in Patients With Chronic Kidney Disease

AMY E. LODOLCE, PHARMD, BCPS Assistant Directorr Drug Information Group University of Illinois at Chicago College of Pharmacy y Chicago, Illinois

C

hronic kidney disease (CKD), which

is increasing in prevalence, results in significant morbidity, mortality,

and health care costs in the United States.1

According to data collected from the National Health and Nutrition Examination Survey (1999 to 2004), 11.5% of adults (more women than men) have evidence of CKD.2,3 These estimates rise in patients with diabetes and hypertension, with more than 35% of adults with diabetes and more than 20% of those with hypertension suffering from CKD.

According to the National Kidney Foundation (NKF), the presence of kidney disease should be established and assigned a level according to the NKF Kidney Disease Outcomes Quality Initiative (KDOQI) classification, which is summarized in Table 1.1 Diagnosis is established by the presence of structural or functional abnormalities with or without decreased glomerular filtration rate (GFR) or a GFR less than 60 mL per minute per 1.73 m2 with or without kidney damage, for a period of at least 3 months.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

Causes and Consequences of Anemia and Iron Deficiency Anemia, defined in the KDOQI guidelines as a hemoglobin less than 13.5 g/dL in adult men and less than 12 g/dL in adult women, is a common complication of CKD. Its prevalence increases with increasing stage of CKD, such that nearly all patients with stage 5 CKD are affected.4 Anemia leads to impaired quality of life (QoL) and is a risk factor for early death among patients

P H A R M AC Y P R AC T I C E N E WS â&#x20AC;˘ J U N E 2 0 1 1

1


with CKD.5 Symptoms associated with anemia include fatigue, depression, decreased exercise tolerance, dyspnea, and symptoms of cardiac dysfunction. The primary cause of anemia in such patients is deficiency of erythropoietin as a result of impaired production in the kidney. Erythropoietin is involved in increasing the production of reticulocytes, restoring normal red blood cell mass, and correcting hypoxia in the tissues. Iron deficiency also plays a role in anemia of CKD in that patients have reduced iron intake, impaired intestinal absorption of iron, blood loss (among dialysis patients), and an increase in iron requirements when erythropoiesis-stimulating agents (ESAs) are given.5 Patients with CKD also may have absolute iron deficiency due to little or no stored iron, or functional iron deficiency, which occurs when erythropoiesis increases due to ESA administration. 5,6 Ferritin concentration and transferrin saturation are indices commonly used to evaluate iron stores and assess for iron-deficiency anemia.4,6 Ferritin is an indirect measure of iron stores, whereas transferrin is the carrier protein s, the goal serum for iron.7 In the KDOQI guidelines, 0 ng/mL (>200 ferritin level is greater than 100 alysis), and the ng/mL in patients undergoing dialysis), target transferrin saturation is greater than 20%.4

Treatment Approaches Iron therapy and ESAs are the mainstay of ia in patients therapy for treatment of anemia es from with CKD.4 The latest guidelines shed the KDOQI initiative were published g to in 2006, with an update relating ed target hemoglobin levels published ure in 2007 in response to literature w).8 regarding ESA therapy (see below). According to the guidelines, es, get clinicians must choose the target vel hemoglobin level and the level ted at which ESA therapy is initiated

2

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

carefully, considering risks and benefits of ESA therapy. Potential benefits of therapy include a reduced need for transfusion and improved QoL, whereas risks include the potential for cardiac events and all-cause mortality. Although selection of the target hemoglobin should be individualized, the guidelines suggest a target level of 11 to 12 mg/dL for patients with CKD (both dialysis and nondialysis). Furthermore, the hemoglobin target should not be greater than 13 g/dL.

IRON THERAPY Patients with CKD frequently experience iron deficiency, especially those with end-stage renal disease (ESRD) who are receiving hemodialysis.5 Hemodialysis results in losses of 6 to 7 mg of iron per day of dialysis, which is compounded by physiologic losses and loss from periodic venipuncture.6 It is estimated that annually patients receiving hemodialysis can have iron losses that exceed 1.5 to 3 g, which exceeds total body stores.5,6 Iron is available in oral or parenteral dosage forms. Oral iron is relatively relat inexpensive and easy to howe administer; however, there are some limitations Gastrointestinal (GI) adverse events to its use.9 Gast (AEs) such as c constipation, dyspepsia, bloating, diarrh nausea, diarrhea, and heartburn may affect up to 20% of patients. p These GI effects can be minimized if iro iron supplements are taken with food, but the presence pre of food will decrease iron absorption. Furthermore, Fu absorption may be impaired by b the use of phosphate binders or acid suppressive therapy, and the use o of ESAs can increase the demand for iiron beyond the amount that can be given orally. Proper adherence to tthe prescribed regimen also is a con concern because of frequent dosing requ requirements (often 3 times per day) and GI effects. Finally, the presence of h hepcidin (produced by the liver


Table 1. KDOQI Classification of CKD

during inflammation) inhibits the absorption of iron from the small intestine.10 Rozen-Zvi and colleagues conducted a systematic review and meta-analysis to compare IV versus oral iron supplementation for the treatment of anemia in patients with stage 3 to 5 CKD.11 Thirteen randomized controlled trials comparing oral iron with IV iron were included in the analysis. The primary outcome of interest was the absolute hemoglobin level or change in hemoglobin from baseline after 2 to 3 months of therapy. There were a variety of secondary outcomes including allcause mortality, cardiovascular morbidity and mortality, bacterial infections, need for renal replacement therapy, iron indices, ESA dose, hospitalizations, QoL, and need for transfusion. Efficacy analyses were conducted separately for patients receiving dialysis and those who were not. Results revealed that the hemoglobin level was significantly increased among patients on dialysis (n=7 trials) who received IV iron compared with those on oral therapy (weighted mean difference [WMD], 0.83 mg/dL; 95% confidence interval [CI], 0.09-1.57).11 Furthermore, ESA dose decreased significantly (WMD, –28.21 units/kg per week; 95% CI, –42.12 to –14.3) and ferritin levels significantly increased (WMD, 172.34 ng/mL; 95% CI, 111.31-233.38) in patients treated with IV iron. No changes were found with regard to transferrin saturation, and data were not available for QoL. In patients with CKD not receiving dialysis, a small increase in hemoglobin associated with IV iron therapy was noted (WMD, 0.31 g/dL; 95% CI, 0.09-0.53); however, the authors judged this change to be clinically important. Ferritin levels (WMD, 213.35 ng/mL; 95% CI, 56.5-370.2) and transferrin saturation (WMD, 9.45%; 95% CI, 1.9-17.1) were also significantly increased in the IV iron group. QoL was reported in a single trial, and IV iron was associated with an improvement among patients not receiving dialysis. Safety was reported for the combined population, and there were no differences in all-cause mortality,

Stage

GFR (mL/min/1.73m2)

1

≥90

2

60-89

3

30-59

4

15-29

5

<15 or receiving dialysis

CKD, chronic kidney disease; GFR, glomerular filtration rate; KDOQI, Kidney Disease Outcomes Quality Initiative Based on reference 1.

serious AEs, or need for transfusion between the oral and IV iron therapy groups.11 Hospitalization rate was reported in a single paper, with no differences found between groups. No data were available for cardiovascular morbidity and mortality and bacterial infections. There was no difference in the need for renal replacement therapy among patients who were not receiving dialysis initially. The authors concluded that IV iron therapy was more effective than oral for improving hemoglobin levels in patients receiving dialysis, but that the effect among those not receiving dialysis was small and clinically unimportant. Either oral or IV iron therapy may be used for initial management of patients not receiving dialysis or those receiving peritoneal dialysis, but IV iron therapy is recommended strongly for patients undergoing hemodialysis.4 The KDOQI guidelines do not recommend any particular preparation of IV iron, and these products generally are considered equivalent on a milligram per milligram basis(Table 2).4,10,12-14 Although iron dextran regimens have been administered safely, it is important to consider that with the information available today on the safety profile of sodium ferric gluconate and iron sucrose, many clinicians would consider these newer agents as first-line therapy.7

ESA THERAPY The ESAs—epoetin alfa (Epogen, Amgen) and darbepoetin alfa (Aranesp, Amgen)—are effective in raising hemoglobin,4 but their use has come under increased scrutiny in recent years. In March 2007, the FDA required that a boxed warning be added to the ESA product labels and that updates be made in the warnings and dosage and administration sections.15

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

3


Table 2. Summary of IV Iron Preparations Preparation

Usual Adult Dose

Administration

Notes

Iron dextran (Infed, Watson; DexFerrum, American Regent)

Total dose (mL)=0.0442 × (desired hemoglobin–observed hemoglobin) × lean body weight (kg) + (0.26 × lean body weight); small doses (such as 50-100 mg), given regularly until response

Given undiluted by slow IV injection (≤50 mg/min)

• Due to the potential for anaphylaxis, a test dose is required prior to the first therapeutic dose. • Resuscitative medication and personnel should be available each time iron dextran is administered.

Sodium ferric gluconate (Ferrlecit, Sanofi-aventis; Nulecit, Watson)

Hemodialysis recipients: 125 mg IV (expressed as elemental iron); most patients will require a minimum dose of 1,000 mg elemental iron over 8 dialysis sessions

May be diluted and given by slow IV infusion over 1 h or given undiluted by slow IV injection at a rate up to 12.5 mg/min at end of dialysis

• Has been associated with hypotension and flushing; reducing the dose and infusing the drug over 4 h has been shown to reduce these effects.

Iron sucrose (Venofer, American Regent)

Hemodialysis recipients: 100 mg at each consecutive dialysis session for a total cumulative dose of 1,000 mg Non-dialysis chronic kidney disease: 200 mg on 5 different occasions within 14 d

Given undiluted by slow IV injection at a rate ≤20 mg/ min (over 2-5 min); may also be given by IV infusion directly into the dialysis line over ≥15 min after dilution in normal saline.

• Slow injection is necessary to reduce the risk for hypotension.

Ferumoxytol (Feraheme, Amag)

510 mg IV × 1 dose, followed by 510 mg IV 3-8 d later

Given undiluted at a rate ≤1 mL (30 mg)/sec

• Regimen may be repeated after 1 mo if needed. • This preparation is relatively well tolerated and may be given rapidly. • There are no published comparative studies with other IV iron preparations.

ESAs, erythropoietin-stimulating agents Based on references 4,10, and 11-14.

Key components of the labeling change, which were strengthened in November 2007, are summarized in Table 3.15,16 In addition to the labeling changes, as of February 2010, ESAs are also prescribed under a risk evaluation and mitigation strategy (REMS).17 Components of the REMS include a medication guide for all patients (previously approved in 2008) and a prescribing program for patients receiving the drugs for cancerassociated anemia. The ESA labeling changes specific for CKD were based largely on results from 2 trials published in 2006— CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) and CREATE (Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta).18,19 In the CHOIR trial, patients with CKD not receiving

4

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

dialysis were randomized to epoetin alfa to achieve a target hemoglobin of 13.5 g/dL (n=715) or 11.3 g/ dL (n=717). The primary end point was the time to the composite of death, myocardial infarction (MI), hospitalization for congestive heart failure (CHF), or stroke. The data and safety monitoring board stopped the trial early when they realized that it was unlikely that the high-hemoglobin group was going to show a benefit. The median study duration was 16 months. The primary end point occurred in more patients in the high-hemoglobin group (125 vs. 97; hazard ratio [HR], 1.34; 95% CI 1.03-1.74; P=0.03). The results were driven by a higher incidence of death and CHF hospitalization in the high-hemoglobin group. No differences were found in QoL between groups, and more patients in the high-hemoglobin group reported at least 1 AE (376 [54.8%] of 686 vs 334 [48.5%] of 688; P=0.02). The


Table 3. Summary of ESA Labeling Changes Section

Key Label Information Related to CKDa

Boxed warning

• Avoid cardiac and thromboembolic events by using the lowest dose possible to avoid the need for transfusion. • ESAs increase the risk for death, serious cardiac events, and stroke when the target hemoglobin level is >12 g/dL. • ESAs should be used to maintain hemoglobin between 10 and 12 g/dL; maintaining higher hemoglobin levels increases the risk for death and serious cardiac events.

Warnings

• Information added about the increased incidence of thrombotic events. • Advises against the use of ESAs in patients with uncontrolled hypertension.

Dosing recommendations

• Monitor hemoglobin twice weekly in patients with CKD until the value is stable. • Carefully monitor and control blood pressure in patients with cardiac disease or hypertension. • If a patient fails to respond or maintain a response, evaluate further. If the transferrin saturation is <20%, give iron therapy.

CKD, chronic kidney disease; ESAs, erythropoiesis-stimulating agents a

Extensive information regarding cancer-associated anemia was added to ESA labeling at this time as well; the reader is referred to the reference or prescribing information for full details.

Based on references 15 and 16.

authors concluded that a target hemoglobin of 13.5 g/ dL was associated with greater risk for harm and no improvements in QoL compared with a target of 11.3 g/dL. A secondary analysis of data from CHOIR found that significantly more patients randomized to the high-hemoglobin group were unable to achieve target hemoglobin concentrations and required high doses of epoetin alfa.20 Patients who were able to achieve their hemoglobin targets (in both groups) had better outcomes than those who could not. Furthermore, no increased risk was found with high-hemoglobin targets in patients who achieved their randomized target. The CREATE trial randomized patients with CKD (GFR, 15-35 mL/min per 1.73 m2) to epoetin beta (not available in the United States) to target hemoglobin levels of 13 to 15 g/dL (n=301) or 10.5 to 11.5 g/dL (n=302).19 The primary end point was time to first cardiovascular event (composite of sudden death, MI, acute heart failure, stroke, transient ischemic attack, angina resulting in hospitalization, complication of peripheral vascular disease, or arrhythmia requiring hospitalization). There was no significant difference between groups in incidence of the primary end point (HR, 0.78; 95% CI, 0.53-1.14; P=0.20). QoL improved significantly with target hemoglobin levels of 13 to 15 g/ dL. Overall, there were no significant differences in AEs between groups, but the incidences of headache and hypertensive episodes were higher in the 13- to 15-g/dL

group. The authors concluded that complete correction of hemoglobin did not lead to a reduction in the risk for cardiac events. A third pivotal trial was published after the ESA labeling changes. TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy) differed from CHOIR and CREATE in that it was a randomized, doubleblind, placebo-controlled trial.21 Patients with CKD and type 2 diabetes were randomized to darbepoetin alfa to achieve a hemoglobin level of 13 g/dL (n=2,012), or placebo (n=2,026) with rescue darbepoetin alfa if the hemoglobin fell below 9 g/dL. The primary end points were the composite of death or a cardiovascular event (nonfatal MI, CHF, stroke, or hospitalization for myocardial ischemia) or the composite of time to death or ESRD. There were no significant differences between groups in terms of death or a cardiovascular event (HR, 1.05; 95% CI, 0.94-1.17; P=0.41) or for death or ESRD (HR, 1.06; 95% CI, 0.95-1.19; P=0.29). Fatal or nonfatal stroke occurred in almost twice as many patients assigned to darbepoetin (101 vs 53; HR, 1.92; 95% CI, 1.38-2.68; P<0.001). Transfusions were significantly more common in placebo recipients (496 vs 297; P<0.001). No clinically important differences in QoL were reported between the groups. The authors concluded that the use of darbepoetin in patients with type 2 diabetes and CKD was not associated with improvements in the primary endpoint of death

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

5


or cardiovascular events, or death or development of ESRD. However, they pointed out that such therapy was associated with an increased incidence of stroke, and they concluded the risk associated with therapy outweigh potential benefits for many patients. Results from CHOIR, CREATE, and TREAT reveal that ESA therapy may be associated with harm in patients with CKD, and that targeting high-hemoglobin levels does not appear to be beneficial. Unanswered questions remain, however, with respect to a precise hemoglobin target and optimal dosing of ESAs. The KDOQI guidelines have not been updated to reflect information in the TREAT trial; however, the CHOIR and CREATE papers were among those considered when the hemoglobin target was reduced to 11 to 12 g/dL.4,8 Therefore, there is still a place in therapy for ESAs to treat anemia in patients with CKD. Subcutaneous therapy is recommended for patients who are not receiving dialysis, whereas IV therapy is suggested for those receiving hemodialysis, based on convenience of administration.4 Frequency of administration and dose are left to the discretion of the prescriber and should be based on the clinical condition of the patient. Red blood cell transfusions are an option for the treatment of anemia in patients with CKD; however, their use should be judicious because patients may develop antibodies that may affect a kidney transplant. There is no recommended hemoglobin level at which transfusion is recommended. The Centers for Medicare & Medicaid Services (CMS) covers the majority of patients with CKD who require dialysis.22 The CMS has recently convened a coverage advisory group meeting and is considering a change in reimbursement. Analysis in response to a public citizen request is ongoing, and a decision is expected in this month.

Conclusion Appropriate management of anemia in patients with CKD requires iron supplementation and ESA therapy.

6

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

IV iron therapy is recommended for patients receiving hemodialysis; however, oral iron supplementation may be appropriate for nondialysis patients or those receiving peritoneal dialysis. The KDOQI guidelines suggest a target hemoglobin level of 11 to 12 g/ dL in patients receiving ESA therapy. Clinicians are encouraged to review these guidelines when managing patients with anemia due to CKD.

References 1.

National Kidney Foundation. Kidney Disease Outcomes Quality Initiative. Clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. http://www.kidney. org/professionals/KDOQI/guidelines_ckd/toc.htm. Accessed May 16, 2011.

2. Centers for Disease Control and Prevention. National CKD Fact Sheet 2010. http://www.cdc.gov/diabetes/pubs/factsheets/kidney. htm. Accessed May 16, 2011. 3. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health: National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC). Kidney and Urologic Diseases Statistics for the United States. http://kidney. niddk.nih.gov/kudiseases/pubs/kustats/index.htm. Accessed May 16, 2011. 4. KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis. 2006;47(5 suppl 3):s11-s145. 5. Hayat A. Safety issues with IV iron products in the management of anemia in chronic kidney disease. Clin Med Res. 2008;6(3-4):93-102. 6. Besarab A, Coyne DW. Iron supplementation to treat anemia in patients with chronic kidney disease. Nat Rev Nephrol. 2010;6(12):699-710. 7.

Hudson JQ. Chapter 47. Chronic Kidney Disease: Management of Complications. In: DiPiro JT, Talbert LR, Yee GC, Matzke GR, Wells BG, Posey ML (eds). Pharmacotherapy: A Pathophysiologic Approach, 7th ed: http://www.accesspharmacy.com/content. aspx?aID=3193406. Accessed May 20, 2011.

8. NKF KDOQI guidelines. KDOQI clinical practice guideline and clinical practice recommendations for anemia in chronic kidney disease: 2007 update on hemoglobin target. http://www.kidney.org/professionals/KDOQI/guidelines_anemiaUP/index.htm. Accessed May 16, 2011. 9. Macdougall IC. Iron supplementation in the non-dialysis CKD


(ND-CKD) patient: oral or intravenous? Curr Med Res Opin. 2010;26(2):473-482. 10. Schwenk MH. Ferumoxytol: a new IV iron preparation for the treatment of iron deficiency anemia in patients with chronic kidney disease. Pharmacotherapy. 2010;30(1):70-79. 11. Rozen-Zvi B, Gafter-Gvili A, Paul M, Leibovici L, Shpilberg O, Gafter U. IV versus oral iron supplementation for the treatment of anemia in CKD: systematic review and meta-analysis. Am J Kidney Dis. 2008;52(5):897-906. 12. McEvoy GK, ed. AHFS: Drug Information. Bethesda, MD: American Society of Health-System Pharmacists; 2011.

Web Exclusive ??????????????????????????????? ??????????????????????????????? ????????????????????.

pharmacypracticenews.com

13. Venofer [package insert]. Shirley, NY: American Regent; 2010. 14. Feraheme [package insert]. Lexington, MA: AMAG Pharmaceuticals; 2010. 15. FDA. Information for healthcare professionals: erythropoiesis stimulating agents (ESA) [Aranesp (darbepoetin), Eopgen (epoetin alfa), and Procrit (epoetin alfa)] (3/2007). http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm126485.htm. Accessed May 17, 2011. 16. FDA. FDA strengthens boxed warnings, approves other safety labeling changes for erythropoiesis-stimulating agents (ESAs). http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm109024.htm. Accessed May 17, 2011. 17. FDA. Information on erythropoiesis-stimulating agents (ESA) epoetin alfa (marketed as Procrit, Epogen) darbepoetin alfa (marketed as Aranesp). Safety announcement. http://www.fda.gov/drugs/ drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm109375.htm. Accessed May 17, 2011. 18. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085-2098. 19. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with CKD and anemia. N Engl J Med. 2006;355(20):2071-2084. 20. Szczech LA, Barnhart HX, Inrig JK, et al. Secondary analysis of the CHOIR trial epoetin-alfa dose and achieved hemoglobin outcomes. Kidney Int. 2008;74(6):791-798. 21. Pfeffer MA, Burdmann EA, Chen CY, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019-2032. 22. Winkelmayer WC. Confusion about the appropriate use of erythropoiesis-stimulating agents in patients undergoing maintenance dialysis. Semin Dial. 2010;23(5):486-491.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

7


V[ F\b_ 6[O\e =UN_ZNPf =_NPaVPR ;Rd` V` [\d NcNVYNOYR N` N[ 2[Rd`YRaaR_

4Ra aUR YNaR`a [Rd` QRYVcR_RQ QV_RPaYf a\ f\b_ P\Z]baR_ N[Q =1. AUR [Rd V[aR_NPaVcR S\_ZNa UN` RZORQQRQ DRO @VaR YV[X` aUNa TVcR f\b V[`aN[a NPPR`` a\ NQQVaV\[NY V[S\_ZNaV\[ b[V^bR `RN_PUV[T SRNab_R` N[Q ]_V[aV[T PN]NOVYVaVR` 2NPU V[`aNYYZR[a P\[aNV[` O_VRS `bZZN_VR` \S aUR Z\`a VZ]\_aN[a N_aVPYR` S_\Z aUR Pb__R[a Z\[aU·` V``bR N` dRYY N` O_RNXV[T [Rd` NURNQ \S ]_V[a

?RTV`aR_ S\_ S_RR - ddd]UN_ZNPf]_NPaVPR[Rd`P\Z


PRINTER-FRIENDLY VERSION AT PHARMACYPRACTICE NEWS.COM

Evolving Treatment Paradigms in

Non-Small Cell Lung Cancer CALEB T. CHU, MD, MPH Postdoctoral Fellow Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

MARGARET E. M. VAN METER, MD Medical Oncology Fellow Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, Texas

EDWARD S. KIM, MD Associate Professor of Medicine Department of Thoracic/Head and Neck Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas

L

ung cancer is the leading cause of cancer-related death in

the United States, accounting for 30% and 26% of all cancer deaths in men and women, respectively, and exceeding the

predicted death rates for breast and colorectal cancers combined.1

Non-small cell lung cancer (NSCLC) is the most common histologic subtype and accounts for more than 80% of lung cancers.

Although locally resectable NSCLC can be cured with surgical intervention, very few patients present with early-stage disease. Unfortunately, the majority present with advanced (stages IIIB and IV) disease; surgery and radiotherapy are not routinely part of care for these patients. Overall survival (OS) for these groups of patients has improved only modestly over the past few decades through advances in chemotherapy; median

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

OS has improved by approximately 2 months, providing 1-year survival rates of about 30% for patients receiving chemotherapy compared with 10% for those receiving supportive care. More recently, the advent of newer chemotherapy regimens has increased median survival times from 8 to 11 months in patients treated with standard doublet chemotherapy regimens.2 The addition of biologic agents and efforts to focus their use

P H A M AC Y P R AC T I C E N E WS â&#x20AC;˘ J U N E 2 0 1 1

1


in specific patient populations have further increased efficacy, with median survival times in some studies exceeding 12 months.3 Although previous studies of cytotoxic chemotherapy demonstrated no improvement in outcome when regimens were administered for more than 4 to 6 cycles, recent studies in the maintenance setting indicate that more prolonged therapy may be desirable.4 As treatment strategies evolve and chemotherapies and biologic therapies are being increasingly integrated, a more personalized approach should be used to provide the most effective and least toxic treatments to patients with advanced NSCLC.

Conventional Chemotherapy Platinum-based doublet regimens are the mainstay of chemotherapy in patients with advanced NSCLC and a good performance status (PS). The survival benefit of cisplatin in the treatment of NSCLC was established in 1995, based on a meta-analysis that included 52 clinical trials with more than 9,000 patients; in the trials involving patients with advanced disease, cisplatin-based chemotherapy showed a 27% reduction in the risk for death at 1 year.5 Thus, in 1997, the American Society of Clinical Oncology (ASCO) issued guidelines recommending the use of cisplatin-based chemotherapy for patients with advanced NSCLC and a good PS. Given the toxicity of cisplatin-based regimens, much effort over the past decade has been directed toward developing better-tolerated, equally efficacious treatments. To this end, trials have evaluated the use of newer agents, either as monotherapy or in combination regimens, as well as the use of carboplatin in lieu of cisplatin in doublet regimens. In comparisons of platinum-based doublets, 2 variables must be considered: the platinum agent used (cisplatin or carboplatin) and the agent combined with the platinum agent. The principal drugs combined with a platinum agent in the third-generation doublets are gemcitabine (Gemzar, Lilly), vinorelbine, docetaxel (Taxotere, Sanofi-aventis), paclitaxel, and pemetrexed (Alimta, Lilly). A large trial comparing cisplatin-paclitaxel with 3 other regimensâ&#x20AC;&#x201D;carboplatin-paclitaxel, cisplatin-docetaxel, and cisplatin-gemcitabineâ&#x20AC;&#x201D;in 1,155 patients with advanced NSCLC showed no significant difference in OS (median 7.9 months) among the 4 regimens.6 It is notable, however, that patients in the carboplatin-paclitaxel arm had a slightly lower rate of serious toxicities and that the study was limited to patients with an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 1; initial analysis showed a higher rate of adverse events in patients with a PS of 2. The largest Phase III study ever performed in the first-line treatment of advanced NSCLC (N=1,725) compared cisplatin-pemetrexed with cisplatin-gemcitabine.7 A statistically significant survival advantage was demonstrated for patients with adenocarcinoma or large-cell carcinoma histology treated with cisplatin-pemetrexed compared with cisplatin-gemcitabine

2

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

(median OS, 11.8 and 10.4 months, respectively; hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.700.94; P=0.005). In contrast, patients with squamous cell histology had a shorter median survival when treated with cisplatin-pemetrexed (OS, 9.4 vs 10.8 months; HR, 1.23; 95% CI, 1.00-1.51; P=0.05). This was the first Phase III trial to prospectively show a survival difference based on NSCLC histology.

Newer Targeted Therapies With the advent of new targeted therapies, first-line chemotherapy for advanced NSCLC is changing. Given the limited ability of current chemotherapy regimens to prolong OS, new drug development has focused on improving tolerance, quality of life, and ease of administration while maintaining at least comparable efficacy to standard first-line therapy. The Phase III ECOG 4599 trial evaluated first-line platinum doublet therapy (carboplatin-paclitaxel) with and without the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab (Avastin, Genentech) in patients with advanced nonsquamous NSCLC.3 Treatment in the experimental arm included bevacizumab combined with chemotherapy every 3 weeks for 6 cycles, followed by maintenance bevacizumab every 3 weeks until progressive disease or intolerable side effects occurred. Median OS, the primary end point, increased by 2 months (12.3 vs 10.3 months; HR, 0.79; 95% CI, 0.67-0.92; P=0.003) with the addition of bevacizumab. Statistically significant improvements in response rate (35% vs 15%) and progression-free survival (PFS; 6.2 vs 4.5 months) also were observed. The pivotal FLEX (First-Line Erbitux in Lung Cancer) trial compared the cisplatin-vinorelbine doublet plus the anti-epidermal growth factor receptor (EGFR) antibody cetuximab (Erbitux, Bristol-Myers Squibb) with cisplatin-vinorelbine alone in patients with EGFRexpressing advanced NSCLC.8 Cetuximab was given together with doublet chemotherapy for 6 cycles and continued as maintenance therapy until progressive disease or intolerable side effects developed. For the entire intention-to-treat population, median OS was 11.3 months in the cisplatin-vinorelbine-cetuximab arm and 10.1 months in those treated with cisplatin-vinorelbine alone (HR, 0.871; 95% CI, 0.762-0.996; P=0.044). Prespecified subgroup analysis showed that the survival benefit of treatment that included cetuximab persisted across most subgroups. However, gender, PS, histology, smoking status, and geographic region all had prognostic significance. Specifically, women had longer survival times than men (12.7 vs 9.3 months), Asians had a longer survival than whites (19.5 vs 9.6 months), and patients with a higher PS and those who had never smoked had better prognoses than patients with lower PS and smokers. Data presented at the ASCO meeting in 2009 expanded on prognostic factors and molecular predictors of OS from the FLEX trial. In one analysis, KRAS


mutational status was found not to be predictive for cetuximab efficacy, but patients taking cetuximab who developed an acne-like rash had a longer median OS than those without the rash (15 vs 8.8 months; HR, 0.63; 95% CI, 0.52-0.77; P<0.001).9 Improvements in OS seen with molecular-targeted therapies against VEGF and EGFR in combination with platinum doublets in patients with advanced NSCLC3,8 have led to further investigation of the combined effects. The SWOG (Southwest Oncology Group) 0536 Phase II study combined 4 drugsâ&#x20AC;&#x201D;cetuximab, bevacizumab, carboplatin, and paclitaxelâ&#x20AC;&#x201D;for up to 6 cycles, followed by maintenance bevacizumab weekly until disease progression.10 The primary end point was the frequency and severity of hemorrhagic toxicities that were grade 4 or higher in patients with advanced-stage nonsquamous NSCLC. Combining carboplatin, paclitaxel, cetuximab, and bevacizumab resulted in a tolerable safety profile, with a 2% incidence of hemorrhage that was grade 4 or higher (95% CI, 0%-7%). An ongoing Phase III trial (SWOG 0819) is comparing the 4-drug regimen used in SWOG 0536 with the 3-drug regimen used in ECOG 4599 (carboplatin-paclitaxel-bevacizumab). The studies described above have evaluated biologic targeted agents in combination with cytotoxic chemotherapy. Two additional Phase III studies, INTEREST (Iressa NSCLC Trial Evaluating Response and Survival against Taxotere) and IPASS (First-line Iressa versus Carboplatin/ Paclitaxel in Asia), compared single-agent biologic therapy using the oral EGFR tyrosine kinase inhibitor (TKI) gefitinib (Iressa, AstraZeneca) with traditional chemotherapeutic agents, with favorable outcomes. INTEREST is a randomized Phase III trial comparing gefitinib with docetaxel in patients with advanced NSCLC who had previously received at least 1 platinum-based chemotherapy regimen.11 Patients received either gefitinib daily or docetaxel every 3 weeks until disease progression or unacceptable toxicity. The primary end point was OS, analyzed via noninferiority in the overall population and superiority in patients with a high EGFR copy number. Results for all 1,433 patients confirmed noninferiority of gefitinib compared with docetaxel for OS (7.6 vs 8 months; HR, 1.020; 95% CI, 0.905-1.150). However, in the 174 patients with a high number of EGFR gene copies, gefitinib did not show superiority for OS (8.4 vs 7.5 months; HR, 1.09; 95% CI, 0.78-1.51; P=0.62). Subsequent biomarker analysis of EGFR and KRAS in tumor biopsies from the INTEREST trial showed similar OS in patients treated with gefitinib and docetaxel, regardless of biomarker subgroup. However, patients with EGFR mutations had longer PFS and higher objective response rate (ORR), and patients with high EGFR copy numbers had higher ORR when treated with gefitinib compared with docetaxel.12 Recent data from the IPASS trial have shown that gefitinib also is a valid first-line therapy for a subset of patients.13 This study included patients in East Asia with advanced NSCLC of adenocarcinoma histology

who had a World Health Organization PS of 0 to 2 and were never smokers or former light smokers. The primary end point was PFS; median PFS was similar in those treated with gefitinib and those treated with carboplatin-paclitaxel (5.7 vs 5.8 months), but the KaplanMeier curves crossed at this point, and patients treated with gefitinib had a significantly higher rate of PFS at 12 months (24.9% vs 6.7%), with an overall HR of 0.74 (95% CI, 0.65-0.85; P<0.0001). Preliminary OS (28% maturity with follow-up ongoing) was similar for gefitinib and carboplatin-paclitaxel, but gefitinib demonstrated improved quality-of-life ratings and a more favorable tolerability profile. In the IPASS trial, EGFR mutational status appeared to be a strong biomarker for gefitinib efficacy.13 Similar analysis has shown that EGFR mutations also are associated with responsiveness to erlotinib (Tarceva, OSI Pharmaceuticals).14 These findings indicate that genetic screening of patients prior to therapy may be warranted to allow clinicians to tailor therapy to individual patients. The study results also highlight a need for a paradigm shift toward molecular profiling in the treatment of advanced NSCLC to improve tolerability of therapy.

Maintenance Therapy Debate continues about delayed (second- or thirdline) versus immediate (maintenance) chemotherapy in patients who already have received first-line therapy. Multiple trials have examined the role of maintenance chemotherapy after completion of initial chemotherapy in advanced NSCLC (Table).4,15-21 Maintenance chemotherapy could be either continuation of 1 or more of the initial chemotherapy agents or the addition of a new chemotherapeutic or targeted agent. In one multicenter Phase III trial, patients with advanced NSCLC who did not have evidence of disease progression after first-line treatment with 4 cycles of carboplatin-gemcitabine were randomized to receive docetaxel either immediately or at disease progression.19 Maintenance docetaxel was associated with a statistically significant improvement in PFS (5.7 vs 2.7 months; P=0.0001) and a trend toward improvement in OS (median 12.3 vs 9.7 months; P=0.0853). Several large Phase III trials of maintenance therapy reported at the 2009 ASCO annual meeting used erlotinib, erlotinib plus bevacizumab, or pemetrexed as maintenance therapy. The large Phase III SATURN trial tested erlotinib maintenance versus placebo after platinum-based doublet chemotherapy in 1,949 patients with advanced NSCLC. The SATURN trial met its primary end point of PFS, with results showing significantly increased PFS with erlotinib in all patients (HR, 0.71; 95% CI, 0.62-0.82; P<0.0001), and improved OS (12 vs 11 months).20 In exploratory analysis, an even greater benefit was seen in a subset of patients who had EGFR mutations. Based on this information, in April 2010, the FDA approved erlotinib for maintenance treatment of patients with advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

3


Table. Selected Trials of Maintenance Therapy in Advanced NSCLC Clinical Trial

Treatment Arms

Fidias et al19

Capuzzo et al20 (SATURN)

N

PFS, mo

Median OS, mo

GC, then immediate 309 docetaxel GC, then delayed docetaxel

5.7 (P=0.001) 2.7

12.3 (P=0.0853) 9.7

CT, then E CT, then P

438 451

PFS was significantly prolonged with E versus P in all patients (HR, 0.71; 95% CI, 0.62-0.82; P<0.0001)

12 11

Pemetrexed + BSC P + BSC

441 222

Overall/NSQ/SQ 4.3/4.5/2.8 2.6/2.6/2.6

Overall/NSQ/SQ 13.4/15.5/9.9 10.6/10.3/10.8

CT + B, then B + P CT + B, then B + E

768

3.7 (P=0.0012) 4.8

NA

Ciuleanu et al4

Miller et al21 (ATLAS)

B, bevacizumab; BSC, best supportive care; CI, confidence interval; CT, first-line platinum-based chemotherapy; E, erlotinib; GC, gemcitabine-carboplatin; HR, hazard ratio; NA, not available; NSCLC, non-small cell lung cancer; NSQ, nonsquamous histology; OS, overall survival; P, placebo; PFS, progression-free survival; SQ, squamous cell histology

platinum-based first-line chemotherapy. Another Phase III trial evaluated pemetrexed and led to its July 2009 FDA approval as maintenance therapy (in patients with locally advanced or metastatic nonsquamous NSCLC whose disease has not progressed after 4 cycles of platinum-based first-line chemotherapy). This trial included 663 patients with advanced NSCLC who did not progress on an initial platinum-based doublet and showed that pemetrexed maintenance resulted in significantly better OS (13.4 vs 10.6 months; HR, 0.79; 95% CI, 0.650.95; P=0.012) and PFS (4.3 vs 2.6 months; HR, 0.50; 95% CI, 0.42-0.61; P<0.0001) than placebo.4 Pemetrexedâ&#x20AC;&#x2122;s efficacy, favorable tolerability profile, ease of administration, and OS benefit make it appealing as a maintenance drug in advanced NSCLC. Although most studies discussing maintenance options at the ASCO 2009 annual meeting tested nonâ&#x20AC;&#x201C;cross-resistant regimens, the ATLAS Phase III trial evaluated bevacizumab with or without erlotinib after completion of chemotherapy with bevacizumab for first-line treatment of advanced NSCLC.21 This study, the first to evaluate combination versus singleagent maintenance therapy options, showed significant improvement in PFS in the group receiving combination therapy (4.8 vs 3.7 months; HR, 0.722; 95% CI, 0.592-0.881; P=0.0012).

Biomarkers and Therapy As discussed above, many of the recent advances in the treatment of NSCLC have involved the integration of targeted therapeutics and can more accurately define the subset of patients who are most likely to benefit from a given treatment. Thus, it is more important now than ever before to explore predictors of efficacy to help direct the best therapy for each patient. In clinical practice, factors such as smoking history,

4

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

histology, gender, or ethnicity may help determine the choice of therapy. Genotypic correlates to response are being actively pursued.

HISTOLOGY The importance of histology has been highlighted clearly for the use of pemetrexed in the treatment of advanced NSCLC in multiple settings. The large study by Scagliotti et al described above found that patients with nonsquamous tumors had a survival advantage when treated first-line with cisplatin-pemetrexed compared with those treated with cisplatin-gemcitabine, whereas those with squamous cell histology had a shorter median survival when treated with cisplatin-pemetrexed.7 This was the first prospective study to show survival differences based on histology. A study by Hanna et al comparing pemetrexed and docetaxel in the second-line setting22 was subsequently analyzed retrospectively using subset histology data23; patients with nonsquamous NSCLC had a significant improvement in OS when treated with pemetrexed compared with those treated with docetaxel (9.3 vs 8.0 months; HR, 0.778; P=0.048). When pemetrexed was used as maintenance therapy by Ciuleanu et al, the improvements in PFS and OS were documented primarily in patients with nonsquamous histology.4 One possible explanation for the observed differential efficacy of pemetrexed is that baseline thymidylate synthase (TS) levels are higher in squamous cell carcinoma than in adenocarcinoma.24 Data on TS expression recently have been broadened to include undifferentiated large cell carcinoma. In a study presented at the ASCO meeting in 2009, significantly higher median mRNA and protein TS levels were detected in large cell and squamous cell carcinoma


Adenocarcinoma or nonsquamous

EGFR mutationpositive

Gefitinib Erlotinib

Squamous

EGFR mutationnegative or unknown

Bevacizumab + chemotherapy doublet a

Chemotherapy doublet with or without cetuximab a

Non-bevacizumab chemotherapy doublet (pemetrexed-based) a

Maintenance therapy • Pemetrexed a • Erlotinib with or without bevacizumab • Docetaxel

Disease progression

• Salvage therapy • Consider clinical trial

Figure. Proposed algorithm for treatment of NSCLC. a

FDA-approved regimens

EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer

samples compared with adenocarcinoma samples (large cell carcinoma: P<0.001 for both mRNA and protein values; squamous cell carcinoma: P=0.002 for mRNA, P<0.001 for protein).25

EGFR, VEGF,

AND

KRAS

Somatic mutations in the tyrosine kinase domains of two erbB genes—the EGFR and HER-2 (human epidermal growth factor receptor 2) genes—have been found in lung adenocarcinomas. EGFR mutations, particularly those in exon 19, are associated with sensitivity to the TKIs gefitinib26-28 and erlotinib.29 However, markers of resistance to EGFR inhibitors also have been identified, including the T790M mutation in exon 20.30,31 Approximately 15% to 30% of lung adenocarcinomas contain activating mutations in the KRAS gene and may be associated with unfavorable outcomes.32 Unlike in colon cancer, mutations in KRAS in lung cancer are not associated with a lack of sensitivity to either of the EGFR TKIs.33 Thus, although patients with EGFR mutations had improved PFS when treated with maintenance erlotinib in the SATURN trial, KRAS mutations had no predictive value.20

BROADER GENOTYPE TESTING With the emergence of EGFR mutations as an important target for therapy, strategies for treating patients harboring other mutations that make them refractory to treatment are being tested. EML4-ALK is a novel fusion oncogene in NSCLC.34 The fusion results from a small inversion within chromosome 2p, leading to expression of a constitutively activated, chimeric tyrosine kinase. Shaw et al have shown that the presence of EML4-ALK results in a similar clinical profile to that seen in patients with EGFR mutations and is particularly frequent in light or never smokers; however, unlike EGFR mutations, EML4-ALK is found more often in men.35 Patients with EML4-ALK tumors did not benefit from EGFR TKIs; there were no responses in the EML4ALK cohort. A promising Phase I trial testing the ALK inhibitor PF-02341066 showed an ORR of 57% (47 of 82 patients; 46 partial responses and 1 complete response) and 33% stable disease in patients with ALK rearrangements, with mainly grade 1 or 2 gastrointestinal side effects.36 This has allowed for the early development of several Phase III trials of ALK inhibitors as single agents, as well as with chemotherapy as second-line therapy.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

5


Another active area of research centers on mechanisms of resistance to EGFR TKIs, including amplification of the MET oncogene and secondary mutations in EGFR, such as the T790M mutation. Molecular testing for these abnormalities may eventually play a role in treatment selection. A recent Phase II study comparing the effects of the MET inhibitor METMAb plus erlotinib with placebo plus erlotinib showed nearly a 50% increase in OS and PFS in patients with high MET expression who received the MET combination therapy.37 However, patients with a low expression of MET fared worse on combination MET-erlotinib versus erlotinib alone, leading to future investigations into the possible interference of METMAb with erlotinibâ&#x20AC;&#x2122;s effectiveness. ARQ 197 is another MET-inhibiting targeted therapy that has showed promise in patients with nonsquamous histology, EGFR wild-type, and KRAS mutations.38 Preliminary results from a Phase II study comparing erlotinib plus ARQ 197 to erlotinib plus placebo indicated a greater median PFS in the experimental arm (16.1 vs 9.7 weeks), with similar adverse effects between the 2 arms. On another molecular front, there has been increasing interest involving irreversible EGFR inhibitors, mainly through the discovery of the small-molecule EGFR TKI BIBW 2992. Differing from its predecessors, BIBW 2992 binds irreversibly to both EGFR and HER-2 and is active against both wild-type and multiple mutant forms of EGFR. Preliminary results from an ongoing Phase II study of patients with NSCLC who had tumors with EGFR-activating mutations and progressive or recurrent disease following chemotherapy showed a 78% to 94% disease control rate, depending on the mutation subset, when BIBW 2992 alone was used.39 Additional Phase II/III studies are under way investigating use of BIBW 2992 in NSCLC patients in other treatment settings.

Conclusion Paradigms in first-line and maintenance settings of advanced NSCLC are evolving toward targeted molecular therapies with better tolerability profiles. Based on recent studies, new standards of management in advanced NSCLC must be considered, evaluating the roles of histology, maintenance therapy, and testing for mutations in EGFR (Figure). Each patient with NSCLC presents a unique challenge, and therapy should be directed by more than simply PS. Agents targeting EGFR, VEGF, and ALK pathways in NSCLC have

6

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

demonstrated that different lung cancers respond differently to therapy. Efforts must continue to be made to understand the biology of individual tumors by emphasizing tissue-based clinical trials to create patient-specific therapy.40

References 1.

Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.

2. Breathnach OS, Freidlin B, Conley B, et al. Twenty-two years of Phase III trials for patients with advanced non-small-cell lung cancer; sobering results. J Clin Oncol. 2001;19(6):1734-1742. 3. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355(24):2542-2550. 4. Ciuleanu T, Brodowicz T, Zielinski C, et al. Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet. 2009;374:1432-1440. 5. Non-small Cell Lung Cancer Collaborative Group (NSCL-CG). Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. BMJ. 1995;311(7010):899-909. 6. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002;346(2):92-98. 7.

Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26(21):3543-3551.

8. Pirker R, Pereira JR, Szczesna A, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009;373(9674):1525-1531. 9. Pirker R, Rodrigues-Pereira J, Szczesna A, et al. Prognostic factors in advanced NSCLC: experience from the FLEX trial. J Clin Oncol. 2009;27(15 suppl): Abstract 8083. 10. Kim ES, Herbst RS, Moon J, et al. S0536: Carboplatin, paclitaxel, cetuximab and bevacizumab followed by cetuximab and bevacizumab maintenance in advanced non-small cell lung cancer (NSCLC), a SWOG phase II study. PD3.5.5. Presented at: 2009 IASLC World Congress on Lung Cancer; July 31-August 4, 2009; San Francisco, CA. 11. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small cell lung cancer (INTEREST): a randomized Phase III trial. Lancet. 2008;372(9652):1809-1818. 12. Douillard JY, Shepherd FA, Hirsh V, et al. Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized Phase III INTEREST trial. J Clin Oncol. 2009;28(5):744-752.


13. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatinpaclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361(10):947-957. 14. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009;361(10):958-967. 15. Socinski MA, Schell MJ, Peterman A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non–small-cell lung cancer. J Clin Oncol. 2002;20(5):1335-1343. 16. Park JO, Kim SW, Ahn JS, et al. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol. 2007;25(33):5233-5239.

26. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350(21):2129-2139. 27. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500. 28. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004;101(36):13306-13311. 29. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer— molecular and clinical predictors of outcome. N Engl J Med. 2005;353(2):133-144.

17. Westeel V, Quoix E, Moro-Sibilot D, et al. Randomized study of maintenance vinorelbine in responders with advanced non-small cell lung cancer. J Natl Cancer Inst. 2005;97(7):499-506.

30. Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786-792.

18. Sculier JP, Lafitte JJ, Lecomte J, et al. A phase III randomised trial comparing sequential chemotherapy using cisplatin-based regimen and paclitaxel to cisplatin-based chemotherapy alone in advanced non-small-cell lung cancer. Ann Oncol. 2007;18(6):1037-1042.

31. Morgillo F, Kim WY, Kim ES, Ciardello F, Waun KH, Lee HY. Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res. 2007;13(9):2795-2803.

19. Fidias PM, Dakhil SR, Lyss AP, et al. Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol. 2009;27(4):591-598. 20. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. SATURN: A doubleblind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol. 2009;27:(15 suppl): Abstract 8001. 21. Miller VA, O’Connor P, Soh C, et al. A randomized, double-blind, placebo-controlled, phase IIIb trial (ATLAS) comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2009;27:(18 suppl): Abstract LBA8002. 22. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non–smallcell lung cancer previously treated with chemotherapy. J Clin Oncol. 2004;22(9):1589-1597. 23. Peterson P, Park K, Fossella F, et al. Is pemetrexed more effective in adenocarcinoma and large cell carcinoma than in squamous cell carcinoma? A retrospective analysis of a phase III trial of pemetrexed vs docetaxel in previously treated patients with advanced non-small cell lung cancer (NSCLC): P2-328. J Thorac Oncol. 2007;2(8):S851: Abstract P2-328. 24. Ceppi P, Volante M, Saviozzi S, et al. Squamous cell carcinoma of the lung compared with other histotypes shows higher messenger RNA and protein levels for thymidylate synthase. Cancer. 2006;107(7):1589-1596, PMID: 16955506. 25. Scagliotti G, Monica V, Ceppi P, et al. Baseline thymidylate synthase expression according to histological subtypes of non-small cell lung cancer. J Clin Oncol. 2009;27:(15 suppl): Abstract 7521.

32. Rodenhuis S, Slebos RJ. The ras oncogenes in human lung cancer. Am Rev Respir Dis. 1990;142(6 pt 2):S27-S30. 33. Pao W, Wang TY, Riely GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2(1):e17. 34. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small cell lung cancer. Nature. 2007;448(7153):561-566. 35. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-4253. 36. Kwak EL, Bang Y-J, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med. 2010;363:1693-1703. 37. Spigel D, Ervin T, Ramlau R, et al. MetMAb added to erlotinib improves survival in a subset of patients with lung cancer. Presented at: the ESMO 35th Congress; October 8-12, 2010; Milan, Italy; Abstract LBA15. 38. Schiller JH, Akerley WL, Brugger W, et al. Results from ARQ 197209: a global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previously treated EGFR inhibitor-naïve patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol. 2010;28:(18 suppl): Abstract LBA7502. 39. Yang CH, Shih JY, Su WC, et al. A phase II study of BIBW 2992 in patients with adenocarcinoma of the lung and activating EGFR mutations (LUX-Lung 2). J Clin Oncol. 2010;28:(15 suppl): Abstract 7521. 40. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE Trial: Personalizing Therapy for Lung Cancer. Cancer Discovery 2011;1:OF42-OF51.

I N D E P E N D E N T LY D E V E L O P E D B Y M C M A H O N P U B L I S H I N G

7


in Your Inbox

... to receive the monthly e-newsletter from

at www.pharmacypracticenews.com

Get the latest news delivered directly to your computer and PDA. The new interactive format has embedded Web site links that give you instant access to additional information as well as unique searching features and printing capabilities. Each installment contains brief summaries of the most important articles from the current monthâ&#x20AC;&#x2122;s issue, and breaking news ahead of print.

Register for free @ www.pharmacypracticenews.com


Pharmacy Practice News • June 2011

Policy 9

Pain Medicine

MARIJUANA continued from page 1

response to a request last year by a New Jersey delegate. It talks primarily about the need for more research and standardization of the drug itself, and is part of a broader effort by the professional association to educate members about legal and clinical issues related to medical marijuana. ASHP officials also plan to hold an educational webinar this fall to reach as many members as feasible, Ms. Reilly said. Pharmacists want to look out for their patients’ safety, she said. “Regardless of whether it’s legal, they do feel an obligation to at least be able to advise their patients.” Pharmacists find themselves working in a gray area between what state laws have legalized and the inherent limitations of federal law. Marijuana is classified as a Schedule I controlled substance under the federal Controlled Substances Act, which means there is no federally recognized use and all possession and distribution is criminalized. Pharmacists “can’t dispense it or handle it or have anything to do with it,” said Tom Van Hassel, RPh, MPA, director of pharmacy at Yuma Regional Medical Center in Yuma, Ariz. This spring, Arizona residents began applying for medical marijuana cards,

‘[Medical marijuana is] not an FDA-approved drug. We don’t have safety studies. And we don’t know how it might interact positively or negatively with other drugs that patients might be taking.’ —David Craig, PharmD

and clinicians began to weigh the “what ifs,” Mr. Van Hassel said. “So if a patient comes in and the doctor has given them an order for [medical marijuana], how do we get it? Do they bring in their own?” One likely scenario, Mr. Van Hassel said, is the case of a cancer patient who has been prescribed marijuana to cope with chemotherapy-related nausea. “Let’s say he wants to smoke his marijuana cigarette prior to or [while] receiving his chemo. What exactly are we supposed to do in that situation?”

preparation or distribution of medical marijuana. But the policy, which could be amended even if it’s approved this month, stated that more assistance is needed to resolve clinical safety questions. Among the organization’s recommendations are the following: • Develop processes that could provide standardized marijuana to facilitate research efforts. • Encourage the Drug Enforcement Administration to eliminate barriers

Providing Guidance In its policy recommendation, ASHP officials laid out the legal issues involved with medical marijuana, stating that it opposed pharmacists or health care facilities being involved in any way with the procurement, storage,

prohibiting marijuana research, including a review of its status as a Schedule I controlled substance. • Foster educational efforts to help pharmacists answer questions about therapeutic and legal issues related to medical marijuana use. Russ Lazzaro, MS, RPh, the New Jersey delegate who at last year’s meeting requested adding medical marijuana as a new business item, said that he doesn’t disagree with the organization’s stance. Mr. Lazzaro, who has since taken a job as a pharmacy manager at NewYork-Presbyterian Hospital, was at that point practicing in New Jersey, where medical marijuana legislation was passed in January 2010. Still, the call for more research doesn’t help pharmacists who worry about medical marijuana users who walk in today, Mr. Lazzaro said. “What are we actually going to do when patients bring in their own? It still leaves us in a legal quandary.” By April, Arizona’s board of pharmacy had already fielded two pharmacist questions, both expressing a related concern. “If a patient comes into our hospital with medical marijuana that is legally prescribed, are we allowed to [keep] it in our vault in the pharmacy with the other home medications that we store?” wrote one. In response, the pharmacy board referred the pharmacist to a state rule, which details when a patient can bring an at-home medication into the hospital. One of the requirements is that the pharmacist or medical practitioner be able to identify the drug. “If I was the hospital, I wouldn’t allow it to be used, because I couldn’t identify it,” said Hal Wand, RPh, MBA, executive director at the

Arizona State Board of Pharmacy.

Mr. Wand said the marijuana could be sent home with the patient’s family member or caregiver, but stressed that he was only expressing a personal opinion. “Each medical staff and P&T [pharmacy and therapeutics] committee is going to make their own decision on this.”

Figure. Fifteen states and Washington, D.C., have legalized medical marijuana use since 1996: Alaska, Arizona, California, Colorado, District of Columbia, Hawaii, Maine, Michigan, Montana, Nevada, New Jersey, New Mexico, Oregon, Rhode Island, Vermont and Washington.

Practice Uncertainties Among the states that have legalized marijuana for medical use, there’s considerable variability regarding specifics, including whether at-home cultivation is permitted, as well as which

see MARIJUANA, page 10


10 Policy

Pharmacy Practice News • June 2011

Pain Medicine

MARIJUANA continued from page 9

medical conditions are covered. Nearly all of the states require the user to carry an identification card. For more stateby-state specifics, the Marijuana Policy Project provides an online chart. (Scan 2-D bar code on this page to access.) In Arizona, which began taking applications in mid-April, hospitals can verify if a patient is legally authorized to use the drug, Mr. Van Hassel said. The names of all cardholders are submitted to the state’s prescription drug monitoring program, he said. But other problems might crop up, he said. For one thing, Yuma Regional is a nonsmoking facility, so where does prescribed marijuana fit in? Plus, there’s the quality and safety issue, given the variability in marijuana products. How can the safety and potency of the product be verified? There also are potential security headaches, Mr. Van Hassel said. Medical marijuana will have to be stored in a locked vault somewhere. Otherwise, the patient could potentially argue that it had been stolen, and the hospital was on the hook to replace it, as it would with a stolen pair of eyeglasses. “It’s a whole can of worms,” he said. “One solution to one problem may cause a problem in another area.” At this point, there’s not much research to assess effectiveness, safety or related issues, such as interactions with other drugs, ASHP officials wrote in their proposed policy recommendation. But marijuana’s classification as a Schedule I drug makes further clinical insights unlikely anytime soon, as existing federal policies largely restrict any research on that class of substances. For that reason, ASHP officials questioned if medical marijuana would need to be reclassified from Schedule I to Schedule II to facilitate research. In the meantime, the clinical uncertainties are numerous, said David Craig, PharmD, a pain specialist at H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla. “It’s not an FDA-approved drug,” he said, ticking off concerns that other clinicians have raised. “We don’t have safety studies.

‘[Patients who use medical marijuana] will behave. They won’t come in and have a big smokefest in the middle of the cancer center.’ —Cindy O’Bryant, PharmD, BCOP

Medical Marijuana: Pro/Con • Increases appetite and counteracts weight loss, nausea and vomiting in patients with debilitating illnesses, such as AIDS and advanced cancer. • Relieves symptoms associated with certain neurologic disorders, including muscle spasticity in patients with multiple sclerosis. • Eases pain in chronic conditions, including sickle cell anemia, migraine headache, phantom limb pain, and cancer. • May reduce frequency of seizures in patients with epilepsy. • Reduces intraocular pressure in glaucoma.

• Contains 50%-70% more carcinogens linked to lung cancer than tobacco. • May lead to psychological dysfunction and addiction. • Cardiac adverse effects include tachycardia, hypertension, syncope, palpitations, stroke, acute myocardial infarction. • Increases symptoms of chronic bronchitis (e.g., coughing, sputum production, wheezing). • Considered a gateway drug, leading to exposure and addiction to more harmful drugs. Source: Am J Health-Syst Pharm 2007;64:1037-1044

‘If I was the hospital, I wouldn’t allow [medical marijuana] to be used because I couldn’t identify it.’ —Hal Wand, RPh, MBA And we don’t know how it might interact positively or negatively with other drugs that patients might be taking.” Additionally, there’s always a question about potency, as well as whether the marijuana might be contaminated in some way, he said.

Assessing Clinical Risk Some of these concerns may be unfounded, based on feedback from

two pharmacists who practice in states where marijuana has been legal for at least 10 years. Elaine Levy, RPh, system director of pharmacy for Sharp HealthCare, a San Diego-based nonprofit hospital system, couldn’t recall any instance in which a patient had been admitted with medical marijuana. Neither do patients ask to use the herb on-site— for example, in the outpatient chemo-

Medical Marijuana: Scan for More Resources Marijuana Policy Project: Key Aspects of DC and State Medical Marijuana Laws (last updated April 4, 2011).

For information on how to scan these bar codes with your smartphone, see p. 3.

Seamon MJ, Fass JA, Maniscalco-Feichtl M, et al. Medical marijuana and the developing role of the pharmacist. AJHP. 2007;64:1037-1044.

therapy room, Ms. Levy said. When compiling a list of patient medications, clinicians don’t ask specifically about medical marijuana, she added. If the patient volunteered it, the drug would be added to their list of admitting medications. Similarly, Cindy O’Bryant, PharmD, BCOP, oncology pharmacy specialist at the University of Colorado Cancer Center in Aurora, couldn’t cite any instances of cancer patients wanting to use on-site. The hospital’s nonsmoking policy would preclude that anyway, she pointed out. “For the most part, these patients are using it because it helps them,” she said, trying to assuage the fears of pharmacists in states where marijuana is on the cusp of medical legalization. “They feel like they are getting some benefit from it. They will behave. They won’t come in and have a big smokefest in the middle of the cancer center.” When asking patients about their medications, Dr. O’Bryant doesn’t specify medical marijuana but does query about alternative therapies. If they ’fess up, she’s not preoccupied with how they obtained the herb but rather with vetting any potential clinical issues. “My concern is what other drugs they are on, are there any potential interactions and are they doing anything that will put them at risk for any synergistic side effects,” she said. To gain some insight, Dr. O’Bryant looks at drug interactions related to dronabinol (Marinol, Unimed Pharmaceuticals, Inc.), an FDA-approved drug therapy that contains tetrahydrocannabinol (THC), the main psychoactive substance in marijuana. But it’s an inexact approach, she acknowledged. “You are trying to extrapolate from dronabinol to smoking marijuana, which might not be all that correct.” Dr. Craig also asks palliative medicine patients at Moffitt about marijuana use, even though the drug hasn’t been legalized for medical purposes in Florida. It’s important to be aware of patient use, so clinicians can watch out for signs of abuse or use of other illegal drugs, he said. Some Moffitt oncologists want to know, because studies have shown that marijuana, used either recreationally or medicinally, can cause immune suppression


Pharmacy Practice News • June 2011

Policy 11

Pain Medicine

Part 1 in series: Do pain therapy databases place patients at risk? Instructions, p. 3

Part 2 in series: Pain contracts: are they worth the hassle? Instructions, p. 3

and increase the risk for infections and even some types of cancer (Eur J Immunol 2010;40:3358-3371). With some diagnoses, it’s particularly important to know if patients are smoking marijuana, Ms. Reilly said. For example, if they have an underlying breathing condition, such as chronic obstructive pulmonary disease or asthma, that needs to be factored into management decisions. “They may be [smoking medical marijuana] for another condition, but it may be exacerbating their asthma,” she said. For some clinical insights, Ms. Reilly suggested a review article in the American Journal of Health-System Pharmacy (2007;64:1037-1044). Along with highlighting marijuana’s immunosuppressive properties, the article cites studies that show that the drug might aggravate underlying psychiatric symptoms or heart disease. The article also listed a litany of potential interactions with other drugs. Combining marijuana with opioids, for example, can “lead to cross-tolerance and mutual potentiation of effects,” the authors wrote. Taken with alcohol, benzodiazepines or muscle relaxants, marijuana can result in excessive depression of the central nervous system (CNS). (For additional risks, as well as some benefits, see sidebar, page 10). At ABQ Health Partners, an Albu­ querque, N.M.-based system of physician-owned clinics, patients initially weren’t prescribed opioids if they were taking medical marijuana because of concerns about CNS effects, said Ernest Dole, PharmD, FASHP, a pharmaceuti-

cal care coordinator there who focuses on pain management. But over time— PRINT

SHARE

RECOMMEND

E-MAIL

COMMENT

prescribe an opioid to someone already using medical marijuana. But it’s a rare circumstance, he stressed. And the doctors at the clinic have decided not to prescribe marijuana to clinic patients. “It’s a risk management issue,” he said. “We can’t with any certainty predict the CNS-cumulative clouding effects.” medical marijuana has been legal in New Mexico since 2007—the clinicians realized that the policy wasn’t necessarily consistent. Even when a patient is taking opioids, it’s difficult despite

one’s best efforts to identify all of the prescriptions they might be getting from another provider, that might amplify an opioid’s effects, Dr. Dole said. So the clinic system will occasionally

—Charlotte Huff Ms. Reilly, Ms. Levy, Mr. Van Hassel, Mr. Lazzaro, Mr. Wand, and Drs. O’Bryant, Dole and Craig reported no relevant conflicts of interest.

For the treatment of iron deficiency anemia in chronic hemodialysis patients undergoing epoetin therapy

Now Available Nulecit

Available in a Vial • Convenient administration of regular low doses of IV iron with 62.5-mg single-dose vials1

AB-Rated by the FDA2 • Nulecit™ is therapeutically equivalent to branded sodium ferric gluconate complex in sucrose injection3

Optimized ESA Usage and Hospital Spending • Sodium ferric gluconate complex in sucrose injection* showed a mean reduction in ESA requirements by up to 60.2%4 • Sodium ferric gluconate complex in sucrose injection* provided significant cost savings when used with ESA therapy5† − $1390 net cost savings per g/dL Hb increase over 12 weeks compared to ESA alone5‡

Stability Data Available6 • Data supports its stability in syringes and saline bags6 − Stability testing with syringes was conducted at room temperature for up to 2 days and at refrigerated conditions for up to 7 days − Stability testing with intravenous infusion bags containing 0.9% sodium chloride solution was conducted at room temperature for up to 1 day and at refrigerated conditions for up to 7 days

More Than 10 Years of Clinical Use7 • Sodium ferric gluconate complex in sucrose injection* is safe7 and effective8

Studies used Ferrlecit®. Nulecit™ is bioequivalent to Ferrlecit®. In anemic patients with high ferritin (500-1200 ng/mL), low TSAT (<25%), and receiving adequate ESA therapy. ‡ Economic model only included drugs and hospitalizations due to serious adverse events. In DRIVE (Dialysis Patients’ Response to IV Iron with Elevated Ferritin), patients were either given no iron (control group) or Ferrlecit® (sodium ferric gluconate in sucrose injection; 125 mg x 8); ESA dosage was raised 25% in each group at randomization with no further dose adjustments. DRIVE-II was a 6-week, observational extension of the DRIVE study designed to evaluate the sustained effects of IV iron administration on epoetin requirements, hemoglobin (Hb), and iron parameters under usual anemia clinical management. Investigators were not restricted in the type of iron product administered. *

What’s Your View? PRINT

SHARE

RECOMMEND

E-MAIL

COMMENT

PRINT

SHARE

RECOMMEND

E-MAIL

COMMENT

For more information, please visit Nulecit.com. Should medical marijuana gain more widespread acceptance? What role should pharmacists play to ensure the safe use of the substance? Do you have any experiences with patients using medical marijuana that you’d like to share?

Important Safety Information • Sodium ferric gluconate complex in sucrose is contraindicated in non iron-deficient anemias, in patients hypersensitive to sodium ferric gluconate complex in sucrose or its inactive components, or with evidence of iron overload • Hypersensitivity reactions have been reported with injectable iron products • Hypotension has been reported with rapid administration of IV iron • In a singledose, placebo-controlled safety study (n=1097), the most frequent adverse events occurring after sodium ferric gluconate complex in sucrose administration were hypotension, nausea, and vomiting and/or diarrhea • In multiple-dose studies (n=126), the most frequent adverse events, whether or not related to sodium ferric gluconate complex in sucrose administration were nausea, vomiting and/or diarrhea, injection site pain, hypotension, cramps, hypertension, dizziness, dyspnea, and chest pain Please see next page for references and brief summary of full Prescribing Information.

Contact the editor at

ppneditor@mcmahonmed.com Ferrlecit® is a registered trademark of A. Nattermann & CIE. GmbH © 2011, Watson Pharma, Inc., Parsippany, NJ 07054. All rights reserved. 06662 4/11


12 Policy

Pharmacy Practice News • June 2011

FDA Watch FDA Expands Zostavax Shingles Indication

weeks, or some people, for months or years after the episode. The likelihood of shingles increases with age. Approval was based on a multicenter study conducted in the United States and four other countries in approximately 22,000 people who were aged 50 to 59. Half of the subjects received Zostavax and half received a placebo. Study participants were then monitored for at least one year to see if they developed shingles. Compared with placebo, Zostavax reduced the risk for developing shingles by approximately 70%.

T

he FDA has approved the use of Zostavax (zoster vaccine live, Merck), a live attenuated virus vaccine, for the prevention of shingles in individuals aged 50 to 59 years. Zostavax is already approved for use in individuals 60 years of age and older. Shingles is characterized by a rash of blisters, which generally develop in a band on one side of the body and can cause severe pain that may last for

References: 1. Nulecit™ full Prescribing Information, Watson Pharma, Inc. 2010. 2. US Department of Health & Human Services, US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations (Database). Silver Spring, MD. http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=078215&Table1=OB_Rx. Accessed April 5, 2011. 3. US Department of Health and Human Services, Food and Drug Administration. Approved Drug Products with Therapeutic Equivalence Evaluations. 31st ed. 2011. 4. García Cortés MJ, Sánchez Perales MC, Borrego Utiel FJ, et al. Estudio de la eficacia del hierro parenteral en pacientes en hemodiálisis tratados con eritropoyetina. Nefrologia. 1997;17:424-429. 5. Pizzi LT, Bunz TJ, Coyne DW, Goldfarb DS, Singh AK. Ferric gluconate treatment provides cost savings in patients with high ferritin and low transferrin saturation. Kidney Int. 2008;74:1588-1595. 6. Data on file, Watson Laboratories, Inc. 7. Michael B, Coyne DW, Fishbane S, et al. Sodium ferric gluconate complex in hemodialysis patients: adverse reactions compared to placebo and iron dextran. Kidney Int. 2002;61:1830-1839. 8. Nissenson AR, Lindsay RM, Swan S, Seligman P, Strobos J. Sodium ferric gluconate complex in sucrose is safe and effective in hemodialysis patients: North American clinical trial. Am J Kid Dis. 1999;33:471-482.

Rx Only

BRIEF SUMMARY See package insert for full Prescribing Information. INDICATIONS AND USAGE Nulecit™ (sodium ferric gluconate complex in sucrose injection) is indicated for treatment of iron deficiency anemia in adult patients and in pediatric patients age 6 years and older undergoing chronic hemodialysis who are receiving supplemental epoetin therapy. CONTRAINDICATIONS All anemias not associated with iron deficiency. Hypersensitivity to Nulecit™ or any of its inactive components. Evidence of iron overload. WARNINGS Hypersensitivity reactions have been reported with injectable iron products. See PRECAUTIONS. PRECAUTIONS General: Iron is not easily eliminated from the body and accumulation can be toxic. Unnecessary therapy with parenteral iron will cause excess storage of iron with consequent possibility of iatrogenic hemosiderosis. Iron overload is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias. Nulecit™ should not be administered to patients with iron overload. See OVERDOSAGE. Hypersensitivity Reactions: One case of a life-threatening hypersensitivity reaction was observed in 1,097 patients who received a single dose of sodium ferric gluconate complex in sucrose injection in a post-marketing safety study. In the post-marketing spontaneous reporting system, life-threatening hypersensitivity reactions have been reported rarely in patients receiving sodium ferric gluconate complex in sucrose injection. See ADVERSE REACTIONS. Hypotension: Hypotension associated with light-headedness, malaise, fatigue, weakness or severe pain in the chest, back, flanks, or groin has been associated with administration of intravenous iron. These hypotensive reactions are not associated with signs of hypersensitivity and have usually resolved within one or two hours. Successful treatment may consist of observation or, if the hypotension causes symptoms, volume expansion. See ADVERSE REACTIONS. Carcinogenesis, mutagenesis, impairment of fertility: Long term carcinogenicity studies in animals were not performed. Studies to assess the effects of sodium ferric gluconate complex in sucrose injection on fertility were not conducted. Sodium ferric gluconate complex in sucrose injection was not mutagenic in the Ames test and the rat micronucleus test. It produced a clastogenic effect in an in vitro chromosomal aberration assay in Chinese hamster ovary cells. Pregnancy Category B: Sodium ferric gluconate complex in sucrose injection was not teratogenic at doses of elemental iron up to 100 mg/kg/day (300 mg/m2/day) in mice and 20 mg/kg/day (120 mg/m2/day) in rats. On a body surface area basis, these doses were 1.3 and 3.24 times the recommended human dose (125 mg/day or 92.5 mg/m2/day) for a person of 50 kg body weight, average height and body surface area of 1.46 m2. There were no adequate and wellcontrolled studies in pregnant women. Nulecit™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: 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 Nulecit™ is administered to a nursing woman. Pediatric Use: Sodium ferric gluconate complex in sucrose injection was shown to be safe and effective in pediatric patients ages 6 to 15 years (refer to CLINICAL STUDIES section). Safety and effectiveness in pediatric patients younger than 6 years of age have not been established. Nulecit™ contains benzyl alcohol and therefore should not be used in neonates. Geriatric Use: Clinical studies of sodium ferric gluconate complex in sucrose injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In particular, 51/159 hemodialysis patients in North American clinical studies were aged 65 years or older. Among these patients, no differences in safety or efficacy as a result of age were identified. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Exposure to sodium ferric gluconate complex in sucrose injection has been documented in over 1,400 patients on hemodialysis. This population included 1,097 sodium ferric gluconate complex in sucrose injection-naïve patients who received a single-dose of sodium ferric gluconate complex in sucrose injection in a placebo-controlled, crossover, post-marketing safety study. Undiluted sodium ferric gluconate complex in sucrose injection was administered over ten minutes (125 mg of elemental iron at 12.5 mg/min). No test dose was used. From a total of 1,498 sodium ferric gluconate complex in sucrose injection-treated patients in medical reports, North American trials, and postmarketing studies, twelve patients (0.8%) experienced serious reactions which precluded further therapy with sodium ferric gluconate complex in sucrose injection. Hypersensitivity Reactions: See PRECAUTIONS. In the single-dose, post-marketing, safety study one patient experienced a life-threatening hypersensitivity reaction (diaphoresis, nausea, vomiting, severe lower back pain, dyspnea, and wheezing for 20 minutes) following sodium ferric gluconate complex in sucrose injection administration. Among 1,097 patients who received sodium ferric gluconate complex in sucrose injection in this study, there were 9 patients (0.8%) who had an adverse reaction that, in the view of the investigator, precluded further sodium ferric gluconate complex in sucrose injection administration (drug intolerance). These included one life-threatening reaction, six allergic reactions (pruritus x 2, facial flushing, chills, dyspnea/chest pain, and rash), and two other reactions (hypotension and nausea). Another 2 patients experienced (0.2%) allergic reactions not deemed to represent drug intolerance (nausea/malaise and nausea/dizziness) following sodium ferric gluconate complex in sucrose injection administration. Seventy-two (7.0%) of the 1,034 patients who had prior iron dextran exposure had a sensitivity to at least one form of iron dextran (INFeD® or Dexferrum®). The patient who experienced a life-threatening adverse event following sodium ferric gluconate complex in sucrose injection administration during the study had a previous severe anaphylactic reaction to dextran in both forms (INFeD® and Dexferrum®). The incidences of both drug intolerance and suspected allergic events following first dose sodium ferric gluconate complex in sucrose injection administration were 2.8% in patients with prior iron dextran sensitivity compared to 0.8% in patients without prior iron dextran sensitivity. In this study, 28% of the patients received concomitant angiotensin converting enzyme inhibitor (ACEi) therapy. The incidences of both drug intolerance or suspected allergic events following first dose sodium ferric gluconate complex in sucrose injection administration were 1.6% in patients with concomitant ACEi use compared to 0.7% in patients without concomitant ACEi use. The patient with a life-threatening event was not on ACEi therapy. One patient had facial flushing immediately on sodium ferric gluconate complex in sucrose injection exposure. No hypotension occurred and the event resolved rapidly and spontaneously without intervention other than drug withdrawal. In multiple dose Studies A and B, no fatal hypersensitivity reactions occurred among the 126 patients who received sodium ferric gluconate complex in sucrose injection. Sodium ferric gluconate complex in sucrose injection-associated hypersensitivity events in Study A resulting in premature study discontinuation occurred in three out of a total 88 (3.4%) sodium ferric gluconate complex in sucrose injection-treated patients. The first patient withdrew after the development of pruritus and chest pain following the test dose of sodium ferric gluconate complex in sucrose injection. The second patient, in the high-dose group, experienced nausea, abdominal and flank pain, fatigue and rash

following the first dose of sodium ferric gluconate complex in sucrose injection. The third patient, in the low-dose group, experienced a “red blotchy rash” following the first dose of sodium ferric gluconate complex in sucrose injection. Of the 38 patients exposed to sodium ferric gluconate complex in sucrose injection in Study B, none reported hypersensitivity reactions. Many chronic renal failure patients experience cramps, pain, nausea, rash, flushing, and pruritus. In the postmarketing spontaneous reporting system, life-threatening hypersensitivity reactions have been reported rarely in patients receiving sodium ferric gluconate complex in sucrose injection. Hypotension: See PRECAUTIONS. In the single dose safety study, post-administration hypotensive events were observed in 22/1,097 patients (2%) following sodium ferric gluconate complex in sucrose injection administration. Hypotension has also been reported following administration of sodium ferric gluconate complex in sucrose injection in European case reports. Of the 226 renal dialysis patients exposed to sodium ferric gluconate complex in sucrose injection and reported in the literature, 3 (1.3%) patients experienced hypotensive events, which were accompanied by flushing in two. All completely reversed after one hour without sequelae. Transient hypotension may occur during dialysis. Administration of Nulecit™ may augment hypotension caused by dialysis. Among the 126 patients who received sodium ferric gluconate complex in sucrose injection in Studies A and B, one patient experienced a transient decreased level of consciousness without hypotension. Another patient discontinued treatment prematurely because of dizziness, lightheadedness, diplopia, malaise, and weakness without hypotension that resulted in a 3 to 4 hour hospitalization for observation following drug administration. The syndrome resolved spontaneously. Adverse Laboratory Changes: No differences in laboratory findings associated with sodium ferric gluconate complex in sucrose injection were reported in North American clinical trials when normalized against a National Institute of Health database on laboratory findings in 1,100 hemodialysis patients. Most Frequent Adverse Reactions: In the single-dose, post-marketing safety study, 11% of patients who received sodium ferric gluconate complex in sucrose injection and 9.4% of patients who received placebo reported adverse reactions. The most frequent adverse reactions following sodium ferric gluconate complex in sucrose injection were: hypotension (2%), nausea, vomiting and/or diarrhea (2%), pain (0.7%), hypertension (0.6%), allergic reaction (0.5%), chest pain (0.5%), pruritus (0.5%), and back pain (0.4%). Similar adverse reactions were seen following placebo administration. However, because of the high baseline incidence of adverse events in the hemodialysis patient population, insufficient number of exposed patients, and limitations inherent to the cross-over, single dose study design, no comparison of event rates between sodium ferric gluconate complex in sucrose injection and placebo treatments can be made. In multiple-dose Studies A and B, the most frequent adverse reactions following sodium ferric gluconate complex in sucrose injection were: Body as a Whole: injection site reaction (33%), chest pain (10%), pain (10%), asthenia (7%), headache (7%), abdominal pain (6%), fatigue (6%), fever (5%), malaise, infection, abscess, back pain, chills, rigors, arm pain, carcinoma, flu-like syndrome, sepsis. Nervous System: cramps (25%), dizziness (13%), paresthesias (6%), agitation, somnolence. Respiratory System: dyspnea (11%), coughing (6%), upper respiratory infections (6%), rhinitis, pneumonia. Cardiovascular System: hypotension (29%), hypertension (13%), syncope (6%), tachycardia (5%), bradycardia, vasodilatation, angina pectoris, myocardial infarction, pulmonary edema. Gastrointestinal System: nausea, vomiting and/or diarrhea (35%), anorexia, rectal disorder, dyspepsia, eructation, flatulence, gastrointestinal disorder, melena. Musculoskeletal System: leg cramps (10%), myalgia, arthralgia. Skin and Appendages: pruritus (6%), rash, increased sweating. Genitourinary System: urinary tract infection. Special Senses: conjunctivitis, abnormal vision, ear disorder. Metabolic and Nutritional Disorders: hyperkalemia (6%), generalized edema (5%), leg edema, peripheral edema, hypoglycemia, edema, hypervolemia, hypokalemia. Hematologic System: abnormal erythrocytes (11%), anemia, leukocytosis, lymphadenopathy. Other Adverse Reactions Observed During Clinical Trials: In the single-dose post-marketing safety study in 1,097 patients receiving sodium ferric gluconate complex in sucrose injection, the following additional events were reported in two or more patients: hypertonia, nervousness, dry mouth, and hemorrhage. Pediatric Patients: In a clinical trial of 66 iron-deficient pediatric hemodialysis patients, 6 to 15 years of age, inclusive, who were receiving a stable erythropoietin dosing regimen, the most common adverse events, whether or not related to study drug, occurring in ≥ 5%, regardless of treatment group, were: hypotension (35%), headache (24%), hypertension (23%), tachycardia (17%), vomiting (11%), fever (9%), nausea (9%), abdominal pain (9%), pharyngitis (9%), diarrhea (8%), infection (8%), rhinitis (6%), and thrombosis (6%). More patients in the higher dose group (3.0 mg/ kg) than in the lower dose group (1.5 mg/kg) experienced the following adverse events: hypotension (41% vs. 28%), tachycardia (21% vs. 13%), fever (15% vs. 3%), headache (29% vs. 19%), abdominal pain (15% vs. 3%), nausea (12% vs. 6%), vomiting (12% vs. 9%), pharyngitis (12% vs. 6%), and rhinitis (9% vs. 3%). Postmarketing Surveillance: The following additional adverse reactions have been identified with the use of sodium ferric gluconate complex in sucrose injection from postmarketing spontaneous reports: dysgeusia, hypoesthesia, loss of consciousness, convulsion, skin discoloration, pallor, phlebitis, and shock. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. OVERDOSAGE Dosages in excess of iron needs may lead to accumulation of iron in iron storage sites and hemosiderosis. Periodic monitoring of laboratory parameters of iron storage may assist in recognition of iron accumulation. Nulecit™ should not be administered in patients with iron overload. Serum iron levels greater than 300 mcg/dL may indicate iron poisoning which is characterized by abdominal pain, diarrhea, or vomiting which progresses to pallor or cyanosis, lassitude, drowsiness, hyperventilation due to acidosis, and cardiovascular collapse. Caution should be exercised in interpreting serum iron levels in the 24 hours following the administration of Nulecit™ since many laboratory assays will falsely overestimate serum or transferrin bound iron by measuring iron still bound to the Nulecit™ complex. Additionally, in the assessment of iron overload, caution should be exercised in interpreting serum ferritin levels in the week following Nulecit™ administration since, in clinical studies, serum ferritin exhibited a non-specific rise which persisted for five days. The Nulecit™ iron complex in sucrose injection is not dialyzable. Sodium ferric gluconate complex in sucrose injection at elemental iron doses of 125 mg/kg, 78.8 mg/kg, 62.5 mg/kg and 250 mg/kg caused deaths to mice, rats, rabbits, and dogs respectively. The major symptoms of acute toxicity were decreased activity, staggering, ataxia, increases in the respiratory rate, tremor, and convulsions. Individual doses exceeding 125 mg may be associated with a higher incidence and/or severity of adverse events based on information from postmarketing spontaneous reports. These adverse events included hypotension, nausea, vomiting, abdominal pain, diarrhea, dizziness, dyspnea, urticaria, chest pain, paresthesta, and peripheral swelling. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Distributed by: Watson Pharma Inc. Corona, CA 92880 USA Manufactured by: Hikma Farmaceutica (Portugal), LDA Estrada Do Rio Da Mo, 8,8 AE 8B-Fervenca 2705-906 Terrugem SNT, Portugal January 2010 192147-1 PIN220-WAT/2

The most common side effects observed in the study were redness, pain and swelling at the site of injection, and headache. Zostavax was originally approved in 2006 for the prevention of shingles in individuals aged 60 years and older.

Actemra Approved To Treat Rare Form Of Juvenile Arthritis

T

he FDA has approved Actemra (Roche; tocilizumab), given alone or in combination with methotrexate, for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in children aged 2 years and older.

SJIA, or Still’s disease, is a rare, potentially life-threatening disorder in children that causes severe inflammation throughout the body. SJIA is distinguished from other forms of juvenile idiopathic arthritis (JIA) by the prominence of systemic and inflammatory features, including spiking fevers; rash; swelling and inflammation of lymph nodes, liver and spleen; and high white blood cell and platelet counts. The prevalence of JIA is an estimated one to two per 1,000 children; SJIA affects about 10% of all JIA patients. Actemra is an interleukin-6 receptor blocker approved by the FDA on Jan. 8, 2010, for treatment of moderately to severely active rheumatoid arthritis in adults who have had an inadequate response to other approved therapies. An international, multicenter controlled trial demonstrated the safety and effectiveness of Actemra, in which 112 patients received either Actemra infusions or placebo infusions every two weeks. Study participants included


Pharmacy Practice News • June 2011

Policy 13

FDA Watch patients aged 2 to 17 years with SJIA, who had inadequate response to or who were unable to take nonsteroidal antiinflammatory drugs and corticosteroids. Of those receiving Actemra, 85% responded to treatment, compared with 24% of patients receiving placebo. Response was defined as at least 30% improvement in the American College of Rheumatology’s JIA efficacy variables, along with absence of fever in the preceding seven days. In the long-term, follow-up period of this trial, there were three cases of macrophage activation syndrome (MAS) among SJIA patients receiving Actemra. MAS is a potentially fatal complication of childhood systemic inflammatory disorders, thought to be caused by excessive activation and proliferation of certain immune cells. Actemra carries a boxed warning for serious infections. Patients treated with Actemra who develop a serious infection should stop Actemra treatment until the infection is controlled. Changes in certain laboratory test results such as liver function tests, blood counts and cholesterol are not uncommon with Actemra and should be monitored with regular blood tests. The most common side effects in trial participants with SJIA included upper respiratory tract infection, headache, sore throat and diarrhea.

recalls, including an April 30, 2010 recall of lots of several liquid products such

as children’s Tylenol (acetaminophen), Motrin (ibuprofen), Zyrtec (ceterizine) and Benadryl (diphenhydramine) products. In January 2010, the FDA issued a Warning Letter to McNeil’s Consumer Healthcare Division regarding violations identified at McNeil’s Las Piedras facility.  The decree, filed by the U.S. Department of Justice’s Office of Consumer Litigation and the U.S. Attorney’s Office for the Eastern District of Pennsylvania, requires McNeil to destroy all drugs under its control that have been recalled from the Fort Washington, Las Piedras and Lancaster

facilities since December 2009. McNeil also must retain an independent expert to inspect the three facilities to determine whether the violations have been corrected, and to ensure that adequate manufacturing processes are in place. After expert certification, the FDA will determine if the facilities are in compliance. If the defendants violate the decree, the FDA may order McNeil to cease manufacturing, recall products and take other corrective action, including levying fines of $15,000 for each day and

DANGEROUS

PHARMACEUTICAL WASTE. Is your facility at risk?

McNeil-PPC Still Suffering Manufacturing Ills

T

he FDA has filed a consent decree of permanent injunction against McNeil-PPC and two of its officers for failing to comply with current good manufacturing practice requirements as mandated by federal law. The action prevents McNeil, a subsidiary of Johnson & Johnson, from manufacturing and distributing drugs from its Fort Washington, Pa., facility until the FDA determines that its operations are compliant with the law. The decree also requires McNeil to adhere to a strict timetable to bring its facilities in Las Piedras, Puerto Rico and Lancaster, Pa., into compliance. FDA inspections at McNeil’s Fort Washington, Las Piedras and Lancaster facilities from 2009 to 2010 found violations of the Federal Food, Drug, and Cosmetic Act. The act requires drug companies to follow current good manufacturing practice requirements. “This is a strong, but necessary, step to ensure that the products manufactured by this company meet federal standards for quality, safety and purity,” said Deborah Autor, director of the Office of Compliance in the FDA’s Center for Drug Evaluation and Research. Manufacturing deficiencies at McNeil’s facilities have resulted in several extensive

Hospital pharmacies throughout the United States purchase well over 4 billion hazardous materials each year, generating more than 84,000 tons of hazardous pharmaceutical waste.1 The EPA has stepped up enforcements to ensure that pharmaceutical waste is managed safely from the moment it is generated and finally disposed.2 Pharmacists are responsible for the “cradle to grave” management of pharmaceuticals. CareFusion now offers Pyxis EcoStation™ system, a proprietary, automated waste management system that helps hospitals identify, classify, sort and segregate pharmaceutical waste, while providing pharmaceutical waste records to facilitate tracking and regulatory controls of more than 180,000 National Drug Codes.

Learn how CareFusion can help your hospital measurably improve pharmaceutical waste management by visiting carefusion.com/rxwastemanagement.

Pyxis

®

1 Fein, Adam J. Pembroke Consulting, Inc. 2010-11 Economic Report on Retail and Specialty Pharmacies, December 2010. 2 Accessed from http://www.epa.gov/oecaerth/civil/rcra/rcraenfstatreq.html. © 2011 CareFusion Corporation or one of its subsidiaries. All rights reserved. EcoStation and Pyxis are trademarks or registered trademarks of CareFusion Corporation or one of its subsidiaries. DI2819 (0511)

see McNeil-PPC, page 14


14 Policy

Pharmacy Practice News • June 2011

FDA Watch

McNeil-PPC continued from page 13

an additional $15,000 for each violation of the law, up to $10 million annually.

Agency Approves Ibuprofen-Famotidine Combination

T

he FDA has approved Duexis (ibuprofen-famotidine, Horizon Pharma), a novel tablet formulation contain-

ing a fixed-dose combination of the nonsteroidal anti-inflammatory drug ibuprofen (800 mg) and the histamine-2 receptor antagonist famotidine (26.6 mg), for the treatment of osteoarthritis and rheumatoid arthritis. The approval was supported by data from the pivotal REDUCE-1 and REDUCE-2 studies, which showed that patients tak-

ing Duexis experienced significantly fewer upper gastrointestinal (GI) ulcers compared with patients receiving ibuprofen alone. Duexis was studied in more than 1,500 patients with mild to moderate pain or arthritis. The primary end point of the REDUCE-1 study was the reduction in incidence of gastric ulcers during the

New User-Friendly Web-Based Search Engine Launched

American Health Packaging is a leading supplier of bar coded unit dose products for health systems and long-term care.

A

Over 300 UD Items Our line has grown wn substantially in the past two years. ears. We now have over 300 items ms across all ps. therapeutic groups.

Many Industry Exclusives And many of our UD items are es — only industry exclusives e in the available in the marketplace from American Health ealth Packaging! Packaging g! Our products are bar coded to the dose level and are stability tested to ensure extended shelf life.

Plus, Added Safety Features In addition, color-coded labels with “tall man” lettering provide an extra safety feature to ensure the correct item is selected to be dispensed. 800.707.4621 americanhealthpackaging.com

Recent product launches include: ABC Item #

Cardinal Health Item #

McKesson Item #

Morris Dickson Item #

NDC

097446

4399804

2117000

540559

68084-0477-01

Donepezil HCl Tablet

5 mg

100UD

AB

097459

4399820

2118495

540567

68084-0478-01

Donepezil HCl Tablet

10 mg

100UD

AB

098931

4416400

2142743

542019

68084-0423-01

Hydromorphone HCl Tablet CII

2 mg

100UD

AB

098956

4416343

2103737

542027

68084-0472-01

Hydromorphone HCl Tablet CII

4 mg

100UD

AB

098968

4416616

2106656

546358

68084-0467-01

Lansoprazole DR Capsule

15 mg

100UD

AB

098988

4416632

2105195

546366

68084-0468-01

Lansoprazole DR Capsule

30 mg

100UD

AB

Product Description

six-month treatment period. The primary end point of the REDUCE-2 study was the reduction in incidence of upper GI (defined as gastric and/or duodenal) ulcers during the six-month treatment period. In REDUCE-1, Duexis demonstrated a statistically significant reduction in the incidence of gastric ulcers versus treatment with ibuprofen alone (8.7% vs. 17.6%). In REDUCE-2, Duexis demonstrated a statistically significant reduction in the incidence of upper GI ulcers versus treatment with ibuprofen alone (10.5% vs. 20%). The most common adverse reactions were nausea, diarrhea, constipation, upper abdominal pain and headache.

Strength

Size

Orange Book Rating

SMART PHONE LINK

s of April 4, the FDA has made searching for recalls of food, drugs and other products easier and faster. The Food Safety Modernization Act (FSMA), which was signed into Scan to access new law earlier this year recall Web page. Instructions, p. 3 by President Barack Obama, called for the FDA to provide a more consumer-friendly recall search engine within 90 days after the law went into effect. The act also requires the FDA to indicate whether a recall is ongoing or has been completed. The FDA’s new search engine meets those requirements. The new web page displays data from news releases and other recall announcements as a table, which can be organized by several parameters, including product brand name, product description, reason for the recall and the firm involved. The table also provides a link to the news release on each recall. The new display is markedly different from the previous one, which provided links in a scroll-down format. To most effectively and easily communicate recall information to the public, the FDA consulted with stakeholder groups, including the Center for Science in the Public Interest, Consumers Union, Food Marketing Institute, Grocery Manufacturers Association, the Pew Health Group and Safe Tables Our Priority. Prior to passage of the FSMA, the FDA did not have mandatory recall authority for food products except infant formula. The new status information will be provided for recalls that the FDA either ordered as mandatory or requested as voluntary under the FDA’s FSMA authority. For more information, scan the bar code on this page. —Staff


Pharmacy Practice News • June 2011

Policy 15

Quality Improvement

ACO CONCEPT continued from page 5

savings generated by reducing adverse events, hospitalizations and emergency department visits would be shared by the ACO. To calculate the savings, CMS would compare actual and expected costs for patients assigned to the ACO. At least 50% of the savings paid back to ACOs would require the achievement of quality measures. Controlling costs will depend heavily on ACOs’ ability to manage more with less. “The way we’re really going to make accountable care succeed is by paying particularly close attention to efficiencies,” said Gloria P. Sachdev, PharmD, clinical assistant professor at Purdue University College of Pharmacy, in West Lafayette, Ind. “Embracing health information technology is essential.” Dr. Sachdev said the health IT effort would require hospitals, primary care physician groups and community pharmacies to adopt functionality that permits “bidirectional communication. Pharmacy could communicate electronically with a physicians’ office and the physicians could communicate back, versus all these other things we do that drown efficiencies.” Improving efficiencies also will be important for pharmacists taking part in outpatient collaborative chronic care management programs, which Dr. Sachdev believes will be an important contributor to ACOs’ ability to keep patients healthy and out of the hospital.

such as drug carousels to try to maximize our efficiency from a distribution standpoint that hopefully will free up pharmacists for these medication reconciliation functions.” Mr. Anderson said Steward also has plans to place pharmacists in some of the physician practices to work with patients “and help them get to goal with their medication

therapy. We think we can prevent some hospital admissions if we take better care of them as outpatients.”

A Slow but Steady Buildup Tim Brown, PharmD, director of clinical pharmacotherapy in family medicine at Akron General Medical Center, in Ohio, is stepping down as chair of ASHP’s Section of Ambulatory Care Practitioners, where he said discussions on ACOs have been taking place “probably for the last 18 months.” He said he hopes that ACOs will “put

an emphasis on the role pharmacists are playing on teams as the ones who do a lot of the counseling and medication therapy management, and even as we suggest, helping to select the drug at the point of care.” Dr. Brown, who will lead the ACO networking session at the ASHP summer meeting, said he is also hopeful that ACOs will fulfill their goal of improving quality and decreasing costs. “I don’t think the health care system can continue the way it is.” —Bruce Buckley

The first generic Aztreonam for Injection, USP Available from APP ®

Vials are back! No thawing required!

Solving the Efficiency Challenge On a recent consulting trip to Hawaii, Dr. Sachdev said that she spent time with a couple of pharmacy residents who had started a medication therapy management program in a community pharmacy setting. They told her they spent an hour with each patient, but because of all the demands, including communications with physicians and documenting interventions, the time per patient visit actually amounted to three and a half to four hours. “There is no sustainable business model around that type of inefficiency,” she said. Steward Health Care is looking to solve part of the efficiency challenge through economies of scale, Mr. Anderson said. One suggestion under consideration would involve shifting to a single systemwide formulary in place of eight separate ones, meaning one pharmacist doing “the [Pharmacy & Therapeutics] legwork” for the entire system and freeing up others for possible medication reconciliation or follow-up patient visits. Additional pharmacy automation also is being considered, Mr. Anderson said. “We’re looking at other technologies

See full prescribing information at www.APPpharma.com ®

APP and are trademarks of APP Pharmaceuticals, LLC. ©2011, APP Pharmaceuticals, LLC. All Rights Reserved. 0217-AZT-05-5/11

Medical Affairs 800.551.7176 Customer Service 888.386.1300


Pharmacy Practice News • June 2011

Policy 17

Drug Costs

continued from page 1

incremental improvement—measured in months, not years.” A case in point: At $120,000 for a single three-month course of treatment, Bristol-Myers Squibb’s Yervoy (ipilimumab) can reportedly extend the life of the average patient with late-stage melanoma by three to four months. Despite evidence that it also poses a high risk for severe side effects, the FDA approved the drug in March. Yervoy is not even the highest-priced cancer therapy on the market—other advanced oncology agents approach $200,000 for a treatment course. Many experts question whether such an imbalance in costs and benefits in cancer care is sustainable, and point to possible approaches to mitigate further threats to the budgets of individual patients and the country.

Projecting 2020 Prices Due in part to the great variability in patterns of care between cancer sites and in the course of each patient’s battle with the disease, predicting where the already steep prices will go in the future is complicated, said Robin Yabroff, PhD, MBA, an epidemiologist at the NCI in Bethesda, Md. In their new report, Dr. Yabroff and her colleagues estimated costs for common cancers across phases of care using linked data from the Surveillance, Epidemiology and End Results (SEER) Program and Medicare claims through 2006. They estimate that the number of cancer survivors will grow from 14 million to 18 million over the next decade. Although most cancers including lung, ovarian and cervical, have been on the decline, others such as kidney and melanoma continue to rise. With a closer look at the data, cancer care costs appeared to be highest in the year right after diagnosis and right before death. But the rates differed by site. The current annualized net costs of lung cancer in the initial phase of care, for example, average far higher than breast cancer: $60,500 versus $23,000. At the same time, breast cancer patients tend to live longer—and there are more of them. The biggest future increases in medical costs are anticipated to fall within the continuing phase of care for breast (32%) and prostate (42%) cancers. Although it is good news that patients are now surviving longer, this also means they are receiving medical care longer. Still, the impact of maintenance therapy “may not be as much as people think,” said Dr. Howard, suggesting that it just “delays the higher end-of-life costs.” Overall, assuming that incidence, survival and cost remain consistent, the team projects that population growth

‘A patient may be prescribed an oral agent that is known to help their disease state, such as nilotinib for CML [chronic myeloid leukemia], but then get turned away because they can’t actually pay.’

—Ali McBride, PharmD

$207

210

Dollars (Billions)

NCI REPORT

180

$158

150 $125 120 90 60 30

alone will raise annual postdiagnosis cancer care costs from $125 billion to $158 billion 2010 U.S. dollars by 2020. And if annual costs increase by an average of 2% or 5% in the initial and final stages of care, the 2020 total may be even higher—$173 billion and $207 billion, respectively.

0

2020a

2020b

Figure. Cost of cancer care in the United States: 2010-2020. a

Constant incidence, survival, cost.

b

 % annual increases in cost of care in initial 5 and last year of life.

Source: J Natl Cancer Inst 2011;103:117-128

Better Cost-Containment Needed Ali McBride, PharmD, clinical pharmacy specialist at Barnes-Jewish Hospital in St. Louis, Mo., suggested that the NCI projections are likely low, unless efforts are made to reverse recent trends and better contain costs. The annual rise of more than 8% for brand-name cancer drug prices is driven by many factors, Dr. McBride noted, including the “exorbitant” costs of bringing a new drug to market. According to one estimate— challenged by several policy experts— it can take upward of $800 million to reach Phase III trials and go through the drug approval process (J Health Econ 2003;22:151-185). A lot of pharmaceutical companies may feel further stress over new legislation proposed by the Obama administration that would make it easier for generic companies to enter the market. If passed, the period of exclusivity for biologics would shorten from 12 to seven years. “You’d almost have to double the price to recoup the initial research and development costs earlier,” Dr. McBride said. “As a result, companies may be leery of investing in future therapies.” Of course, when generics do come to market, prices dramatically drop. Most first-line cancer therapeutics are now available in generic versions. But overall, Dr. McBride sees costs increasing. Another contributor to escalating costs could be the fact that patients do not typically pay full price for the drugs out of their own pockets; insurance companies dole out the funds. And they have shown willingness to pay as long as the treatment is FDA-approved, noted Peter B. Bach, MD, a physician and health care policy expert at Memorial Sloan-Kettering Cancer Center in New York City. “So, it’s a question of how bold the manufacturers get in terms of prices they are willing to charge and how much headline risk they’re willing to take,” Dr. Bach said.

2010

“They seem to continue to get more and more bold,” he added. “And there are no checks to slow them down. Why not charge $200,000 for the drug?” Greater availability of information also may play a role. “If patients find a drug on the Internet, they want to know about it and how they can get it,” said Niesha Griffith, MS, RPh, director of pharmacy and infusion services at The Arthur G. James Cancer Hospital at The Ohio State University (OSU), in Columbus. Ms. Griffith recalled one pancreatic cancer patient at OSU who found a case report online—research that had not yet been peer-reviewed. The patient pushed to receive the medication, she said, taking the request directly to the insurance company and the hospital’s medical leadership.

Costly Consequences Although patients may not necessarily be concerned about cost when scouring the Web for leads, money often does pose a significant obstacle for them. Out-of-pocket expenses are particularly staggering for oral chemotherapy, which accounts for about half of the new agents in the pipeline. And it is not only the uninsured that face sticker shock. When a drug does not have an IV equivalent, its coverage falls under Medicare Part D for qualified patients over the age of 65. This means that many are paying full price while in the notorious “donut hole” between payment thresholds. (The gap will be eliminated by 2020 under the new Patient Protection and Affordable Care Act.) For patients with private insurance, copays for high-priced drugs often run between 20% and 40%—a hefty sum for courses that run tens of thousands of dollars. “A patient may be prescribed an oral agent that is known to help their disease state, such as nilotinib for CML [chronic myeloid leukemia] but then get turned

‘[Pharmaceutical companies] seem to continue to get more and more bold. And there are no checks to slow them down. Why not charge $200,000 for the drug?” —Peter B. Bach, MD away because they can’t actually pay,” said Dr. McBride. For infusion therapies, which are covered under Medicare Part B, patients pay 20% of a drug’s price regardless of how high costs go. Many patients have supplemental insurance to bridge the difference. For off-label use, Part B may provide some coverage, but Part D does not. About half of all cancer drugs and biologics in the United States are prescribed off-label, according to the National Comprehensive Cancer Network. Experts do not expect Medicare and other payers to be able to keep up with price increases. “My best guess is that insurers will eventually have to put their foot down and say no,” said Dr. Howard. “The Medicare program is in such dire financial straits that they will not be able to continue to cover new [medications] without regard to the cost.”

Strategies for Affordable Care Medicare and some other payers are already becoming more restrictive regarding what they will and will not pay for by defining coverage rules. Ms. Griffith said that new coverage determinations target several of the priciest oncology agents, require many to be precertified and require specific indications for coverage, sometimes more restrictive than the FDA-approved indications.

see NCI REPORT, page 18


18 Policy

Drug Costs

Pharmacy Practice News • June 2011

Easing the financial hit via pharmaceutical assistance programs. See article, page 24

NCI REPORT continued from page 17

“The way that we use these very expensive drugs is being much more heavily scrutinized than it was 10 years ago,” she said. “That isn’t necessarily a bad thing. I think it is one of the ways that we will control costs moving forward.” Ms. Griffith also emphasized the need to use the drugs appropriately. At her medical center, if the indication is not part of the drug’s FDA labeling, then one of the following conditions has to be met: a listing in a Centers for Medicare & Medicaid Services-approved compendia, two or more Phase II trials, or one Phase III trial showing efficacy in the specific cancer type. She and her colleagues know that many effective indications may never even make it onto a label because it can be an expensive venture for a drug company to add to its FDA indications. Still, not every insurance company will agree, forcing hospitals to implement safeguards to avoid rejections that affect their bottom line. Appropriate use also means matching the right drug to the right patient. Using genomic-based prognostic markers to decipher what targeted therapy may be most effective for a particular person could effectively increase a medication’s “average” survival gain, potentially helping to balance out its costs and benefits. Payers are already requiring test results before providing coverage for certain drugs, such as a HER2 status for patients prescribed Herceptin. It is not just efficacy that can be personalized via biomarkers. Some patients may lack certain enzymes required to break down a drug, triggering a toxic reaction, Ms. Griffith explained. “It is a little bit easier of a pill to swallow if you know that you’re giving a more targeted drug that is going to be the most effective and safe agent for that specific patient,” she said. As for patients’ wallets, some of those who are uninsured or underinsured can qualify for help through patient-assistance programs (see page 24) and copay assistance foundations, which include funds and medications donated by pharmaceutical companies. And to lessen the discrepancy in price tags for oral and IV drugs, parity laws are popping up in some states and could soon become a national standard. Dr. Bach offered another idea to help enhance the cost-effectiveness of cancer drugs. He and his colleagues recently laid out a framework of episode-based Medicare payments, which could provide incentive for doctors to choose therapies based partially on their costs (Health Aff 2011;30:500-509). One payment would cover the costs of drugs and their administration for a predefined

‘It is a little bit easier of a pill to swallow if you know that you’re giving a more targeted drug that is going to be the most effective and safe agent for that specific patient.’ —Niesha Griffith, MS, RPh period of treatment. This alternative approach would not only rein in costs, they suggest, it might improve patient outcomes as well. New guidelines from the American Society of Clinical Oncology also aim

to help clinicians talk with patients about costs and incorporate those costs into treatment decisions. (Scan 2-D bar code on this page to access.) Although a seemingly awkward proposition, it could prove a welcome addi-

tion to the physician’s role. Many oncologists are “unnerved by pricing,” said Dr. Howard. “Some may be reluctant to prescribe a drug that’s very costly, even Scan for ASCO tips if insurers pay.” on discussing drug —Lynne Peeples costs with patients. Ms. Griffith, as well as Drs. McBride, Howard and Yabroff, report no relevant conflicts of interest. Dr. Bach discloses that he has received speaking fees from Genentech/Roche.

Step up to a range of insulin delivery options.

As part of Eli Lilly and Company’s ongoing commitment, we provide healthcare facilities with a choice of vial sizes. Humalog® (insulin lispro injection [rDNA origin]), Humulin® R U-100 (regular insulin human injection, USP [rDNA origin]), and Humulin® N (NPH human insulin [rDNA origin] isophane suspension) are available in a smaller vial size.* The smaller vials are designed to give healthcare facilities flexibility when evaluating insulin storage and distribution (floor stock vs individual patient supply), in addition to the 10 mL vial and Humalog® KwikPen™. • Humalog Smaller Vial* NDC Number - 0002-7510-17 • Humulin R U-100 Smaller Vial* NDC Number - 0002-8215-17 • Humulin N Smaller Vial* NDC Number - 0002-8315-17 * Smaller vials contain 3 mL of insulin in a 5 mL vial.

Humalog Indication Humalog (insulin lispro injection [rDNA origin]) is for use in patients with diabetes mellitus for the control of hyperglycemia. Humalog should be used with longeracting insulin, except when used in combination with sulfonylureas in patients with type 2 diabetes.

HI69632

0211 PRINTED IN USA

©2011, LILLY USA, LLC. ALL RIGHTS RESERVED.

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


Pharmacy Practice News • June 2011

New Product 19

Advertisement FIRST® “Magic Mouthwash” Kits Make Compounding Fast, Accurate And Profitable

T

hese innovative kits from Cutis Pharma contain everything needed to compound “magic mouthwash” scripts quickly and easily. All ingredients

are pre-weighed/pre-measured, saving prep, compounding and cleanup time. Every dispensing container is bar coded and one NDC number for all components facilitates reimbursement. Kits are available for BLM, BXN, Duke’s and Mary’s formulations. More at www.cutispharma.com or contact Jim Nagle, V.P. Business Development at (800) 461-7449.

American Health Packaging Launches New Unit-Dose Products

A

merican Health Packaging recently added three additional products to its growing unit-dose line: Donepezil 5 and 10 mg tablets (compares to

Aricept®); Hydromorphone HCl Cll 2 and 4 mg tablets (AB-rated to Dilaudid®); and lansoprazole DR 15 and 30 mg capsules (AA-rated to Prevacid®). All of these items are part of the company’s rapidly expanding family of cardiovascular and circulatory unit-dose products. The company’s line now stands at well

Humalog Important Safety Information, continued

Humalog Important Safety Information, continued

Warnings, continued Starting or changing insulin therapy should be done cautiously and only under medical supervision.

Other Side Effects, continued 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 potassiumlowering drugs, or taking drugs sensitive to serum potassium level).

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. Because of the difference

Please see adjacent pages for Brief Summary of full Prescribing Information for Humalog. 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.

over 300 SKUs—over 90 of them are industry exclusives. These unit-dose launches are part of an ongoing commitment to support health systems’ vital patient safety and bar-coding initiatives. All American Health Packaging unit-dose items are bar coded to the dose level and are stabilitytested to support extended shelf life. In addition, packages feature color-coded labels with “tall man” lettering to more easily distinguish products when selecting them for dispensing. For additional information, please visit americanhealthpackaging.com.


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 Humalogtreatment 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 wellcontrolled 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 longeracting 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) 5 x 3 mL cartridges3 NDC 0002-7516-59 (VL-7516) 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

MiniMed® and Polyfin® are registered trademarks of MiniMed, Inc. Disetronic®, H-TRONplus®, D-TRON®, and Rapid® are registered trademarks of Roche Diagnostics GMBH. 3 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. 2

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]) 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 3 mL 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.


22 Technology

Pharmacy Practice News • June 2011

UnSummit

Implementing BCMA Good for Patients and Good for Business Louisville, Ky.—Central pharmacy automation is instrumental for establishing a bar-code infrastructure, and results in improved medical practice and good business, according to findings presented at the 2011 unSummit for Bedside Barcoding. “A well-planned deployment of pharmacy automation and dispensing technology improves patient safety, operational efficiency and frees pharmacists to participate more fully in interdisciplinary, patient-centric care models and achieve medication-related quality measures,” said Wayne Nye, RPh, pharmacist and pharmacy information systems coordinator at Martha Jefferson Hospital, Charlottesville, Va. Mr. Nye detailed how achieving barcode readiness benefited his 176-bed community hospital, and how central pharmacy automation was instrumental in getting the most out of the bar-code infrastructure. In 2001, as part of the organization’s strategic plan to deliver the best care possible, Martha Jefferson Hospital established a bar-code medication-use infrastructure with a pharmacy automation system. In the following years, the pharmacy continued to refine its technology, processes and procedures, maximizing the value of medication bar coding. This resulted in significant improvements in patient safety and efficiency.

Bolstering Existing Systems Mr. Nye said the bar code readiness project was preceded by earlier technology rollouts. “We first decided to buy a pharmacy robot and were using it just for cart fill with our old pharmacy system,” he said. “In 2002 and 2003, we converted to an integrated clinical software platform with Cerner Millennium, including PharmNet, PowerChart, PathNet and other hospital applications. We then got our robot and the Cerner systems to work together through an interface.” The hospital decided to go with one automation vendor—in this case McKesson. “That was mostly because they were doing it all—robotic dispensing, automated shelving and packaging, narcotic inventory management, nursing unit-based dispensing cabinets—and we only had to work with one database rather than two or three from multiple vendors,” he explained. Soon after, the hospital began to deploy unit-based dispensing cabinets throughout its patient care areas. The facility began using smart pumps in 2008 and medical order imaging in 2009. Moreover, “we had the ability to enter orders either centrally in

the pharmacy or decentrally on nursing units if we needed to. We decided to decentralize.” Four pharmacists at Martha Jefferson work on the nursing units in integrated care teams. The hospital tracked several outcomes in an effort to gauge the impact of the technology initiatives. Between 2009 and 2010, the hospital saw a 19% increase in medication order imaging, a 23.4% increase in order-entry volume, a 10% increase in unit-dose packaging using bar codes, and the percentage of bar-code scanning for medication dispensing went from 91% to 93%. “We also cut down our order turn-

around time,” Mr. Nye said. Although pre- and post-implementation data on that particular outcome were not collected, ‘I don’t need a weatherman to tell me when it’s raining,’ he quipped. “Order images are now scanned and transmitted instantaneously to the pharmacist, as opposed to having to physically travel to the pharmacy and often through the pharmacy.” Based on that change in workflow, “a reduction in turnaround time [was] to be expected, and did in fact occur,” Mr. Nye said. Deciding on which medication safety technology to pursue first was an interesting challenge, Mr. Nye said. “As with

most organizations, we had to choose between bar code–assisted medication administration [BCMA] or computerassisted physician order entry systems. We chose to implement BCMA primarily because we had a well-established bar-code foundation and we were prepared to fully leverage its advantages. Moreover, in the short run, we believed the BCMA safety net offered the greatest immediate benefit to patient safety.” (The hospital plans to go live with computerized prescriber order entry in 2012, Mr. Nye said.) From early on, the initiative saved money: For fiscal year (FY) 2001 and 2002, one year following robotics implementation, drug expense was under budget by $262,012; drug cost per dose was down 9% and doses per patient-day were up 8%, according to Mr. Nye. In addition, adverse drug reactions were trending down. In FY 2000, there were 753 adverse drug reactions; in FY 2001, there were 636, and in FY 2002, there were 573 documented adverse drug reactions. More recently, pharmacy clinical interventions have increased as much as threefold, he added. In September 2009, pharmacists spent 51.8 hours on 340 interventions. In 2010, they were spending 152 hours on 673 interventions. Mr. Nye said the most important thing he learned from this experience is that strong relationships and open communications with both technology vendors and professional colleagues will help ease the transition challenges.

Implementation ‘Pearls’ For hospitals just starting to implement bar coding and safe medication administration, Mr. Nye offered the fol-

‘In the short run, we believed the BCMA safety net offered the greatest immediate benefit to patient safety.’ —Wayne Nye, RPh

lowing “practice pearls”: • Gain support and consensus from invested C-suite executives for goals, timelines and funding for bar-code technology implementation. Scan for more BCMA lessons learned. • In planning your Instructions, p. 3 implementation, understand your organization’s current state of medication processes— what these processes actually are, and not what these processes are supposed to be. • Invest significant resources in both training and post-implementation surveillance, reporting, and follow-up so that your organization’s safety and productivity benefits from bar-code technology are both measurable and sustained.

Patient-centric Care is Key “If there is a message to take home about bar coding and technology, it’s this,” Mr. Nye said. “Pharmacists have to help our hospitals defend revenue and ensure positive patient outcomes. This means having pharmacists deployed on patient-centric care units and models. Get pharmacists out of the pharmacy by having automated technology and bar-code technology, and do this at every point you can. You do it when the medication product is first received, when you stock that product on your shelves, when you dispense that medication from the pharmacy and when that medication is administered to the patient. Make everything as safe as possible with your medication process by using bar-coding technology, and that safety will allow you to redeploy your pharmacists where they need to be to fulfill their professional mission.” Commenting on this presentation for Pharmacy Practice News, Jerry Fahrni, PharmD, formerly an IT pharmacist at Kaweah Delta Medical Center in Visalia, Calif., and currently product manager for Talyst in Bellevue, Wash., said, “Most facilities fail to look at the big picture when it comes to technology. Martha Jefferson Hospital, in contrast, took advantage of the technology to improve their pharmacy presence outside the physical pharmacy and, as a result, had a positive impact on patient care. And that’s the ultimate goal— improving patient care.” —Fran Lowry

Robotic dispensing was a crucial component of Martha Jefferson Hospital’s process of establishing a bar-code medication-use infrastructure.

Mr. Nye disclosed that he currently serves on a customer advisory board with McKesson Automation Solutions. Dr. Fahrni disclosed that he is an employee of Talyst.


IV Clinical Integration enhances efficiency and patient safety through simplified delivery and documentation. The days of writing IV information on scrub legs, bed sheets or the back of your hand are over. IV Clinical Integration captures pump settings from the physicianâ&#x20AC;&#x2122;s order and provides real-time documentation by linking the IV pump, patient, order and record. As the most experienced provider of IV Clinical Integration, Hospira is committed to giving you and your staff the knowledge, expertise and support to help you set new standards in IV drug delivery workďŹ&#x201A;ow.

To see IV Clinical Integration in a live setting, scan this code with your mobile device or go to http://hospiramobile.com/ivclinicalintegration. For more information, call 1-800-237-5512.

Hospira, Inc., 275 North Field Drive, Lake Forest, IL 60045

P11-3131E-May, 11


24 Operations & Management

Pharmacy Practice News • June 2011

Drug Costs

Pharmaceutical Assistance Programs Joan Stachnick, PharmD

100

Clinical Assistant Professor Drug Information Group University of Illinois at Chicago College of Pharmacy Chicago, Illinois

Branded Prescriptions for Less Pharmaceutical ­assistance programs (PAPs) provide branded prescription drugs at a lower cost to eligible patients.5 How these lower costs are provided varies and ranges from coupons, discount cards, rebates, and lower copayments to free supplies of prescription drugs.5,6 The criteria for patient eligibility also

Table 1. Patients’ Disease Indicators Before and After Program Enrollment Mean±SD Disease Indicator

Pre-Enrollment Post-Enrollment P value

HbA1c (%)

3±2.4

5±1.5

.018

Total cholesterol (mg/dL)

196±40

183±38

.017

HDL cholesterol (mg/dL)

3±12.2

2±11.3

NS

LDL cholesterol (mg/dL)

118±36

102±31

<0.001

Triglycerides (mg/dL)

234±202

199±150

.049

SCr (mg/dL)

85±0.2

0±0.3

<0.001

Systolic blood pressure (mm Hg)

1±22.8

0±23.3

NS

Diastolic blood pressure (mm Hg)

8±11.7

0±11.5

NS

HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NS, not significant; SCr, serum creatinine; SD, standard deviation Based on reference 8.

Patients, %

Spending on prescription drugs has more than doubled in recent years, increasing from around $424 per person in 1996 to $950 per person in 2003.1 Prescription drugs also contribute substantially to out-of-pocket health care costs for many individuals who have chronic medical conditions. For low-income, non-elderly individuals with a single chronic condition, costs of prescription drugs can account for up to 36% of health care spending. This percentage increases to 55% if 2 or more chronic conditions are present.2 These numbers far exceed spending for hospital inpatient and outpatient costs. Although health care reform will provide more insurance coverage to individuals in the United States, many of them will still have difficulty affording prescription drugs.3 To help reduce the cost of prescription drugs, pharmaceutical manufacturers have developed programs to increase access to these medications for selected populations of patients.4

vary and generally include income (often a percentage of the poverty level) and insurance status (underinsured or uninsured). Applications for the PAPs usually are available online and less often in print.6 Medications are delivered to the physician’s office, a health care center, or directly to the patient. Pharmaceutical assistance programs have been shown to be a useful resource for patients with limited income for prescription drugs. Marie ChisholmBurns, PharmD, professor and head of the Department of Pharmacy Practice and Science at the University of Arizona College of Pharmacy, in Tucson, is the founder and executive director of the Medication Access Program, established to increase access to prescription drugs for transplant patients. “Not only are our patients faced with the high cost of immunosuppressive medications, many also have chronic medical conditions, such as diabetes and hypertension, adding to the cost of their prescription drugs. Pharmaceutical assistance programs have been invaluable for obtaining medications for our patients.”

67 60 48 40

40 26

20 0

Reaching HbA1c goal

Reaching fasting glucose level goal Prescription insurance

120

Lipid Values, mg/dL

Introduction

80

100

PAP Group

112 96

80 60 40

34

41

20 0

LDL cholesterol

HDL cholesterol

Figure 1. Impact of pharmaceutical assistance programs on clinical outcomes. Based on references 7 and 8. HbA1c, glycosylated hemoglobin; HDL, high-density lipoprotein; LDL, low-density lipoprotein; PAP, pharmaceutical assistance programs

The value of PAPs for patient access to prescription drugs also has been confirmed by several studies. Consistent access to prescription drugs through PAPs has been shown to improve markers of chronic conditions such as type 2 diabetes and dyslipidemia. Additionally, cost savings to both the patient and the pharmacy have been seen when pharmacists facilitate program enrollment.7-9 In a retrospective review, Trompeter and Havrda compared outcomes for treatment of diabetes between patients with prescription insurance and those using PAPs for obtaining prescription drugs.7 Patients using PAPs tended to be older and had more medical conditions than those with prescription insurance. Patients using PAPs also demonstrated better control of diabetes. Goal hemoglobin A1C (HbA1C) was achieved by 67% of patients using PAPs compared with 40% of patients with prescription insurance. The percentage of patients achieving goal fasting glucose levels was also higher in the PAP group (48% vs 26%) (Figure 1). In the same study, patients with dyslipidemia who used PAPs for their prescription drugs were found to have better

lipid profiles than those using prescription insurance. For example, patients in the PAP group had lower low-density lipoprotein cholesterol (LDL-C) values (95.8±28.0 mg/dL [mean ±SD]) and higher high-density lipoprotein cholesterol (HDL-C) values (40.8±12.1 mg/dL) compared with patients in a traditional prescription insurance group (111.8 ±37.5 mg/dL; P<0.001 and 33.7±13.6 mg/dL; P=0.011, respectively)(Figure 1). Strum reported similar results in a retrospective evaluation of a pharmacymanaged medication assistance program using PAPs.8 After enrollment in a medication assistance program, patients had a significant reduction in HbA1C, total cholesterol, low-density lipoproteins, and triglycerides (Table 1). Additionally, use of PAPs resulted in a savings of more than $900,000 for the pharmacy while still assisting indigent patients in obtaining medications.

Limitations of Pharmaceutical Assistance Programs The many steps required in the application process can make use of PAPs cumbersome, according to Dr. Chisholm-Burns. “Patients will need advocates to help navigate the system.


Pharmacy Practice News • June 2011

Operations & Management 25

Drug Costs Table 2. United States Poverty Guidelines For 2011 Family Size, N

Annual Incomea,b

1

$10,890

2

$14,710

3

$18,530

4

$22,350

5

$26,170

6

$29,990

7

$33,810

8b

$37,630

a

 laska and Hawaii have separate income A guidelines.

b

 3,820 is added for each additional individual $ for families with more than 8 members.

‘Not only are our patients faced with the high cost of immunosuppressive medications, many also have chronic medical conditions, such as diabetes and hypertension, adding to the cost of their prescription drugs.’ —Marie Chisholm-Burns, PharmD may be included. Some of the available resources to assist patients and health care providers are described below. Partnership for Prescription Assistance (PPA) is funded by pharmaceutical research companies and provides information on PAPs as well as public and private foundation-sponsored assistance programs.14 This site

References 1. Zuvekas SH, Cohen JW. Prescription drugs and the changing concentration of health care expenditures. Health Aff. 2007;26(1):249-257. 2. Cunningham PJ. Chronic burdens: the persistently high out-of-pocket health care expenses faced by many Americans with chronic conditions. Commonwealth Fund. 2009;1303(63):1-14.

Based on reference 13.

Follow-up for the patient is an important part of using PAPs, as is consistency in pharmacy involvement,” she said. Adding to the challenge is the complexity of the application forms for some programs.6,10,11 The forms are written at a reading level that may be too advanced for some patients and can be time-consuming for medical offices when patients cannot apply directly to the PAP. Furthermore, documentation of income is required, such as paycheck stubs, Social Security statements, or federal income tax returns.12 Medications frequently are sent directly to the patient’s physician’s office, adding another step for patients to obtain the medication. Patients may not be notified for 3 to 4 weeks regarding their eligibility for the program. The income levels determining eligibility for PAPs are low and are based on the US poverty guidelines13 (Table 2). As an example, for a PAP that requires an income at 200% of the poverty level, a 2-person household would need to have an income of $29,420 or less to be eligible. Finally, patients taking several maintenance medications may need to apply to several PAPs, because most programs cover only a few prescription drugs or there are different programs for different prescription drugs. Generic drugs usually are not included in PAPs.

Resources Numerous resources are available to assist patients in identifying companies that offer PAPs, including those sponsored by not-for-profit organizations as well as by pharmaceutical companies. Most of these resources allow searching by drug name or by pharmaceutical company to identify assistance programs. Some offer links to the online applications. Information on governmental or other public assistance programs also

is described as a “single point of entry” for 475 available prescription drug assistance programs. Patients can enter their prescription drugs and personal information, and the site identifies assistance programs for those medications, with links to online applications for the programs. There is no charge to patients or health care providers for use of the Web site. RxAssist is an information resource for patients to locate specific PAP programs.15 Developed with funding from the Robert Wood Johnson Foundation,

this site is maintained through donations and company sponsorships. The site includes directories of PAPs and prescription drugs covered under a PAP. The site is searchable for companies offering PAPs and for prescription drugs. Similar to other Web sites, RxAssist has information on governmental programs, coupons, and prescription drug discount cards. There is no fee to use the Web site. RxHope is part of the Triplefin group,

as PPA, RxAssist, and NeedyMeds to assist patients in locating appropriate PAPs and programs offering discount cards for prescription drugs. Of interest to pharmacists, the ASHP offers “Tools for Practice” to help pharmacists set up protocols and policies for using PAPs. These tools include sample policies, spreadsheets for tracking medications, resources for assessing health and financial outcomes, and information on software to facilitate the use of PAPs.

an outsourcing company. This site was developed to assist health care providers in the PAP application process.16 Although patients can search the site for programs that include their prescription drugs, the physician’s office must complete the application for the patient. RxHope is a professional service that facilitates the process and tracks PAP applications. RxHope contracts with pharmaceutical companies to provide this service, which is free of charge to patients and health care providers. The site is searchable by brand name, PAP, and pharmaceutical company. NeedyMeds is described as a notfor-profit organization that lists prescription drugs by brand and generic

3. Felder T, Palmer N, Lal L, Mullen P. What is the evidence for pharmaceutical patient assistance programs? A systematic review. J Health Care Poor Underserv. 2011;22(1):24-49. 4. Chisholm MA, DiPiro JT. Pharmaceutical manufacturer assistance programs. Arch Intern Med. 2002;162(7):780-784. 5. NeedyMeds. www.needymeds.org/index.htm. Accessed April 3, 2011. 6. Choudhry N, Lee JL, Angew-Blais J, Corcoran C, Shrank WH. Drug company-sponsored patient assistance programs: a viable safety net? Health Aff. 2009;28(3):827-834. 7. Trompeter J, Havrda D. Impact of obtaining medications from pharmaceutical company assistance programs on therapeutic goals. Ann Pharmacother. 2009;43(3):469-477. 8. Strum M, Hopkins R, West DS, Harris BN. Effects of a medication assistance program on health outcomes in patients with type 2 diabetes mellitus. Am J Health Syst Pharm. 2005;62(10):1048-1052. 9. Sarrafizadeh M, Waite NM, Hobson EH, Migden H. Pharmacist-facilitated enrollment in medication assistance programs in a private ambulatory care clinic. Am J Health Syst Pharm. 2004;61(17):1816-1820. 10. Pisu M, Richman J, Allison J, William O, Kiefe CI. Pharmaceutical companies’ medication assistance programs: potentially useful but too burdensome to use? South Med J. 2009;102(2):139-144.

names, along with lists of pharmaceutical companies offering PAPs, governmental health care programs, and local organizations that provide help with PAP applications.5 Information on 548 programs and companies is available on the Web site. There is no charge to use the service, but donations to maintain the site are accepted. NeedyMeds also offers a subscription-based software program to health care providers—PAPTracker—that helps in tracking PAP applications. Professional organizations also provide information on PAPs. The American Society of Health-System Pharmacists (ASHP) has compiled information on PAPs under its Practice and Policy Resource Center.17 The ASHP’s Web site provides links to programs such

11. Richardson K, Basskin LE. Use of drug manufacturers’ patient assistance programs by safety net providers. Am J Health Syst Pharm. 2002;59(11):1105-1109. 12. Pfizer Connection to Care. Pfizerhelpfulanswers.com. www.pfizerhelpfulanswers.com/ files/C2C_Eligibility_10.25.10.pdf. Accessed April 1, 2011. 13. Department of Health and Human Services. Office of the Secretary. Annual update of the HHS poverty guidelines. Fed Regist. 2011;76(13):3637-3638. 14. Partnership for Prescription Assistance. www. pparx.org. Accessed April 3, 2011. 15. RxAssist. Patient Assistance Program Center. www.rxassist.org/default.cfm. Accessed April 3, 2011. 16. RxHope. Hope for everyone. www.rxhope.com/ about.aspx. Accessed April 4, 2011. 17. American Society of Health-System Pharmacists. Practice and Policy. Resource Centers. Patient Assistance Programs. www.ashp.org/ Import/PRACTICEANDPOLICY/PracticeResourceCenters/PatientAssistancePrograms. aspx. Accessed March 24, 2011.


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

Important Risk Information NEXTERONE (amiodarone HCl) Premixed Injection is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE, including iodine • Cardiogenic shock • Marked sinus bradycardia • Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available • NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment. • Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported in 16% (288/1836) of patients treated with intravenous amiodarone. Monitor the initial rate of infusion closely and do not exceed the recommended rate. In some cases, hypotension may be refractory and result in a fatal outcome. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including: vasopressors, positive inotropic agents and volume expansion. • In 4.9% (90/1836) of patients in clinical trials, drug-related bradycardia that was not dose-related occurred while patients were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available. • Like all antiarrhythmics, NEXTERONE may cause worsening of existing arrhythmias or precipitate a new arrhythmia. • The most common adverse reactions leading to discontinuation (1-2%) of intravenous amiodarone therapy are hypotension, asystole/cardiac arrest/pulseless electrical activity, VT, and cardiogenic shock. • Other important adverse reactions are torsade de pointes (TdP), congestive heart failure, liver function test abnormalities, pulmonary disorders, and thyroid abnormalities. • Drug Interactions: Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone. Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. Please see brief summary of Full Prescribing Information on the following pages.

Medication Delivery

111514

07/11


Nexterone. Emergent. Extensive. Evolved.

IT’S ABOUT TIME.

Emergent. Premixed. Patient ready. It can be standing by, nearby, until the instant you need it.

Extensive. This is the amiodarone you want, the way you need it – premixed for rapid and slow loading infusions, and maintenance, too.

Evolved. Introducing NEXTERONE. The first premixed, cGMP manufacturer-prepared amiodarone from Baxter Healthcare Corporation.

NEXTERONE.COM 888-229-0001


NEXTERONE (amiodarone HCl) Premixed Injection for intravenous use Brief Summary of Prescribing Information. See PI for Full Prescribing Information. 1 INDICATIONS AND USAGE NEXTERONE is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy [see Dosage and Administration (2) in full prescribing information]. Use NEXTERONE for acute treatment until the patient's ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary. 4 CONTRAINDICATIONS NEXTERONE is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE Premixed Injection, including iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage (bleeding), fever, arthralgias (joint pains), eosinophilia (abnormal blood counts), urticaria (hives), thrombotic thrombocytopenic purpura, or severe periarteritis (inflammation around blood vessels). • Cardiogenic shock. • Marked sinus bradycardia. • Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available. 5 WARNINGS AND PRECAUTIONS NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment. 5.1 Hypotension Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with intravenous amiodarone. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in intravenous amiodarone therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor the initial rate of infusion closely and do not exceed the recommended rate [see Dosage and Administration (2) in full prescribing information]. In some cases, hypotension may be refractory and result in a fatal outcome [see Adverse Reactions (6.2) in full prescribing information]. 5.2 Bradycardia and Atrio-ventricular Block In 90 (4.9%) of 1836 patients in clinical trials, drug-related bradycardia that was not dose-related occurred while they were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available. 5.3 Liver Enzyme Elevations Elevations of blood hepatic enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)] are commonly seen in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical defibrillations. Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment. Acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone at a much higher loading dose concentration and much faster rate of infusion than recommended [see Dosage and Administration (2) in full prescribing information]. In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE for evidence of progressive hepatic injury. In such cases, consider reducing the rate of administration or withdrawing NEXTERONE.

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


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

Table 4 lists the most common (incidence â&#x2030;Ľ2%) adverse reactions during intravenous amiodarone therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled because none of the adverse reactions appeared to be dose-related. Table 4: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN

The institution of antithyroid drugs, β-adrenergic blockers or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. Neonatal Hypo- or Hyperthyroidism Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient of the potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patient becomes pregnant while taking NEXTERONE. Hypothyroidism Hypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the NEXTERONE dose and considering the need for thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue oral amiodarone in some patients. 5.9 Surgery Perform close perioperative monitoring in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction defects of halogenated inhalational anesthetics. 5.10 Corneal Refractive Laser Surgery Advise patients that most manufacturers of corneal refractive laser surgery devices contraindicate corneal refractive laser surgery in patients taking amiodarone. 5.11 Electrolyte Disturbances Correct hypokalemia or hypomagnesemia whenever possible before initiating treatment with NEXTERONE, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

CONTROLLED AND OPEN-LABEL STUDIES (> 2% INCIDENCE) Study Event

Controlled Studies (n=814)

Open-Label Studies (n=1022)

Total (n=1836)

Body as a whole Fever

Body as a whole 24 (2.9%)

Body as a whole 13 (1.2%)

Body as a whole 37 (2.0%)

Cardiovascular System Bradycardia Congestive heart failure Heart arrest Hypotension Ventricular tachycardia

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

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

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

Digestive System Liver function tests normal Nausea

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

Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, atrial fibrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting. 6.2 Post-Marketing Experience The following adverse reactions have been identified during post-approval use of amiodarone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: anaphylactic/anaphylactoid reaction (including shock), fever Cardiovascular: hypotension (sometimes fatal), sinus arrest Dermatologic: toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, skin cancer, pruritus, angioedema Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hematologic: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, agranulocytosis, granuloma Hepatic: hepatitis, cholestatic hepatitis, cirrhosis Injection Site Reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing Musculoskeletal: myopathy, muscle weakness, rhabdomyolysis Nervous System: hallucination, confusional state, disorientation, and delirium, pseudotumor cerebri Pancreatic: pancreatitis

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

Renal: renal impairment, renal insufficiency, acute renal failure

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

Vascular: vasculitis

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

Baxter Healthcare Corporation Deerfield, IL 60015 Baxter, Galaxy and the Sphere Graphic are registered trademarks of Baxter International Inc. NEXTERONE is a registered trademark of Prism Pharmaceuticals, Inc.

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


30 Operations & Management

Pharmacy Practice News • June 2011

Leadership in Action

‘Active Listening’ And Other Leadership Nuggets I am known for collecting anecdotes and “war stories” that have left me with memorable life lessons. I try to keep a few of these in my back pocket for those moments when I need some wisdom—either to help myself or to help someone else. This month’s column includes some of my favorite leadership “nuggets.” Most are based on the book “Leadership Gold,” by John Maxwell (Nashville: Thomas Nelson Publishers; 2008). Let’s see how they can apply to the profession of pharmacy.

Good Communication Starts With Listening Most of us believe that we are good listeners. I certainly like to think that I am. However, if you ask my wife, she is likely to paint a different picture. So, maybe I still have some work to do. I try to take her wise counsel to heart. Good listening is an active—not a passive—endeavor. Sometimes I catch myself thinking I can multitask while I am listening to someone. It doesn’t work. In fact, I’ve come to realize that it demeans the person I am speaking with and sends a message that they are not important. Active listening requires eye contact, acknowledgment (even a nod) and a reflection back of what you took away from the other person’s words. We need to listen before we speak. See if you can catch yourself so wrapped up in what you are going to say to someone during a conversation that you haven’t been listening to a word they said. I see this frequently in group situations. I feel that my role is to listen to what individuals are saying and to notice when people do not understand one another. I try to stop the conversation and explain to both parties what I hear each of them saying. This often is followed by an “aha moment,” as each realizes that they have been talking, but not communicating, with one another. True leadership begins with understanding. Understanding begins with listening. And listening requires going beyond the spoken words to the unspoken. “Hearing” the unspoken requires insight into the heart of the other person. When you connect at this level, the other person feels validated. You then have an individual willing to give of themselves to the team, the organization or the vision. As leaders, we have to remember that listening is essential. Pharmacy is a complex profession. We cannot know everything. There is a need to be good listeners, learners and then leaders.

Reading your co-workers and asking questions helps avert crises. Having that sixth sense that something is wrong and exposing the issue through good communication is essential for a department or an organization. This breeds trust in relationships, which furthers cooperation and moves everyone closer to achieve the shared vision.

Working Your Strengths Have you ever seen a child try to play a sport that he or she just didn’t have a knack for? As hard as the child tries and as much as you coach him or her, it’s just not going to happen. I trust that most of us ended up in pharmacy because we were good in science and math or because we had a sense that taking patient care to new levels would be rewarding. Pharmacy has many different avenues to which we can aspire. Regardless of your particular direction in pharmacy, does it define you and your purpose? Have you found a niche related to your personal strengths? We often hear about “natural-born leaders.” I believe in this—to a certain extent. Some people do seem naturally gifted to lead. Does that mean leaders can’t learn more? Of course not. Does that mean others can’t grow into leadership positions if they aren’t as strongly gifted? No, but it will require harder work. The encouragement is to work on your strengths. As Maxwell states, “The greater your natural ability, the greater your potential for improvement.” I remember one time when I gave a lecture in a clinical area that was not a specialty of mine. I bombed. I told myself that I would not make the same mistake again. Understanding your strengths requires a personal assessment. Ask yourself what you are good at. Ask others what you do well. Be specific. Then figure out how you can maximize your strengths in the practice of pharmacy. We need to go through this same exercise with our staffs. Successful leaders determine people’s strengths, help them to grow and position them to maximize those strengths. If you don’t have a spot for someone with particular

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

Ernest R. Anderson Jr., MS, RPh

strengths, you might consider encouraging him or her to pursue a job in a different setting. Some people excel in academia, whereas others thrive in a hospital-pharmacy environment. Why not do what you’re good at?

advantage, don’t compete. We need to base our visions for our departments on reality—identifying our areas of strength and playing to them.

Defining Moments of Reality

The People Reflect the Leader

As we look at our strengths, we may find that we need a dose of reality from time to time. If you find yourself to be unrealistically optimistic, you might look to incorporate some “truth tellers” in your life. As leaders, we can get so caught up in our vision that we distort reality. For example, health care is experiencing turbulent times. This is the reality. It requires thinking well beyond our pharmacy departments. We cannot continue to operate the way we have in the past. Jack Welch, in his book “Straight from the Gut” (Nashville, Boston, New York: Business Plus; 2001) highlights six rules of successful leadership that are applicable to pharmacy. 1. Control your destiny, or someone else will. 2. Face the world as it is—not as it was, or as you wish it was. 3. Be candid with everyone. 4. Don’t manage—lead. 5. Change before you have to. 6. If you don’t have a competitive

It has been said, “Everything rises and falls on leadership.” Good leaders produce good departments. Poor leadership has a trickle-down effect throughout a department. The leader is responsible. The more you understand leadership, the more you understand how your leadership impacts everything around you. Leadership expert Max Depree says, “The signs of outstanding leadership appear primarily among the followers.” In other words, your staff and your department are reflections of you as a leader. So, as you evaluate your employees, ask yourself if you are doing a good job. Maxwell continues, “People may teach what they know, but they reproduce what they are.” So the question is not “How am I doing as a leader” but rather “How are the people I lead doing?” Are your people learning and growing in their areas of strength? Do you have the right people in the right positions? Are people willing to change? Are you? Are people following your lead? As the Rev. E.V. Hill once stated, “The man who is leading but no one is following, is merely going for a walk.”

See if you can catch yourself so wrapped up in what you are going to say to someone during a conversation that you haven’t been listening to a word they said.


UNMET NEED. FILL IT.

FREE VVATER V2

CLEARANCE

Order SAMSCA® (tolvaptan)

15 mg

30 mg

NDC: 59148-020-50

NDC: 59148-021-50

Unique oral treatment for clinically significant hypervolemic and euvolemic hyponatremia

100 %

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

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

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

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

Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the following page. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. US Patent Nos: 5,258,510 and 5,753,677. Samsca is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

©2011 Otsuka America Pharmaceutical, Inc.

February 2011

0711A-2015B


6$06&$Š WROYDSWDQ WDEOHWVIRURUDOXVH %ULHI6XPPDU\RI3UHVFULELQJ,QIRUPDWLRQ)RUFRPSOHWHSUHVFULELQJLQIRUPDWLRQFRQVXOWRI¿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¿FDQW K\SHUYROHPLF DQG HXYROHPLF K\SRQDWUHPLD VHUXPVRGLXPP(T/RUOHVVPDUNHGK\SRQDWUHPLDWKDWLVV\PSWRPDWLFDQGKDVUHVLVWHGFRUUHFWLRQZLWK ÀXLGUHVWULFWLRQ LQFOXGLQJSDWLHQWVZLWKKHDUWIDLOXUHFLUUKRVLVDQG6\QGURPHRI,QDSSURSULDWH$QWLGLXUHWLF+RUPRQH 6,$'+  ,PSRUWDQW/LPLWDWLRQV 3DWLHQWVUHTXLULQJLQWHUYHQWLRQWRUDLVHVHUXPVRGLXPXUJHQWO\WRSUHYHQWRUWRWUHDWVHULRXVQHXURORJLFDOV\PSWRPVVKRXOGQRW EHWUHDWHGZLWK6$06&$ ,WKDVQRWEHHQHVWDEOLVKHGWKDWUDLVLQJVHUXPVRGLXPZLWK6$06&$SURYLGHVDV\PSWRPDWLFEHQH¿WWRSDWLHQWV &2175$,1',&$7,2166$06&$LVFRQWUDLQGLFDWHGLQWKHIROORZLQJFRQGLWLRQV 8UJHQWQHHGWRUDLVHVHUXPVRGLXPDFXWHO\6$06&$KDVQRWEHHQVWXGLHGLQDVHWWLQJRIXUJHQWQHHGWRUDLVHVHUXPVRGLXP DFXWHO\ ,QDELOLW\RIWKHSDWLHQWWRVHQVHRUDSSURSULDWHO\UHVSRQGWRWKLUVW3DWLHQWVZKRDUHXQDEOHWRDXWRUHJXODWHÀXLGEDODQFH DUHDWVXEVWDQWLDOO\LQFUHDVHGULVNRILQFXUULQJDQRYHUO\UDSLGFRUUHFWLRQRIVHUXPVRGLXPK\SHUQDWUHPLDDQGK\SRYROHPLD +\SRYROHPLFK\SRQDWUHPLD5LVNVDVVRFLDWHGZLWKZRUVHQLQJK\SRYROHPLDLQFOXGLQJFRPSOLFDWLRQVVXFKDVK\SRWHQVLRQDQG UHQDOIDLOXUHRXWZHLJKSRVVLEOHEHQH¿WV &RQFRPLWDQW XVH RI VWURQJ &<3 $ LQKLELWRUV .HWRFRQD]ROH PJ DGPLQLVWHUHG ZLWK WROYDSWDQ LQFUHDVHG WROYDSWDQ H[SRVXUHE\IROG/DUJHUGRVHVZRXOGEHH[SHFWHGWRSURGXFHODUJHULQFUHDVHVLQWROYDSWDQH[SRVXUH7KHUHLVQRWDGHTXDWH H[SHULHQFHWRGH¿QHWKHGRVHDGMXVWPHQWWKDWZRXOGEHQHHGHGWRDOORZVDIHXVHRIWROYDSWDQZLWKVWURQJ&<3$LQKLELWRUVVXFK DVFODULWKURP\FLQNHWRFRQD]ROHLWUDFRQD]ROHULWRQDYLULQGLQDYLUQHO¿QDYLUVDTXLQDYLUQHID]RGRQHDQGWHOLWKURP\FLQ $QXULFSDWLHQWV,QSDWLHQWVXQDEOHWRPDNHXULQHQRFOLQLFDOEHQH¿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ÀXLG)OXLGUHVWULFWLRQGXULQJWKH¿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ÀXLGLQWDNH 'HK\GUDWLRQ DQG K\SRYROHPLD FDQ RFFXU HVSHFLDOO\ LQ SRWHQWLDOO\ YROXPHGHSOHWHG SDWLHQWV UHFHLYLQJ GLXUHWLFV RU WKRVH ZKR DUHÀXLGUHVWULFWHG,QPXOWLSOHGRVHSODFHERFRQWUROOHGWULDOVLQZKLFKK\SRQDWUHPLFSDWLHQWVZHUHWUHDWHGZLWKWROYDSWDQ WKH LQFLGHQFH RI GHK\GUDWLRQ ZDV  IRU WROYDSWDQ DQG  IRU SODFHERWUHDWHG SDWLHQWV ,Q SDWLHQWV UHFHLYLQJ 6$06&$ ZKRGHYHORSPHGLFDOO\VLJQL¿FDQWVLJQVRUV\PSWRPVRIK\SRYROHPLDLQWHUUXSWRUGLVFRQWLQXH6$06&$WKHUDS\DQGSURYLGH VXSSRUWLYH FDUH ZLWK FDUHIXO PDQDJHPHQW RI YLWDO VLJQV ÀXLG EDODQFH DQG HOHFWURO\WHV )OXLG UHVWULFWLRQ GXULQJ WKHUDS\ ZLWK 6$06&$PD\LQFUHDVHWKHULVNRIGHK\GUDWLRQDQGK\SRYROHPLD3DWLHQWVUHFHLYLQJ6$06&$VKRXOGFRQWLQXHLQJHVWLRQRIÀ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¶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ÀXLGYROXPHZKLFKFRXOGUHVXOWLQLQFUHDVHGVHUXPSRWDVVLXP6HUXPSRWDVVLXPOHYHOVVKRXOGEHPRQLWRUHG DIWHULQLWLDWLRQRIWROYDSWDQWUHDWPHQWLQSDWLHQWVZLWKDVHUXPSRWDVVLXP!P(T/DVZHOODVWKRVHZKRDUHUHFHLYLQJGUXJV NQRZQWRLQFUHDVHVHUXPSRWDVVLXPOHYHOV $'9(56(5($&7,216 &OLQLFDO 7ULDOV ([SHULHQFH %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV DGYHUVH UHDFWLRQV UDWHV REVHUYHGLQWKHFOLQLFDOWULDOVRIDGUXJFDQQRWEHGLUHFWO\FRPSDUHGWRUDWHVLQWKHFOLQLFDOWULDOVRIDQRWKHUGUXJDQGPD\QRW UHÀ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•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

7ROYDSWDQ PJGD\PJGD\  1 

Q 

3ODFHER 1 

Q 

*DVWURLQWHVWLQDO'LVRUGHUV 'U\PRXWK  

 

&RQVWLSDWLRQ  

 

*HQHUDO'LVRUGHUVDQG$GPLQLVWUDWLRQ6LWH&RQGLWLRQV D 7KLUVW  

 

$VWKHQLD  

 

3\UH[LD  

 

0HWDEROLVPDQG1XWULWLRQ'LVRUGHUV E +\SHUJO\FHPLD     

$QRUH[LDF  

 

5HQDODQG8ULQDU\'LVRUGHUV 3ROODNLXULDRUSRO\XULDG  

 

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

6$06&$Š WROYDSWDQ  7KHIROORZLQJDGYHUVHUHDFWLRQVRFFXUUHGLQRIK\SRQDWUHPLFSDWLHQWVWUHDWHGZLWK6$06&$DQGDWDUDWHJUHDWHUWKDQ SODFHERLQGRXEOHEOLQGSODFHERFRQWUROOHGWULDOV 1 WROYDSWDQ1 SODFHER RULQRISDWLHQWVLQDQXQFRQWUROOHG WULDO RI SDWLHQWV ZLWK K\SRQDWUHPLD 1    DQG DUH QRW PHQWLRQHG HOVHZKHUH LQ WKH ODEHO %ORRG DQG /\PSKDWLF 6\VWHP 'LVRUGHUV 'LVVHPLQDWHG LQWUDYDVFXODU FRDJXODWLRQ &DUGLDF 'LVRUGHUV ,QWUDFDUGLDF WKURPEXV YHQWULFXODU ¿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¿QDYLUULWRQDYLUDQGQHID]RGRQH DWWKHKLJKHVWODEHOHG GRVHZRXOGEHH[SHFWHGWRFDXVHDQHYHQJUHDWHULQFUHDVHLQWROYDSWDQH[SRVXUH7KXV6$06&$DQGVWURQJ&<3$LQKLELWRUV VKRXOGQRWEHFRDGPLQLVWHUHG>VHH'RVDJHDQG$GPLQLVWUDWLRQ  DQG&RQWUDLQGLFDWLRQV  @ 0RGHUDWH&<3$,QKLELWRUV7KHLPSDFWRIPRGHUDWH&<3$LQKLELWRUV HJHU\WKURP\FLQÀ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¶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¿FDQWGHJUHH /RYDVWDWLQ6$06&$LVDZHDNLQKLELWRURI&<3$&RDGPLQLVWUDWLRQRIORYDVWDWLQDQG6$06&$LQFUHDVHVWKHH[SRVXUHWR ORYDVWDWLQDQGLWVDFWLYHPHWDEROLWHORYDVWDWLQȕK\GUR[\DFLGE\IDFWRUVRIDQGUHVSHFWLYHO\7KLVLVQRWDFOLQLFDOO\UHOHYDQW FKDQJH 3KDUPDFRG\QDPLF,QWHUDFWLRQV7ROYDSWDQSURGXFHVDJUHDWHUKRXUXULQHYROXPHH[FUHWLRQUDWHWKDQGRHVIXURVHPLGHRU K\GURFKORURWKLD]LGH&RQFRPLWDQWDGPLQLVWUDWLRQRIWROYDSWDQZLWKIXURVHPLGHRUK\GURFKORURWKLD]LGHUHVXOWVLQDKRXUXULQH YROXPHH[FUHWLRQUDWHWKDWLVVLPLODUWRWKHUDWHDIWHUWROYDSWDQDGPLQLVWUDWLRQDORQH $OWKRXJKVSHFL¿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¿FDWLRQDQGHPEU\RIHWDOGHDWKRFFXUUHG6$06&$VKRXOGEHXVHGGXULQJSUHJQDQF\RQO\LIWKHSRWHQWLDOEHQH¿WMXVWL¿HV WKHSRWHQWLDOULVNWRWKHIHWXV ,QHPEU\RIHWDOGHYHORSPHQWVWXGLHVSUHJQDQWUDWVDQGUDEELWVUHFHLYHGRUDOWROYDSWDQGXULQJRUJDQRJHQHVLV5DWVUHFHLYHGWR WLPHVWKHPD[LPXPUHFRPPHQGHGKXPDQGRVH 05+' RIWROYDSWDQ RQDERG\VXUIDFHDUHDEDVLV 5HGXFHGIHWDOZHLJKWV DQGGHOD\HGIHWDORVVL¿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¿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¿WFDQEH H[SHFWHGLQSDWLHQWVZKRDUHDQXULF>VHH&RQWUDLQGLFDWLRQV  @ 8VH LQ 3DWLHQWV ZLWK &RQJHVWLYH +HDUW )DLOXUH 7KH H[SRVXUH WR WROYDSWDQ LQ SDWLHQWV ZLWK FRQJHVWLYH KHDUW IDLOXUH LV QRW FOLQLFDOO\UHOHYDQWO\LQFUHDVHG1RGRVHDGMXVWPHQWLVQHFHVVDU\ 29(5'26$*(6LQJOHRUDOGRVHVXSWRPJDQGPXOWLSOHGRVHVXSWRPJRQFHGDLO\IRUGD\VKDYHEHHQZHOOWROHUDWHG LQ VWXGLHV LQ KHDOWK\ VXEMHFWV 7KHUH LV QR VSHFL¿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¿UVWVWHS$WKRURXJKKLVWRU\DQGGHWDLOVRIRYHUGRVH VKRXOGEHREWDLQHGDQGDSK\VLFDOH[DPLQDWLRQVKRXOGEHSHUIRUPHG7KHSRVVLELOLW\RIPXOWLSOHGUXJLQYROYHPHQWVKRXOGEH FRQVLGHUHG 7UHDWPHQW VKRXOG LQYROYH V\PSWRPDWLF DQG VXSSRUWLYH FDUH ZLWK UHVSLUDWRU\ (&* DQG EORRG SUHVVXUH PRQLWRULQJ DQG ZDWHUHOHFWURO\WHVXSSOHPHQWVDVQHHGHG$SURIXVHDQGSURORQJHGDTXDUHVLVVKRXOGEHDQWLFLSDWHGZKLFKLIQRWPDWFKHGE\ RUDOÀXLGLQJHVWLRQVKRXOGEHUHSODFHGZLWKLQWUDYHQRXVK\SRWRQLFÀXLGVZKLOHFORVHO\PRQLWRULQJHOHFWURO\WHVDQGÀXLGEDODQFH (&*PRQLWRULQJVKRXOGEHJLQLPPHGLDWHO\DQGFRQWLQXHXQWLO(&*SDUDPHWHUVDUHZLWKLQQRUPDOUDQJHV'LDO\VLVPD\QRWEH HIIHFWLYHLQUHPRYLQJWROYDSWDQEHFDXVHRILWVKLJKELQGLQJDI¿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¿QDYLUVDTXLQDYLULQGLQDYLUULWRQDYLU RUPRGHUDWH&<3$ LQKLELWRUV HJDSUHSLWDQWHU\WKURP\FLQGLOWLD]HPYHUDSDPLOÀXFRQD]RO RU3JSLQKLELWRUV HJF\FORVSRULQH >VHH'RVDJHDQG $GPLQLVWUDWLRQ  &RQWUDLQGLFDWLRQV  :DUQLQJVDQG3UHFDXWLRQV  DQG'UXJ,QWHUDFWLRQV  @ 1XUVLQJ$GYLVHSDWLHQWVQRWWREUHDVWIHHGDQLQIDQWLIWKH\DUHWDNLQJ6$06&$>VHH8VH,Q6SHFL¿F3RSXODWLRQV  @ )RUPRUHLQIRUPDWLRQDERXW6$06&$FDOORUJRWRZZZVDPVFDFRP 0DQXIDFWXUHGE\2WVXND3KDUPDFHXWLFDO&R/WG7RN\R-DSDQ 'LVWULEXWHGDQGPDUNHWHGE\2WVXND$PHULFD3KDUPDFHXWLFDO,QF5RFNYLOOH0' 863DWHQW1RVDQG 6$06&$LVDWUDGHPDUNRI2WVXND3KDUPDFHXWLFDO&R/WG7RN\R-DSDQ

 ‹2WVXND3KDUPDFHXWLFDO&R/WG



/%

5HY


Pharmacy Practice News • June 2011

Clinical 33

Practice Pearl Understanding uses and risks of dietary supplements:

A Teaching Opportunity for Pharmacists M. Chandra Sekar, Vaiyapuri Subramaniam, PharmD, MS RPh, PhD Associate Chief Consultant Associate Professor College of Pharmacy University of Findlay Findlay, Ohio

Pharmacy Benefits Management Services Department of Veterans Affairs (VA), Washington, DC Clinical Affiliate Professor Nova Southeastern University College of Pharmacy West Palm Beach, Florida

T

he use of dietary supplements both to treat disease and for disease prevention continues to grow, increasing the need for pharmacists and other health care professionals to improve their awareness of the efficacy and the risks associated with these supplements.1 The American Society of Health-System Pharmacists (ASHP) has stated that pharmacists, as medication-use experts and as the most accessible members of the health care team, are uniquely qualified and positioned to counsel patients on the use of dietary supplements.2 However, most pharmacists lack the confidence to counsel patients on these products because the curriculum in most US pharmacy schools does not include any formal training on dietary supplements and herbal products. Additionally, the content of dietary supplements is not standardized, therapeutic goals are vague, and evidence of efficacy and safety in most cases is absent and/or

Shin Hsien Shen, BS Pharm Team Leader Traditional Chinese Medicine Pharmacy Department Chung Gung Memorial Hospital Taipei, Taiwan

ambiguous. Furthermore, the resources pharmacists typically use to establish pharmaceutical treatment regimens lack information on dietary supplements. However, motivated pharmacists with appropriate continuing education can play an essential role in preventing adverse drug events caused by dietary supplements, if they have sound, evi-

Sheila Yesquen PharmD Candidate Nova Southeastern University College of Pharmacy Fort Lauderdale, Florida

dence-based professional resources. This article reviews herbal products that are commonly used in the United States and provides information regarding their effectiveness and their safety. Dietary supplements are defined in the Dietary Supplement Health and Education Act of 1994 (DSHEA) as products “intended to supplement the diet that contain vitamins, minerals, herbs

or other botanical amino acids.”3 The sale of prescription drugs and dietary supplements is a multibillion-dollar business in the United States. It has been estimated that at least 40% of the US population uses dietary supplements often and that almost twice as many have used at least 1 of the estimated 29,000 dietary supplements on the market.4 Out-of-pocket expenditures on dietary supplements and complementary and alternative medicine total in excess of $34 billion annually.5 As the biotechnology revolution unfolds, pharmaceutical companies are developing more specific and targeted (often very expensive) therapies. Surprisingly, at the same time, patient use of herbal products and supplements is growing exponentially. According to the Nutrition Business Journal, herbal and dietary supplements, which constitute

see HERBALS, page 34

Table. Commonly Used Herbal Products on the US Market Herbal Supple- Known Uses ment Product

Safety Profile

GCE Approved

Major Drug Interactions

Echinacea

Immune system stimulant

S

Yes

• No clinically significant interaction

Ginseng

General tonic for improved health and for erectile dysfunction

S

Yes

• Modest interaction with warfarin (decreases INR)

Ginkgo biloba

Memory enhancement

S

Yes

• Interaction with antiplatelet drugs • May increase bleeding • Increases nifedipine level in blood

Garlic

Cardiovascular health

S

Yes

• Decreased plasma level of the protease inhibitor saquinavir • Might enhance effects of warfarin

St. John’s wort

Depression

S

Yes

• Decreases plasma level of benzodiazepines, such as alprazolam, midazolam, and quazepam; calcium channel blockers, such as nifedipine and verapamil; digoxin; hormonal contraceptives; non-nucleoside reverse transcriptase inhibitors; and protease inhibitors • Serotonin syndrome can occur when it is used with SSRIs and triptans • Reduction in anticoagulant effect of warfarin

Peppermint

Nausea and vomiting

S

Yes

• Interacts with antacids and calcium channel blocker felodipine

Ginger

Nausea and vomiting

S

Yes

• No clinically significant interaction

Soy

Menopausal symptoms and cardiovascular health

S

Yes

• Increase in levothyroxine dose required; avoid its use with MAOI, due to presence of tyramine, and with warfarin, due to the presence of vitamin K

Kava

Anxiety

U

Yes

• Potentiation possible with drugs acting on CNS

Valerian

Insomnia

S

Yes

• No clinically significant interaction

Omega-3 fatty acids

Cardiovascular health

S

Yes

• Patients with or at risk for bleeding disorders or taking anticoagulants should consult physicians before starting omega-3 fatty acids

CNS, central nervous system; GCE, German Commission E; INR, international normalized ratio; MAOI, monoamine oxidase inhibitor; S, safe; SSRIs, selective serotonin reuptake inhibitors; U, unsafe Based on references 9 and 10.


34 Clinical

Pharmacy Practice News • June 2011

Practice Pearl

HERBALS continued from page 33

specialty supplements, represent the fastest-growing segment of the overall supplement product category.6 The demographic profile of the predominant herbal supplement user in the United States shows them to be white and female, with a median age of 49 years and an annual income above $64,000.7 Some of the factors responsible for this exponential growth are increased consumer involvement in personal

health; over-the-counter availability of these products; the general belief that these products are “natural,” and therefore safe; and finally, an overall disillusionment with the medical and pharmaceutical establishment.

‘Don’t Ask, Don’t Tell’ Despite increased use of these products by patients, most health care professionals continue to choose to remain ignorant, hoping that this trend will reverse itself. Several studies have demonstrated that the majority of the 40%

of the US population that uses herbs and supplements do not inform their health care professionals (neither doctors nor pharmacists), about their use of these products.4,8 We believe this scenario is the result of the following factors: Most practitioners of “Western medicine” believe that herbs and supplements have “no real use” in a patient’s therapeutic management, and therefore patients do not want to discuss their use of these products with their health care providers. At the same time, because health care providers lack education

in Your Inbox ... to receive the monthly e-newsletter from

at www.pharmacypracticenews.com

Get the latest news delivered directly to your computer and PDA. The new interactive format has embedded Web site links that give you instant access to additional information as well as unique searching features and printing capabilities. Each installment contains brief summaries of the most important articles from the current month’s issue, and breaking news ahead of print.

Register for free @ www.pharmacypracticenews.com

about herbal products, they do not press patients on the use of these preparations with true earnestness, lest their ignorance would be exposed. In other words, our current unofficial policy on herb and supplement use appears to be that of “Don’t ask, don’t tell.”

Are Herbs Effective? When it comes to this category of dietary supplement products (herbs and supplements), there are substantial differences even among Western countries in recognizing their overall therapeutic potential. Herbs appear to have greater legitimacy in Europe than in the United States, and within Europe, Germany has given greater recognition to herbal products. In 1978, Germany’s Federal Institute for Drugs and Medical Devices (formerly the Federal Health Agency), established the German Commission E, an expert committee composed of physicians, pharmacists, pharmacologists, toxicologists, representatives of the pharmaceutical industry, and laypeople, who evaluated the safety and efficacy of phytomedicines. This committee identified several therapeutically useful herbs and listed them in the German Commission E monographs. These listed herbal products can be prescribed by health care practitioners as prescription medications and are covered by insurance companies. (In 1998, these monographs were translated by the American Botanical Council,9 and we have used this reference in lieu of original German-language reports for this article.) Many health care professionals in the United States remain skeptical about the efficacy and safe use of those products. Therefore, it is incumbent on pharmacists and other health care professionals to educate themselves about these products so they can provide guidance to patients about their safe use.

Counseling on Herbs 101 The products listed in the Table are approved by the German Commission E, and thus their use has a rational and logical basis for consumer consideration, especially when associated costs and side-effect profiles of existing prescription medications are factored against these herbal products.9,10 However, issues such as drug interactions and side effects underscore the need for thorough review of a patient’s current medications when these agents are used. Of the agents listed in the Table on page 33, 2 herbal products raise red flags: St. John’s wort and kava. Taking St. John’s wort alone should not present problems, but if the patient is taking other prescription medications, pharmacists should carefully check the possibility for drug interactions and take extra time counseling the

see HERBALS, page 36


The bookstore division of

mcmahoNmedicalbooks.com order books oNliNe

an online bookstore

The book Page

Visit our site to get a FREE financial planning audio CD!

Publisher’s ToP Picks of The moNTh oN mcmahoNmedicalbooks.com These books and thousands more...

1

1

2

3

4

5

6

7

8

Applied Clinical Pharmacokinetics Larry A. Bauer

The most current, hands-on book in the field, Applied Clinical Pharmacokinetics gives you clear and useful coverage of drug dosing and drug monitoring that no other text can match. It offers the latest standardized techniques and approaches to patient-specific dosing, plus new information on more recently monitored drugs.

2

Applied Therapeutics: The Clinical Use of Drugs

Mary Anne Koda-Kimble; Lloyd Yee Young; Brian K. Alldredge; Robin L. Corelli; B. Joseph Guglielmo; Wayne A. Kradjan; Bradley R. Williams

ORDER ONLINE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com. We can supply any medical book in print, so if you don’t find the book you want, email your request with billing information to RMcMahon@McMahonMed.com. If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@McMahonMed.com.

Using a case-based approach, this book enables students to master the fundamentals of drug therapeutics. All the contributors are leading clinicians with many years of evidence-based care. As students progress through the text, they will learn the basics of common diseases and disorders and develop practical problem-solving skills for devising and implementing successful drug treatment regimens.

3

Clinical Skills for Pharmacists: A Patient-Focused Approach, Edition 3

Karen J. Tietze This book describes fundamental skills such as communication, physical assessment and laboratory and diagnostic information, as well as patient case presentation, therapeutic planning and monitoring of drug intake. Numerous case examples show how skills are applied in clinical situations. Now in full color, this edition adds more illustrations and new coverage on taking a medication history, physical assessment, biomarkers and drug information.

4

Instant Clinical Pharmacology, Second Edition Evan J. Begg

Content in this revised second edition covers the accepted core curriculum of clinical pharmacology: clinical pharmacokinetics, factors affecting dosing, altered drug effects, pharmacovigilance and principles of optimal therapeutics. Simple illustrations and tables support the text and provide rapid access to and explanation of key facts.

5

Lippincott’s Illustrated Reviews: Pharmacology, North American Edition, Fourth Edition

Richard A. Harvey; Pamela C. Champe; Richard Finkel; Luigi X Cubeddu; Michelle A. Clarke This guide enables rapid review and assimilation of large amounts of complex information about the essentials of medical pharmacology. Clear, sequential pictures of mechanisms of action actually show students how drugs work, instead of just telling them. The book features an outline format, more than 500 full-color illustrations, cross-references to other volumes in the series, and more than 125 review questions. Content has been thoroughly updated, and a new chapter covers toxicology.

6

Mosby’s Drug Reference for Health Professions, Edition 3

Mosby Filled with the details you need to know about your patients’ medications, this updated edition features concise, reliable information that is easy to navigate and simple to follow. Key details are presented in short monographs for 1,000 generic drugs (including 4,500 trade-name drugs) that are listed alphabetically. In fact, it’s the only drug book on the market written specifically for health professionals!

7

Nursing 2011 Drug Handbook, 31st Edition

8

Pharmacology and Therapeutics: Principles to Practice: Expert Consult: Online and Print

Lippincott

This edition has been updated and revised to appeal to both student and practicing nurses. Organized by therapeutic class, the handbook provides quick access to current, comprehensive, accurate information on more than 900 generic and 3,000 brand-name drugs.

Scott A. Waldman, Andre Terzic Pharmacology and Therapeutics: Principles to Practice presents everything you need to know about all of today’s drugs in a coherent, easy-touse format—from the underlying science through innovation, translation, regulation and clinical implementation. PPN0611


36 Clinical

Pharmacy Practice News • June 2011

Medication Safety

REPORTING TOOL continued from page 1

nonprofit group based in Cambridge, Mass., the Global Trigger Tool starts with chart reviews by multiple health care workers—typically a nurse or pharmacist­—who look for signs of a potential adverse event, such as an abnormal laboratory result, a medication stop order or the use of a drug antidote. These signals trigger additional investigation into the nature and severity of the event, and eventually confirmation of the case by a physician. For the latest study (Health Aff 2011;4:581-589), which was partly funded by the IHI, researchers compared the three assessment methods in 795 patient records culled randomly from three large teaching hospitals in the United States. All of the patients were adults admitted in October 2004, who spent at least 24 hours in the hospital.

The three methods combined identified 393 adverse events, the researchers said (some patients had more than one event). Of those, most involved medication errors (150) or procedure-related episodes (109). Hospital-acquired infections (72), pressure ulcers (11), device failures (six), falls (three) and “other” (26) rounded out the list. Eight of the events were fatal. After accounting for patients who had multiple adverse events, and conditions that were present at the time of admission, the incidence was about 30%, according to the researchers. In a subanalysis of a single hospital, the Global Trigger Tool demonstrated a sensitivity of nearly 95% for detecting at least one adverse event and a specificity of 100% for detecting patients with no adverse events. Patient safety indicators had a sensitivity of 8.5% and a specificity of 98.5%, and the hospital’s voluntary

‘Hospitals have no clue how safe they are, and neither does the public, for that matter.’ —David C. Classen, MD reporting system had a sensitivity of 0% and a specificity of 100%. David C. Classen, MD, associate professor of medicine at the University of Utah, in Salt Lake City, who led the study, said only a small percentage of hospitals are using the Global Trigger Tool. As a result, he said, “hospitals have no clue how safe they are, and neither does the public, for that matter.” Although the 30% rate for adverse events seems high, it’s in line with that found in two recent studies of the report-

ing method (see, for example, N Engl J Med 2010;363:2124-2134). Dr. Classen said policy makers such as the Joint Commission and federal government should push for wider adoption of the Global Trigger Tool. One way would be to include it in so-called “meaningful use” requirements for electronic medical records. In fact, he and his colleagues have shown that the tool can work with an EMR system to automate the collection of its measures. By doing so, he added, hospitals can track in real time their adverse events and take steps to remedy them before they lead to patient harm. Scan for Web exclusive: The ISMP’s Michael R. Cohen, RPh, MS, discusses the Global Trigger Tool.

—Adam Marcus

Practice Pearl

HERBALS continued from page 34

patient. Because St. John’s wort uses the cytochrome P450 pathway, there is an increased potential for interactions with several classes of prescription medications.11 A recent article in The Journal of the American Medical Association reported on the FDA advisory regarding kava’s hepatotoxicity.12 This is of particular concern because many patients take acetaminophen and alcohol, which also can cause liver damage. Adding kava to the mix in such patients clearly would be unsafe. Because kava acts on the central nervous system, simultaneous use of alcohol while taking kava should be avoided. Kava has pharmacologic effects that are similar to those of benzodiazepines, so patients taking benzodiazepines to treat symptoms of anxiety or convulsions should avoid kava.13 Although kava already has been banned in Canada but not yet in the United States, pharmacist education and counseling on this important subject will likely lead to better patient outcomes. Many herbal products not listed in the Table also are being used, and pharmacists should be aware of some of the risks related to these agents, so that they can inform their patients. Red yeast rice, an herbal product used by patients to reduce their cholesterol, contains an active ingredi-

ent, monacolin K, which is similar to the active ingredient in statin agents. Combining red yeast rice with a statin increases the risk for rhabdomyolysis.14,15 Ephedra and aristolochic acid, although banned by the FDA, are still present as ingredients in combination herbal products and supplements. Patients also are able to secure these products through the Internet. Ephedra, obtained from the plant ma huang, has been traditionally used in Chinese medicine to relieve upper respiratory tract problems, such as asthma. In the United States, patients are primarily using it for weight loss. Not only is ephedra’s effectiveness as a weight loss agent questionable, because of its sympathomimetic action, it can lead to sudden cardiac arrest.16 Aristolochic acid is a component of several other herbs, including aristolochia, which is used in Chinese herbal medicine. Several cases of end-stage renal disease have been associated with aristolochic acid.17 Ephedra and aristolochia-containing products should not be stocked in the pharmacy, and pharmacists should educate patients about the significant risks associated with these products. With the increasing need to enhance the understanding of dietary supplements, there are opportunities for pharmacy schools and universities to implement academic instructional programs on pharmaceutical and therapeutic uses of dietary supplements and herbal products. A few schools offer online elective courses, such as the University of Findlay’s Medicinal Herbs course, to pharmacy students.18 Students’ interest and evalu-

ation of the course clearly support the idea that pharmacy students and pharmacists have a desire for knowledge with which they can become more empowered to counsel patients on this important subject. As the medication experts, pharmacists must become proactive in educating themselves and their patients on dietary supplements to ensure their appropriate use and prevent adverse effects associated with their misuse.

References 1. Radimer K, Bindewald B, Hughes J, Ervine B, Swanson C, Picciano M. Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1991-2000. Am J Epidemiol 2004;160(4):339-349. 2. Kroll DJ. ASHP statement on the use of dietary supplements. Am J Health Syst Pharm. 2004; 61(16):1707-1711. 3. US Food and Drug Administration. Dietary supplement health and education act of 1994: public law 103-417. http://ods.od.nih.gov/about/ dshea_wording.aspx. Accessed May 5, 2011. 4. Office of Inspector General. Dietary supplement labels: key. Report OEI-01-01-00120. http://oig.hhs.gov/oei/reports/oei-01-01-00120. pdf. Accessed May 5, 2011. 5. Eisenberg DM, Davis RB, Ettner SL, et al. Trends in alternative medicine use in the United States, 1990-1997; results of a follow-up national survey. JAMA. 1998;280(18):1569-1575. 6. Brush M. Nov/Dec 2010. U.S. practitioner channel supplement sales & growth: 19992010e. http://newhope360.com/NovDec2010-US-Practitioner-Channel-SupplementSales-Growth-1999-2010e. 7. Kelly JP, Kaufman DW, Kelley K, Rosenberg L, Anderson TE, Mitchell AA. Recent trends in use of herbal and other natural products. Arch Intern Med. 2005;165(3):281-286. 8. Gardiner P, Graham RE, Legedza AT, Eisenberg DM, Phillips RS. Factors associated with dietary supplement use among prescription medication users. Arch Intern Med.

2006;166(18):1968-1974. 9. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Blumenthal M, ed. Austin, TX: American Botanical Council; 1998. 10. Dasgupta A. Prescription or Poison? 1st ed. Alameda, CA: Hunter House; 2010. 11. Fugh-Berman A. Herb-drug interactions. Lancet. 2000;355(9198):134-138. 12. Teschke R, Schulze J. Risk of kava hepatotoxicity and the FDA consumer advisory. JAMA. 2010;304(19):2174-2175. 13. Almeida JC, Grimsley EW. Coma from the health food store: interaction between kava and alprazolam. Ann Intern Med. 1996;125(11):940-941. 14. Chatzizisis YS, Koskinas KC, Misirli G, Vaklavas C, Hatzitolios A, Giannoglou GD. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf. 2010; 33(3):171-187. 15. Prasad GV, Wong T, Meliton G, Bhaloo S. Rhabdomyolysis due to red yeast rice (Monascus purpureus) in a renal transplant recipient. Transplantation. 2002;74 (8):1200-1201. 16. Naik SD, Freudenberger RS. Ephedra-associated cardiomyopathy. Ann Pharmacother. 2004; 38(3):400-403. 17. Debelle FD, Vanherweghem JL, Nortier JL. Aristolochic acid nephropathy: a worldwide problem. Kidney Int. 2008;74(2):158-169. 18. The University of Findlay, College of Pharmacy, Findlay, Ohio. On-Line Elective Course on Medicinal Herbs. (Contact person: Chandra M. Sekar, PhD, Associate Professor of Pharmaceutical Sciences, 300 Davis Street #108 Findlay, OH 45840.) http://www.findlay.edu/ directory/facstaff/S/sekar.htm?deptId=PHRM. This article was written by the authors in their private capacity and the views expressed do not necessarily reflect those of the VA or University of Findlay. No official support or endorsement by the VA or the University of Findlay is intended or should be inferred. The authors report no relevant conflicts of interest.


Visit the NEW

Late-breaking News Links to Other Therapeutic Areas

Online Buyer’s Guides

Medical Education Archives

Most Popular Articles & Reader Comments Tabbed Navigation Podcast Library

Digital Editions

Free CME

Su m

AS

Co Pre me vi r m ew M e e vi si arti eti tu cl ng s at e, p Iss bo ag oth e 6 ue #5 19

Most-read Articles From Sister Publications

pharmacypracticenews.com

The Pharmacist’s News Source Hematology/Oncology Pharmacy Edition

HP

Volume 38 • Number 5 • May 2011

Printer-friendly versions available online

Psychiatric Medication in this issue Error Rates Slashed Via Clinical Hem/Onc Pharmacy e-Prescribing Initiative Japan nuclear crisis shakes U.S. drug supply.

C

omputerized prescribing and error reporting systems combined to reduce the rate of medication mistakes in the psychiatric unit at an inner-city Baltimore hospital by more than 80%, report Johns Hopkins researchers. The findings, published in the March issue of the Journal of Psychiatric Practice Practice, represent the largest study to date evaluating such an intervention in the field and extend evidence of the benefit of electronic prescribing in reducing drug errors across all areas of medicine ((J Psychiatr Pract 2011;17:81-88). “Whenever there is a human interface with medication, there is a possibility of error,” said Geetha Jayaram, MD, MBA, associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, in Baltimore. Everything from indecipherable handwriting and inaccurate transcriptions, to miscalculations and administration mistakes, even

Opti

mize d for wide scr disp een lays

see DRUG ERRORS, page 71

14

Critical Care Statins in the ICU: ready for prime time?

Pain Medicine Pain contracts: are they really worth the hassle?

A

n advanced e-learning program offers pharmacists the opportunity to build the skills needed to be tomorrow’s clinical and management leaders, while also earning advanced credit toward master’s degree programs. The program is the result of an alliance between the ASHP Foundation’s Center for Health-System Pharmacy Leadership and GlobalHealth Education, an online educational services firm based in West Palm Beach, Fla. The initiative is an extension of efforts that began in 2008, when the center enrolled its first Pharmacy Leadership Academy (PLA) class. That first class came about in response to research that suggested a dramatic crisis in leadership within health-system pharmacy. “The world has only gotten more complicated

see ACADEMY, page 64

Helping Cancer Patients Quit Smoking Pays Off

28 52

Operations & Mgmt

Leadership in Action It shouldn’t be lonely at the top.

62

Technology

Telepharmacy Rural health-system reaps benefits of round-the-clock drug order review.

67

Policy

FDA Watch

Online Academy Prepares Future Pharmacy Leaders

A call to action for the profession

Finally, a new drug for melanoma approved.

72

Educational Reviews

Drug Interactions in Post-Kidney Transplant Patients See page

36

Optimizing Warfarin Therapy Insert after page

38

Quality-of-Life Implications for Patients With Hereditary Angioedema Who SelfAdminister C1 Inhibitor

Salt Lake City—Smokers who develop cancer may think it is too late to improve their health by kicking the habit. That is a dangerous misconception that caregivers need to correct, according to Jane Pruemer, PharmD, BCOP, professor of clinical pharmacy practice at the James L. Winkle College of Pharmacy, University of Cincinnati Barrett Cancer Center, in Ohio. “You really need to stress that if they continue to smoke, they are at a greater risk for developing a second

maligancy, worse outcomes in general and poorer quality of life [QoL] than patients who manage to quit.” But merely highlighting those risks is not enough. Pharmacists who encounter such patients “should consider it their duty to also help them quit,” Dr. Pruemer said at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA). In fact, quitting smoking can be one of the single most effective strategies to improve outcomes in

see QUIT SMOKING, page 9

In ER-positive breast cancer …

Presurgical Endocrine Therapy May Be Clue to Tumor Resistance Salt Lake City—The way a tumor responds to a short course of endocrine therapy given before scheduled surgery in women with estrogen receptor (ER)–positive breast cancer may predict how the malignancy will respond to long-term adjuvant

antiestrogen treatment, according to new research presented at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA). Just two weeks of treatment with letrozole in presurgical ER-positive

see BIOMARKERS, page 23

See page 32

New Product Watson to Launch Nulecit , a generic version of Ferrlecit

SEVENTH ANNUAL CONFERENCE

More Coverage: ✜ MTM program a boon to cancer patients

✜ Tips for enhancing rituximab safety, efficacy

See page

43

✜ Navigating cancer pain and drug dependency

11 12 22


44

Hem/Onc Pharmacy

Pharmacy Practice News • June 2011

In Focus

Dispensing Drugs Inside the Cancer Clinic: Who Benefits? A ‘We are creating conversations about side effects and what

s oral agents increasingly replace intravenous therapies for cancer, more and more oncologists are forced to send their patients outside the clinic to recieve treatments. But many practices are now trying to reel them back in, according to the Association of Community Cancer Centers (ACCC). In the May/June issue of ACCC’s Oncology Issues, the association highlights a panel discussion of the group’s

the patients can expect from their medications. It has been a differentiator [for our practice].’

—John Hennessy, MBA

dispensing pharmacy initiative, an educational program aimed at identifying when an in-house pharmacy is a good

idea and how it is best implemented. “The effort was to educate the membership on what

in Your Inbox ... to receive the monthly e-newsletter from

at www.pharmacypracticenews.com

Get the latest news delivered directly to your computer and PDA. The new interactive format has embedded Web site links that give you instant access to additional information as well as unique searching features and printing capabilities. Each installment contains brief summaries of the most important articles from the current month’s issue, and breaking news ahead of print.

Register for free @ www.pharmacypracticenews.com

goes into establishing a dispensing pharmacy, including the clinical, financial and operational aspects,” said panel moderator Steven L. D’Amato, RPh, BCOP, clinical pharmacy specialist at the Maine Center for Cancer Medicine, in Scarborough. The panel discussion was a follow-up to a 2010 survey on office-based dispensing conducted by a team led by Mr. D’Amato. The researchers interviewed 15 practices that either had begun dispensing or decided against it because of concerns about staffing, reimbursement or profit margins. (Not all clinics even have this option because states vary in their regulations for dispensing outside of pharmacies.) At the top of the list of advantages were improved convenience, education and safety for patients. Financial gains were also cited as a benefit by some practices, although most of the respondents indicated that they were not seeking a sigificant profit from drug dispensing. Still, all interviewees said that they were either breaking even or making a profit on the pharmacy operations, according to a report on the survey, which appeared in the September/October edition of Oncology Issues.

A Question of Counseling David H. Henry, MD, a medical oncologist at the Joan Karnell Cancer Center at Pennsylvania Hospital, in Philadelphia, opened an in-house pharmacy three years ago, in part to improve his patients’ access to in-depth education about their cancer medications. “There’s really no time or privacy to do the teaching necessary in many pharmacies,” said Dr. Henry, who was not involved in the ACCC initiative. “You can’t talk about breast or rectal cancer at the counter at CVS [a chain drugstore].” Dr. Henry added that he is pleased with the resulting changes to his practice. “Nurses can talk to patients about what’s bothering them, how the drug works, and any toxicities or complications to watch for,” he said. “A lot of teaching goes on.” This kind of patient education, which oncologists anticipate will lead to improved adherence, is one of the goals of dispensing closer to the point of care, noted Mr. D’Amato, who spoke during the panel discussion about his own experiences bringing drug dispensing in-house. However, not all pharmacists are convinced that the benefits outweigh their


Hem/Onc Pharmacy 45

Pharmacy Practice News • June 2011

In Focus costs. “We don’t have enough information about how oral cancer drugs are being provided from office practices,” said William Guss, PharmD, vice president at Aptium Oncology, Inc., in Los Angeles, which manages five comprehensive cancer programs. “The model varies from dispensing being an added responsibility of existing staff, to the addition of a pharmacist, to a nearly full-fledged pharmacy operation,” noted Dr. Guss, who was not involved in the ACCC initiative. Nevertheless, Dr. Guss suggested that “coupling provision of oral cancer drugs with the setting for cancer care” may do “clinical good” if the entire range of challenges is addressed, including medication handling and disposal, compliance and adherence, storage and security, and safety processes. Before opening their pharmacy, Dr. Henry’s practice considered many of the same factors as those surveyed—from patients’ benefit plans to the number and range of agents to carry. His office now dispenses cancer drugs as well as supportive agents such as antidepressants and anti-nausea medications. With hundreds of oral oncolytics in development, and with Medicare reimbursement rates for injectable drugs dwindling, the small revenue stream from bringing pharmacy in-house—“just above break-even,” in Dr. Henry’s case—can provide some help for struggling practices.

‘I also fear that the office-based dispensing model will contribute to an already fragmented provider network, where the patient is getting drugs and information from multiple sources.’ —Phil Johnson, MS, RPh, FASHP affairs at Albany College of Pharmacy and Health Sciences, in New York, voiced an additional concern. She said she worries about the “increasing fragmentation in patients’ drug regimens with office-

based pharmacies, mail-order mandates and specialty pharmacy companies, all of which circumvent the normal comprehensive medication review process that community pharmacists provide.”

A better approach, she said, would be “to ensure that our community-based pharmacists become more engaged with oncology practices.” Dr. Henry agreed that a stronger role for community pharmacy would be welcome. For pharmacies located near cancer clinics, he suggested putting aside private space for patient instruction and stocking the array of drugs that cancer patients may need. In fact, “if a lot of drugstores did what I’m doing—if they can address the special

see INSIDE JOB, page 46

Weighing the Financial Benefits The more drugs, the better the practice’s bottom line, data in the ACCC survey suggested. But what does it all mean for a patient’s pocketbook? The answer depends on the various practice sites in play. “If a patient was affiliated with a hospital participating in the 340B [federal drug discount] program, then the hospital’s retail pharmacy, or a contract retail pharmacy, could actually obtain expensive oral cancer drugs at a lower cost than a physician’s office [with an in-house pharmacy service],” noted Dr. Guss. Timothy Tyler, PharmD, director of pharmacy services for the Comprehensive Cancer Center at Desert Regional Medical Center, an Aptium center located in Palm Springs, Calif., cited a couple of potential downsides to office-based pharmacy services. If that service does not include a very involved and knowledgeable pharmacist with training in cancer care, for example, that could be a problem. “While an oncologist likely knows a lot about the drugs they prescribe, they might be less aware of potential drug interactions. Pharmacists have always been their “safety net,” he said. Moreover, any ownership in the pharmacy venture could change a physician’s prescribing behaviors, Dr. Tyler noted. Sarah Scarpace, PharmD, BCOP, assistant dean for pharmacy professional

A Responsive Leader in Anesthesia and Analgesia Responsiveness is our commitment to clinicians. APP Pharmaceuticals has continually demonstrated our dedication to meeting your clinical needs by supplying the market during times of critical shortages. We will continue to offer high-quality injectable pharmaceutical products that help provide affordable healthcare for your patients. This is the commitment we have demonstrated in the past and continue to live by. A trusted leader in injectable products See full prescribing information at www.APPpharma.com

®

APP and are trademarks of APP Pharmaceuticals, LLC. ©2011, APP Pharmaceuticals, LLC. All Rights Reserved. 0101-AAB-05-07/10

Medical Affairs 800.551.7176 www.APPpharma.com Customer Service 888.386.1300


46

Hem/Onc Pharmacy

Pharmacy Practice News • June 2011

In Focus

Another Look at Paclitaxel Premedication Salt Lake City–Premedicating breast cancer patients before each dose of paclitaxel may not be necessary if there has been no hypersensitivity reaction to the first two doses, according to new research presented at the Seventh Annual Conference of the Hematology/ Oncology Pharmacy Association. “It is well characterized in the literature that if you are going to have a hypersensitivity reaction with paclitaxel, it’s usually with the first couple of doses,” said Michael Berger, RPh, PharmD, specialty practice pharmacist at the James Care Comprehensive Breast Center, Ohio State University, in Columbus. “So we wanted to test that in our practice: What would happen if we stopped giving the premeds after the first two doses? Would patients be at any greater risk for hypersensitivity?” In the study, 55 patients received dexamethasone, diphenhydramine and famotidine prior to paclitaxel for the first two doses. If there was no hypersensitivity reaction, the premedications were discontinued for the third and all subsequent paclitaxel doses. The use of rescue medication for the treatment of hypersensitivity reactions was recorded for up to six cycles of paclitaxel. The study found that none of the 55 patients included in the primary analy-

sis required rescue medication, and none experienced a hypersensitivity reaction of any grade.

“In our study, there were 204 doses of paclitaxel administered without premedication, and zero patients had need for rescue medication. Our 95% confidence interval was zero to 6.5%,” Dr. Berger said. Interestingly, nine (13%) patients not included in the primary analysis with no hypersensitivity reaction felt that the side effects attributed to paclitaxel were ameliorated by premedication and requested that they be continued or resumed after stopping. “Our study had relatively small numbers of patients, but it was prospective,” Dr. Berger said. “For patients who inquire about the need for premedications, we feel comfortable offering this option after two doses. We tell them we can safely take away the meds that are causing sedation, or making them

Dr. Berger added that although there are alternatives to premedication, such as incorporation of a paclitaxel test dose, dexamethasone dose reduction or tapering over time, “our results suggest that simply stopping therapy is a more straighforward—and effective—option.”

INSIDE JOB

tor of the Kansas City Cancer Center in Overland Park and a participant in the ACCC dispensing pharmacy panel, said that in his state, an RPh or PharmD is required to be present during all opening hours of the practice. “If not, the phar-

pharmacy and its increasingly restricted distribution networks. “More and more cancer drugs—especially oral agents—are part of these networks and thus have to be dispensed from predetermined sites, such as community pharmacies, or are shipped directly to

continued from page 45

needs of cancer patients—then I would be less inclined to have a dispensing pharmacy,” he said. If there was true coordination with the oncology practice, a pharmacy could order expensive oral cancer drugs only when they are needed, saving inventory space, added Dr. Guss.

jittery and hyperactive, without necessarily putting them at any greater risk for hypersensitivity.

‘For patients who inquire about the need for [paclitaxel] premedications, we feel comfortable offering this option after two doses.’

—Michael Berger, RPh, PharmD

‘Exciting’ Research “It is quite exciting to see research conducted to improve the subjective experience and reduce medication side effects from ancillary treatments for patients receiving chemotherapy,” commented Polly E. Kintzel, PharmD, BCPS, BCOP, clinical pharmacy specialist for adult oncology at Spectrum Health Butterworth Hospital in Grand Rapids, Mich. But she expressed some caveats about applying the results too broadly in clinical practice.

“The data presented by Dr. Berger is not sufficiently robust to prompt universal adoption of this method,” Dr. Kintzel said. “However, the report is useful for providing guidance to clinicians managing patients who are tolerating infusions of paclitaxel without hypersensitivity reactions but are intolerant to the endocrine, anticholinergic, or other side effects of the premedications.” Laura Michaud, PharmD, manager, clinical pharmacy services at the University of Texas MD Anderson Cancer Center in Houston, also offered both congratulations and caution in commenting on the study. “I applaud the authors for their willingness to take a calculated risk and minimize unnecessary medications,” she told Pharmacy Practice News. “However, we need more information regarding the patient population they actually studied, as well as the impact on other side effects ameliorated with premedications, such as nausea, rashes and nail changes, and perhaps more patients before widespread adoption of this approach to paclitaxel administration is undertaken.” —Fran Lowry Drs. Berger, Kintzel, and Michaud report no relevant conflicts of interest.

multiple sources,” Mr. Johnson said. “I’m just not sure that’s the direction we need to be going in, if we want to ensure high quality and cost-effective care.” Mr. Hennessey took a different view. “The best benefit for our practice has been happy patients—pure and simple.

‘[Pharmacists are] best equipped to dispense and provide drug education.’

—Ernest R. Anderson Jr., MS, RPh

Is There a Pharmacist In the House? Ernest R. Anderson Jr., MS, RPh, system vice-president of pharmacy, Steward Health Care System, in Boston, stressed that if physician offices are considering bringing dispensing in-house, they should be looking to pharmacists to play a primary role. “We’re best equipped to dispense and provide drug education,” he said. “And there are plenty of physician practices that use pharmacists that could serve as a model.” If for some reason a practice still wants to rely on physicians or other non-pharmacist caregivers to dispense, Mr. Anderson reiterated the point “that it’s not always legal, depending on the state in which you operate.” John Hennessy, MBA, executive direc-

SEVENTH ANNUAL CONFERENCE

macy needs to be locked,” he said. As for the question of optimal staffing, Mr. Hennessy said he worked with his staff pharmacist to develop the program, but ultimately decided to go with an FTE pharmacist (RPh or PharmD) to handle the day-to-day drug dispensing.

More Caveats Phil Johnson, MS, RPh, FASHP, pharmacy advocacy director, Moffitt Cancer Center and Research Institute, in Tampa, Fla., said that any oncologist considering the pharmacy dispensing model should be aware of several challenges, not the least of which is the growth of specialty

patients via mail order,” he said. “So at the least, the physician practice simply may not be able to obtain the oral cancer drugs that it wants to prescribe and dispense. Or the practice will have to deal with the problematic issue of patients walking in with their own oral meds in a bag, presumably obtained from some type of specialty pharmacy, but with the attendant questions of pedigree, whether the drugs were stored properly, etc. So it may not be as streamlined a process as you might have initially envisioned.” Beyond those concerns, “I also fear that the office-based dispensing model will contribute to an already fragmented provider network, where the patient is getting drugs and information from

We are creating conversations about side effects and what the patients can expect from their medications. It has been a differentiator [for our practice].” As for overcoming the challenges posed by specialty pharmacy’s restricted distribution networks, Diane Gerards-Benage, CMPE, director of Medical Oncology at Quincy Medical Group, the Cancer Center at Blessing Hospital in Quincy, Ill., and another ACCC panel participant, suggested a potential solution: A physician practice can contract to become a specialty pharmacy, because that model “is where [increasing numbers of ] payers are sending their business.” —Lynne Peoples, David Bronstein


Visit the NEW

Late-breaking News Links to Other Therapeutic Areas

Online Buyer’s Guides

Medical Education Archives

Most Popular Articles & Reader Comments Tabbed Navigation Podcast Library

Digital Editions

Free CME

Su m

AS

Co Pre me vi r m ew M e e vi si arti eti tu cl ng s at e, p Iss bo ag oth e 6 ue #5 19

Most-read Articles From Sister Publications

pharmacypracticenews.com

The Pharmacist’s News Source Hematology/Oncology Pharmacy Edition

HP

Volume 38 • Number 5 • May 2011

Printer-friendly versions available online

Psychiatric Medication in this issue Error Rates Slashed Via Clinical Hem/Onc Pharmacy e-Prescribing Initiative Japan nuclear crisis shakes U.S. drug supply.

C

omputerized prescribing and error reporting systems combined to reduce the rate of medication mistakes in the psychiatric unit at an inner-city Baltimore hospital by more than 80%, report Johns Hopkins researchers. The findings, published in the March issue of the Journal of Psychiatric Practice Practice, represent the largest study to date evaluating such an intervention in the field and extend evidence of the benefit of electronic prescribing in reducing drug errors across all areas of medicine ((J Psychiatr Pract 2011;17:81-88). “Whenever there is a human interface with medication, there is a possibility of error,” said Geetha Jayaram, MD, MBA, associate professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, in Baltimore. Everything from indecipherable handwriting and inaccurate transcriptions, to miscalculations and administration mistakes, even

Opti

mize d for wide scr disp een lays

see DRUG ERRORS, page 71

14

Critical Care Statins in the ICU: ready for prime time?

Pain Medicine Pain contracts: are they really worth the hassle?

A

n advanced e-learning program offers pharmacists the opportunity to build the skills needed to be tomorrow’s clinical and management leaders, while also earning advanced credit toward master’s degree programs. The program is the result of an alliance between the ASHP Foundation’s Center for Health-System Pharmacy Leadership and GlobalHealth Education, an online educational services firm based in West Palm Beach, Fla. The initiative is an extension of efforts that began in 2008, when the center enrolled its first Pharmacy Leadership Academy (PLA) class. That first class came about in response to research that suggested a dramatic crisis in leadership within health-system pharmacy. “The world has only gotten more complicated

see ACADEMY, page 64

Helping Cancer Patients Quit Smoking Pays Off

28 52

Operations & Mgmt

Leadership in Action It shouldn’t be lonely at the top.

62

Technology

Telepharmacy Rural health-system reaps benefits of round-the-clock drug order review.

67

Policy

FDA Watch

Online Academy Prepares Future Pharmacy Leaders

A call to action for the profession

Finally, a new drug for melanoma approved.

72

Educational Reviews

Drug Interactions in Post-Kidney Transplant Patients See page

36

Optimizing Warfarin Therapy Insert after page

38

Quality-of-Life Implications for Patients With Hereditary Angioedema Who SelfAdminister C1 Inhibitor

Salt Lake City—Smokers who develop cancer may think it is too late to improve their health by kicking the habit. That is a dangerous misconception that caregivers need to correct, according to Jane Pruemer, PharmD, BCOP, professor of clinical pharmacy practice at the James L. Winkle College of Pharmacy, University of Cincinnati Barrett Cancer Center, in Ohio. “You really need to stress that if they continue to smoke, they are at a greater risk for developing a second

maligancy, worse outcomes in general and poorer quality of life [QoL] than patients who manage to quit.” But merely highlighting those risks is not enough. Pharmacists who encounter such patients “should consider it their duty to also help them quit,” Dr. Pruemer said at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA). In fact, quitting smoking can be one of the single most effective strategies to improve outcomes in

see QUIT SMOKING, page 9

In ER-positive breast cancer …

Presurgical Endocrine Therapy May Be Clue to Tumor Resistance Salt Lake City—The way a tumor responds to a short course of endocrine therapy given before scheduled surgery in women with estrogen receptor (ER)–positive breast cancer may predict how the malignancy will respond to long-term adjuvant

antiestrogen treatment, according to new research presented at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA). Just two weeks of treatment with letrozole in presurgical ER-positive

see BIOMARKERS, page 23

See page 32

New Product Watson to Launch Nulecit , a generic version of Ferrlecit

SEVENTH ANNUAL CONFERENCE

More Coverage: ✜ MTM program a boon to cancer patients

✜ Tips for enhancing rituximab safety, efficacy

See page

43

✜ Navigating cancer pain and drug dependency

11 12 22


W W W. BA X T E R . C O M

LIQUID & FROZEN PREMIX MEDICATIONS

1.888.229.0001

Consulting versus filling prescriptions. Optimizing new products versus existing processes. Spending more here versus spending less there. You weigh decisions

MINI-BAG PLUS CONTAINER SYSTEMS

like these every day.

VIAL-MATE ADAPTORS

Drug delivery from Baxter Healthcare Corporation can

MINI-BAG CONTAINERS

help you strike a balance between the give and take. And we do it by combining the right products and services

PHARMACYADVISOR.COM

to help you achieve a more effective relationship between

CONSULTING SERVICES

costs and benefits, custom and standard solutions, operational and clinical activities.

E-COMMERCE That’s the true value we bring. That’s how drug delivery from Baxter delivers more.

Medication Delivery

111335D 11/10


June 2011 digital edition of Pharmacy Practice News  

June 2011 digital edition of Pharmacy Practice News

Read more
Read more
Similar to
Popular now
Just for you