june 2011 digital edition of pharmacy practice news

T hree years after the U.S. Pharmacopeia (USP) issued a major revision to General

Chapter <797> concerning pharmaceutical com-pounding 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 well-publicized incidents of patient infections and deaths tied to contaminated products prepared at compounding pharmacies. Most recently, in March, nine patients at six Alabama hospi-tals 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

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 chemother-apy,” 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

Part 1 of a two-part series

Tainted TPN Cases Put Focus on <797> Rules

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

The standard methods for detecting adverse

events in hospitalized patients could be under-reporting the true inci-dence 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

New Reporting Tool May Provide Better Measure of Hospital Safety

A 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 require-ments and effectively treating their patients.

Fifteen states and the District of Columbia have approved medical usage of mari-juana and at least a dozen more are considering various stages of legisla-tion, according to the Marijuana Policy Project, a Washington, D.C.-based lob-bying organization. Meanwhile, phar-macists say they are facing more questions than answers. Among their concerns: what to do if a hospital patient brings in marijuana; what about medication reconcilia-tion and potential clinical interac-tions; 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 mari-juana policy during the group’s Summer Meeting. The policy was developed in

Pharmacists’ Role in Medical Marijuana Remains a Bit HazyASHP House of Delegates vote may yield more direction

Printer-friendly versions available online

c pharmacypracticenews.com The Pharmacist’s News Source Volume 38 • Number 6 • June 2011 cHematology/Oncology Pharmacy Edition

in this issue

Drug CostsHelping patients benefit from pharmaceutical assistance programs. 24Leadership in ActionListening: the first step on road to success. 30

Operations & Mgmt

Bar CodingThe clinical and business case for BCMA. 22

Technology

Quality ImprovementAccountable care organization initiatives gain momentum.

4

Policy

Practice PearlDietary supplements: a teaching opportunity for pharmacists. 33Hem/Onc PharmacyWhen drugs are dispensed from oncology offices, do patients benefit? 44Is it ever safe to stop premedicating paclitaxel patients? 46

Clinical

Managing Anemia in CKD PatientsInsert after page 8

Evolving Treatment Paradigms In NSCLCInsert after page 16

Educational Reviews

• see MARIJUANA, page 9

• see TAINTED TPN, page 7

• see NCI REPORT, page 17 •

see REPORTING TOOL, page 36

New Products

See page 19

FIRST® “Magic Mouthwash”

Compounding Kits from Cutis Pharma.

American Health Packaging launches three new unit-dose products, including

Donepezil 5 and 10 mg tablets.

UnSumm

it 2011

Coverage, page 22

Now Available from Sandoz

Argatroban Injectionin 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 drugsto the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088.

a Novartis companywww.us.sandoz.com

© 2011 Sandoz Inc.

SDZ0095

MCPPN2049.indd 1 5/12/11 5:27:54 PM

FDA Issues Final Guidance for Boosting Liquid OTC Drug Safety

The FDA has released its final guidance to companies that manufacture, market or distribute over-the-

counter (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, cough syrups and digestion aids.

The FDA issued the guidance because of continuing concerns about the potential unintended drug overdoses that can result from dosage delivery devices with markings that are confusing, unclear or inconsistent with the labeled dosage directions. Key recommendations in the guidance include:

• Dosage delivery devices should be included for all orally ingested OTC liquid drug products.

• Devices should be marked with calibrated units of measurement for liquids (e.g., teaspoon, tablespoon or milliliter) that are the same as the units of liquid measure specified in the directions for the product; there should not be any unnecessary markings.

• Manufacturers should ensure that dosage delivery devices are used only with the products with which they are 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, phar-macist or other health care professional.

—Staff

10 Safety Tips To Pass on to Patients1. Always read and follow the Drug Facts

label on your OTC medicine.

2. Know the “active ingredient” in your child’s medicine.

3. Give the right medicine, in the right amount, to your child.

4. Talk to your doctor, pharmacist or nurse to find out what mixes well and what doesn’t.

5. Use the dosing tool that comes with the medicine, such as a dropper or a dosing cup.

6. Know the difference between a tablespoon and a teaspoon.

7. Know your child’s weight.

8. Prevent a poison emergency by always using a child-resistant cap.

9. Store all medicines in a safe place.

10. Check the medicine three times.

Source: FDA

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.

JUNE 2011watch

surf

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

immunosuppressive medications, many also have

chronic medical conditions, suchas diabetes and hypertension, adding to the cost of their prescription drugs.’

—Marie Chisholm-Burns, PharmD

heardherefirst

See article, page 24

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.

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EDITORIAL BOARD

ADMINISTRATION

Robert Adamson, PharmD, Livingston, NJ

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

ANESTHESIOLOGy/PAIN

Julie A. Golembiewski, PharmD, Chicago, IL

Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY

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

BIOTECHNOLOGy

Indu Lew, PharmD, Livingston, NJ

CARDIOLOGy

C. Michael White, PharmD, Storrs, CT

CNS/PSyCHIATRy

Charles F. Caley, PharmD, Storrs, CT

Lawrence Cohen, PharmD, BCPP, FASHP, FCCP, Spokane, WA

Larry Ereshefsky, PharmD, San Antonio, TX

COMPLEMENTARy AND ALTERNATIvE MEDICINE

Cathy Rosenbaum, PharmD, Cincinnati, OH

CRITICAL CARE

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

INFECTIOUS DISEASES

Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH

Peggy McKinnon, PharmD, Detroit, MI

David P. Nicolau, PharmD, Hartford, CT

Robert P. Rapp, PharmD, Lexington, KY

INTERNAL MEDICINE

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

NUCLEAR PHARMACy

Jeffrey Norenberg, PharmD, Albuquerque, NM

ONCOLOGy

Robert T. Dorr, PhD, RPh, Tucson, AZ

Robert Ignoffo, PharmD, San Francisco, CA

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

Cindy O’Bryant, PharmD, Aurora, CO

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

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

PEDIATRICS

Gretchen Brummel, PharmD, BCPS, Hudson, OH

REIMBURSEMENT

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

TECHNOLOGy

Thomas Van Hassel, RPh, Yuma, AZ

EDITORIAL STAFFDavid Bronstein, Editorial Director [email protected]

Sarah Tilyou, Senior Editor [email protected]

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

Pharmacy Practice News • June 2011

Capsules

Up Front 3

A ccountable care organizations, or ACOs, are finally gaining momen-

tum. 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 Medi-care’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. Health-systems 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 fed-eral legislative affairs. “Pharmacists can play an integral role in ACOs through medication and chronic disease man-agement,” he said. “In addition, pharma-cists 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 coordi-nated care models that will satisfy ACO quality standards.

Steward Health Care System in Mas-sachusetts, 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 presi-dent 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 recon-ciliation 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

ACO Concept Is Gaining Traction

IMPORTANT SAFETY INFORMATION: Venofer® is contraindicated in patients with evidence of iron overload, inpatients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia notcaused 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-threateningreactions (anaphylactic shock, loss of consciousness or collapse, bronchospasm with dyspnea, or convulsion) associated withVenofer® administration.

Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receivingIV 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 toVenofer® 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 treatedNDD-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%).

Over 9 million patients treatedwith 180 million units*1

12

240

First-line IV iron for adultpre-dialysis CKD patients...In treatment of iron deficiency anemia

• Raises hemoglobin levels and improves iron stores2

• 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-dialysisdependent-chronic kidney disease patients whether or notreceiving an erythropoietin.Contraindicated in patients with evidence of iron overload, inpatients with known hypersensitivity to Venofer ® or any of itsinactive components, and in patients with anemia not causedby iron deficiency. Serious hypersensitivity reactions havebeen reported in patients receiving Venofer ®.

Take IV iron therapy to a proven place:

Responsewith toleration!

*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 Leading anemia management.™

Millions prescribed. Millions treated.™


Quality Improvement

4 Policy

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 sys-tem signed an Alternative Quality Con-tract with Blue Cross Blue Shield of Massachusetts. The agreement prom-ises performance-based incentives for meeting nationally recognized measures of quality, efficiency and patient experi-ence. Mr. Anderson said the first-year

results of the program will not be recon-ciled until later this summer.

Other CMS pilot programs have shown that ACO-style provider–hospital net-

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

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 coor-dination; patient–caregiver experiences; patient safety; preventive health; and care for the frail, elderly population. The

‘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

• see ACO CONCEPT, page 15

IMPORTANT SAFETY INFORMATION: Venofer® is contraindicated in patients with evidence of iron overload, inpatients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia notcaused 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-threateningreactions (anaphylactic shock, loss of consciousness or collapse, bronchospasm with dyspnea, or convulsion) associated withVenofer® administration.

Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receivingIV 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 toVenofer® 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 treatedNDD-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%).

Over 9 million patients treatedwith 180 million units*1

12

240

First-line IV iron for adultpre-dialysis CKD patients...In treatment of iron deficiency anemia

• Raises hemoglobin levels and improves iron stores2

• 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-dialysisdependent-chronic kidney disease patients whether or notreceiving an erythropoietin.Contraindicated in patients with evidence of iron overload, inpatients with known hypersensitivity to Venofer ® or any of itsinactive components, and in patients with anemia not causedby iron deficiency. Serious hypersensitivity reactions havebeen reported in patients receiving Venofer ®.

Take IV iron therapy to a proven place:

Responsewith toleration!

*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 Leading anemia management.™

Millions prescribed. Millions treated.™


Quality Improvement

Policy 5

Brief Summary (See Package Insert For Full Prescribing Information)Therapeutic Class: HematinicCLINICAL INDICATIONS AND USAGEVenofer® (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 erythropoietinCONTRAINDICATIONSThe 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 patientswith anemia not caused by iron deficiency.WARNINGSHypersensitivity reactions have been reported with injectable iron products. See PRECAUTIONS and ADVERSE REACTIONS.PRECAUTIONSGeneral: 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 oftissue 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 valuesmay 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 theclinical studies. Several cases of mild or moderate hypersensitivity reactions were observed in these studies. There are post-marketing spontaneous reports of life-threateninghypersensitivity 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 innon-dialysis dependent and peritoneal dialysis dependent-chronic kidney disease patients receiving intravenous iron. Hypotension following administration of Venofer® may be relatedto 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 mousemicronucleus 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 andreproductive 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 bodysurface 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 noevidence 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 reproductionstudies 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 beexercised 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, fivepremature 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 othermedications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer® or any other drugscould 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 betweenthe elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.ADVERSE REACTIONSAdverse Events observed in all treated populationsThe frequency of adverse events associated with the use of Venofer® has been documented in six randomized clinical trials involving 231 hemodialysis dependent, 139 non-dialysisdependent 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 1,496patients. In addition, over 2,000 patients treated with Venofer® have been reported in the medical literature.

(Table 2 continued) (Table 3 continued)

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 tastedisturbance (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® withvarying 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 occurredin 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 orcollapse, bronchospasm with dyspnea, or convulsion) associated with Venofer® administration.OVERDOSAGEDosages 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 parameterssuch 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 discontinuedwhen serum ferritin levels equal or exceed established guidelines [1]. Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment has beenincorrectly 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 andmuscle pain, edema, and cardiovascular collapse. Most symptoms have been successfully treated with IV fluids, hydrocortisone, and/or antihistamines. Infusing the solution asrecommended 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 ADMINISTRATIONThe 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 responseand 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 IVinjection 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 maximumof 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 Dependent-Chronic Kidney Disease (NDD-CKD) Patients and ADVERSE REACTIONS, Adverse Events Observed in Non-Dialysis Dependent-Chronic Kidney Disease (NDD-CKD) Patients sections.)HOW SUPPLIEDVenofer® 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 (20mg/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.SterileNDC-0517-2340-01 100 mg/5 mL Single Dose Vial Individually Boxed NDC-0517-2310-01 200 mg/10 mL Single Dose Vial Individually BoxedNDC-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 5NDC-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 OnlyREFERENCE: [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 VENJARev.5/10 Rev.5/2010Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2010 American Regent, Inc

NDD-CKDAdverse Events Venofer® Oral Iron(Preferred Term) (N=139) (N=139)

% %Musculoskeletal and Connective Tissue DisordersBack pain 2.2 3.6Muscle cramp0.7 0.7Myalgia 3.6 0Pain in extremity 4.3 0Nervous System DisordersDizziness 6.5 1.4Headache 2.9 0.7Hypoesthesia 0.7 0.7Respiratory, Thoracic and Mediastinal DisordersCough 2.2 0.7Dyspnea 3.6 0.7Dyspnea exacerbated 2.2 0.7Nasal congestion 1.4 2.2Pharyngitis 0 0Rhinitis allergic NOS 0.7 2.2Skin and Subcutaneous Tissue DisordersPruritus 2.2 4.3Rash NOS 1.4 2.2Vascular DisordersHypertension NOS 6.5 4.3Hypotension NOS 2.2 0.7

NDD-CKDAdverse Events 200 mg 500 mg(Preferred Term) (N=109) (N=30)

% %Subjects with any adverse event 23.9 20.0Gastrointestinal DisordersDiarrhea NOS* 0 0Dysgeusia 7.3 3.3Nausea 2.8 0

General Disorders and Administration Site ConditionsInfusion site burning 3.7 0Injection site pain 2.8 0Peripheral edema 1.8 6.7

Nervous System DisordersDizziness 2.8 6.7Headache 2.8 0

Vascular DisordersHypotension NOS 0 6.7


% %Musculoskeletal and Connective Tissue DisordersPain in extremity 4.6 3.3Nervous System DisordersDizziness 5.5 10.0Headache 3.7 0Respiratory, Thoracic and Mediastinal DisordersCough 0.9 6.7Dyspnea 1.8 10.0Pharyngitis 0 0Skin and Subcutaneous Tissue DisordersPruritus 0.9 6.7Vascular DisordersHypertension NOS 6.4 6.7Hypotension NOS 0.9 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)


NDD-CKDAdverse Events Venofer® Oral Iron(Preferred Term) (N=139) (N=139)

% %Subjects with any adverse event 76.3 73.4Ear and Labyrinth DisordersEar Pain 2.2 0.7Eye DisordersConjunctivitis 0 0Gastrointestinal DisordersAbdominal pain NOS* 1.4 2.9Constipation 4.3 12.9Diarrhea NOS 7.2 10.1Dysgeusia 7.9 0Nausea 8.6 12.2Vomiting NOS 5.0 8.6General Disorders and Administration Site ConditionsAsthenia 0.7 2.2Chest pain 1.4 0Edema NOS 6.5 6.5Fatigue 3.6 5.8Feeling abnormal 0 0Infusion site burning 3.6 0Injection site extravasation 2.2 0Injection site pain 2.2 0Peripheral edema 7.2 5.0Pyrexia 0.7 0.7Infections and InfestationsCatheter site infection 0 0Nasopharyngitis 0.7 2.2Peritoneal infection 0 0Sinusitis NOS 0.7 0.7Upper respiratory tract infection NOS 0.7 1.4Urinary tract infection NOS 0.7 5.0Injury, Poisoning and ProceduralComplicationsGraft complication 1.4 0InvestigationsCardiac murmur NOS 2.2 2.2Fecal occult blood positive 1.4 3.6Metabolism and Nutrition DisordersFluid overload 1.4 0.7Gout 2.9 1.4Hyperglycemia NOS 2.9 0Hypoglycemia NOS 0.7 0.7Musculoskeletal and Connective Tissue DisordersArthralgia 1.4 2.2Arthritis NOS 0 0


% %Subjects with any adverse event 75.2 80.0Ear and Labyrinth DisordersEar Pain 0.9 6.7Eye DisordersConjunctivitis 0 0Gastrointestinal DisordersAbdominal pain NOS* 1.8 0Constipation 3.7 6.7Diarrhea NOS 6.4 10.0Dysgeusia 9.2 3.3Nausea 9.2 6.7Vomiting NOS 5.5 3.3General Disorders and Administration Site ConditionsAsthenia 0.9 0Chest pain 0.9 3.3Edema NOS 7.3 3.3Fatigue 4.6 0Feeling abnormal 0 0Infusion site burning 3.7 3.3Injection site pain 2.8 0Peripheral edema 5.5 13.3Pyrexia 0.9 0Infections and InfestationsCatheter site infection 0 0Nasopharyngitis 0.9 0Peritoneal infection 0 0Sinusitis NOS 0 3.3Upper respiratory tract infection NOS 0.9 0Injury, Poisoning and ProceduralComplicationsGraft complication 1.8 0InvestigationsCardiac murmur NOS 2.8 0Fecal occult blood positive 1.8 0Metabolism and Nutrition DisordersFluid overload 1.8 0Gout 1.8 6.7Hyperglycemia NOS 3.7 0Hypoglycemia NOS 0.9 0Musculoskeletal and Connective Tissue DisordersArthralgia 0.9 3.3Back pain 1.8 3.3Muscle cramp 0 3.3Myalgia 2.8 6.7

Treatment-emergent adverse events reported by 2% of treated patients with NDD-CKD 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 SafetyPopulation)

Treatment-emergent adverse events reported in 2% of patients by dose groupare shown in Table 3.

Table 3. Most Common Treatment-Emergent Adverse Events Reported in2% of Patients with NDD-CKD by Dose Group

(Multidose Safety Population)

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.

pharmacy in Birmingham, Ala., that used a tap water spigot to rinse a mix-ing 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 hap-pening, 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 require-ments, Mr. Kastango reviewed the Ala-bama incident and seven other cases in which patients became infected with Serratia and other pathogens. He cited a recent survey in which 34% of phar-macy directors at more than 400 health systems nationwide reported experi-encing at least one patient incident due to compounding errors during the pre-vious five years.

“That’s a terrifying statistic,” Mr. Kas-tango said. “There are lots of systems and processes in <797> designed to pre-vent this from happening,” he said dur-ing 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 “prob-ably 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, sup-plies, equipment or failure of engineering controls.

The revised chapter separates sampling into facility- and personnel-related metrics. In the former, viable (microbial) air testing via volumet-ric (impaction) methods must occur as part of the commissioning and cer-tification of facilities and equipment; following any ser-vicing or major change, such as when a hood or isolator is installed or moved; and as part of the semian-nual recertification process.

Personnel fingertip sampling should be done during initial training and also accompanying media fills to assess employee competency, another chapter

requirement. “We know that person-nel 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 employ-ees must successfully don sterile gloves three times with zero colony-forming 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 disinfec-tion, another competency requirement. Growth media for bacteria include soy-bean-casein digest media (trypticase soy broth/agar); fungi can be cultured via malt extract agar or other media.

TAINTED TPNcontinued from page 1

‘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

• see TAINTED TPN, page 8

Table. CFU Identification and Sources

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; clothing-borne, 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)

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.

Table. CFU Identification and Sources

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; clothing-borne, 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)

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.


Chapter <797> Compliance

Policy 7

One pending change to Chapter <797> would require use of both bacterial and fungal growth-supporting media in all compounding environments, regard-less of risk level. “We have to be con-cerned 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, gown-ing and cleaning. Sampling is required during initial facility commissioning and then semiannually for all risk lev-els. Doing it more frequently will pro-vide earlier detection of problems.

“Environmental sampling is a snap-shot 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 fre-quently will allow you to do that.”

Problems With PaddlesSettling plates and paddles are com-

monly used for air sampling, but they have limitations: They are not qualita-tive 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 labo-ratory director at Microbiology Spe-cialists Inc., a reference laboratory she cofounded in Houston. “There is not enough surface area and they are not manufactured with the same media for-mulation as are used in the round sur-face 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 clean-ing. “Isopropyl alcohol is not the end-all, be-all,” Mr. Kastango said. ISA is disin-fectant, 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 insuf-ficient. “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-effec-tive cleaners formulated with accelerated hydrogen peroxide. Even the old stand-by, sodium hypochlorite bleach, is still one of the primary appropriate cleaners because it inactivates many pathogens, including spores, and is effective in deac-tivating some hazardous drugs.

“But even with bleach, you need a sur-factant—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, depend-ing on the concentration. The choice to use it in primary engineering con-trols 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 appro-priate 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 moni-tored so they continue to do it properly.”

—Ted Agres

Next Month: ISMP urges more over-sight 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.

P urdue University’s College of Phar-macy has developed a three-dimen-

sional (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 educa-tion, according to the instructors—was to enhance the students’ ability to con-fidently follow the sterile-compounding requirements. Another important aim was for students to gain a better under-standing of the extent to which a typical hospital is at risk for making errors dur-ing 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 Edu-cation (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 com-pleted the program said they disagreed with the notion that the risk for a highly skilled pharmacist making a sterile com-pounding error was low, compared with a baseline pre-assessment.

The virtual clean room learning option was offered as a voluntary add-on to a conventional, classroom-based course on parenteral products, Dr. Patel noted. She explained that although stu-dents were happy with that course, which includes some hands-on lab ses-sions on IV admixtures, many of them expressed concerns about the prospect of actually preparing IV medications in a real-world setting—for example, dur-ing 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 condi-tions, 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 interac-tive via images that are projected on several wall-sized panels and computer screens. Students used 3-D eyeglass-es and a wireless controller to navi-gate 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 vir-tual sessions, including product veri-fication, 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 expe-rience in handling look-alike/sound-alike 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 mark-ers of successful learning emerged. For example, 92% of the participating students who went on to an APPE pro-gram said the virtual classroom helped prepare them for that real-world expe-rience by enhancing their understand-ing 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 class-room increased student confidence when working in an IV room, and fos-tered a greater appreciation for the role pharmacists have in promoting safe IV product preparation.”

—David Bronstein

virtual Clean Room Boosts USP <797> Learning

TAINTED TPNcontinued from page 7

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


Chapter <797> Compliance

8 Policy

Managing Anemia in Patients With Chronic Kidney Disease

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.

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

AMY E. LODOLCE, PHARMD, BCPS Assistant Director

Drug Information Group University of Illinois at Chicago

College of PharmacyChicago, Illinois

Chronic 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.

r

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1INDEPEND ENT LY DEVELOPED BY MCMAHON PUBL ISHING PHARMACY PRACTICE NEWS • JUNE 201 1

PRINTER-FRIENDLY VERSION AT PHARMACYPRACTICENEWS.COM

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 for iron.7 In the KDOQI guidelines, the goal serum ferritin level is greater than 100 ng/mL (>200 ng/mL in patients undergoing dialysis), and the target transferrin saturation is greater than 20%.4

Treatment ApproachesIron therapy and ESAs are the mainstay of

therapy for treatment of anemia in patients with CKD.4 The latest guidelines from the KDOQI initiative were published in 2006, with an update relating to target hemoglobin levels published in 2007 in response to literature regarding ESA therapy (see below).8

According to the guidelines, clinicians must choose the target hemoglobin level and the level at which ESA therapy is initiated

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 inexpensive and easy to administer; however, there are some limitations to its use.9 Gastrointestinal (GI) adverse events (AEs) such as constipation, dyspepsia, bloating, nausea, diarrhea, and heartburn may affect up to 20% of patients. These GI effects can be

minimized if iron supplements are taken with food, but the presence of food will decrease iron

absorption. Furthermore, absorption may be impaired by the use of phosphate binders

or acid suppressive therapy, and the use of ESAs can increase the demand for iron beyond the amount that can be given orally. Proper adherence to the prescribed regimen also is a concern because of frequent dosing requirements (often 3 times per day) and GI effects. Finally, the presence of hepcidin (produced by the liver

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INDEPENDENT LY DEVELOPED BY MCMAHON PUBL ISHING2

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 all-cause 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,

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

Table 1. KDOQI Classification of CKD

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.

INDEPENDENTLY DEVELOPED BY MCMAHON PUBL ISHING 3

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 cancer-associated 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

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 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 ana-phylaxis, a test dose is required prior to the first therapeutic dose.

• Resuscitative medication and personnel should be avail-able 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 hypo-tension 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 mgNon-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 relative-ly well tolerated and may be given rapidly.

• There are no published com-parative studies with other IV iron preparations.

ESAs, erythropoietin-stimulating agents

Based on references 4,10, and 11-14.


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, double-blind, 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

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.


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.

ConclusionAppropriate management of anemia in patients with

CKD requires iron supplementation and ESA therapy.

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 Uro-logic 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 recom-mendations 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 man-agement of anemia in chronic kidney disease. Clin Med Res. 2008;6(3-4):93-102.

6. Besarab A, Coyne DW. Iron supplementation to treat ane-mia 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 Pathophysiolog-ic 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.kid-ney.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 treat-ment 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 ane-mia 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.

13. Venofer [package insert]. Shirley, NY: American Regent; 2010.

14. Feraheme [package insert]. Lexington, MA: AMAG Pharmaceuti-cals; 2010.

15. FDA. Information for healthcare professionals: erythropoiesis stim-ulating agents (ESA) [Aranesp (darbepoetin), Eopgen (epoetin alfa), and Procrit (epoetin alfa)] (3/2007). http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatient-sandProviders/ucm126485.htm. Accessed May 17, 2011.

16. FDA. FDA strengthens boxed warnings, approves other safe-ty labeling changes for erythropoiesis-stimulating agents (ESAs). http://www.fda.gov/NewsEvents/Newsroom/PressAnnounce-ments/2007/ucm109024.htm. Accessed May 17, 2011.

17. FDA. Information on erythropoiesis-stimulating agents (ESA) epo-etin alfa (marketed as Procrit, Epogen) darbepoetin alfa (marketed as Aranesp). Safety announcement. http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandpro-viders/ucm109375.htm. Accessed May 17, 2011.

18. Singh AK, Szczech L, Tang KL, et al. Correction of ane-mia 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 hemo-globin 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 eryth-ropoiesis-stimulating agents in patients undergoing maintenance dialysis. Semin Dial. 2010;23(5):486-491.


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Evolving Treatment Paradigms inNon-Small Cell Lung Cancer

Although locally resectable NSCLC can be cured with surgical intervention, very few patients present with early-stage disease. Unfortunately, the majority pres-ent with advanced (stages IIIB and IV) disease; sur-gery 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

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 surviv-al times from 8 to 11 months in patients treated with standard doublet chemotherapy regimens.2 The addi-tion of biologic agents and efforts to focus their use

CALEB T. CHU, MD, MPHPostdoctoral Fellow

Department of Thoracic/Head and Neck Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, Texas

MARGARET E. M. VAN METER, MDMedical Oncology Fellow

Division of Cancer MedicineThe University of Texas

MD Anderson Cancer CenterHouston, Texas

EDWARD S. KIM, MDAssociate Professor of Medicine

Department of Thoracic/Head and Neck Medical Oncology

The University of Texas MD Anderson Cancer Center

Houston, Texas

Lung 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.

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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 reg-imens 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 treat-ment strategies evolve and chemotherapies and bio-logic therapies are being increasingly integrated, a more personalized approach should be used to pro-vide the most effective and least toxic treatments to patients with advanced NSCLC.

Conventional ChemotherapyPlatinum-based doublet regimens are the mainstay

of chemotherapy in patients with advanced NSCLC and a good performance status (PS). The survival ben-efit of cisplatin in the treatment of NSCLC was estab-lished 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, cispla-tin-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 chemother-apy 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 treat-ments. To this end, trials have evaluated the use of newer agents, either as monotherapy or in combina-tion regimens, as well as the use of carboplatin in lieu of cisplatin in doublet regimens.

In comparisons of platinum-based doublets, 2 vari-ables must be considered: the platinum agent used (cis-platin 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-pacli-taxel with 3 other regimens—carboplatin-paclitaxel, cisplatin-docetaxel, and cisplatin-gemcitabine—in 1,155 patients with advanced NSCLC showed no significant difference in OS (median 7.9 months) among the 4 reg-imens.6 It is notable, however, that patients in the carbo-platin-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-gem-citabine.7 A statistically significant survival advantage was demonstrated for patients with adenocarcinoma or large-cell carcinoma histology treated with cispla-tin-pemetrexed compared with cisplatin-gemcitabine

(median OS, 11.8 and 10.4 months, respectively; haz-ard ratio [HR], 0.81; 95% confidence interval [CI], 0.70-0.94; 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 TherapiesWith 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 admin-istration 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 fac-tor (VEGF) antibody bevacizumab (Avastin, Genen-tech) in patients with advanced nonsquamous NSCLC.3 Treatment in the experimental arm includ-ed bevacizumab combined with chemotherapy every 3 weeks for 6 cycles, followed by maintenance beva-cizumab every 3 weeks until progressive disease or intolerable side effects occurred. Median OS, the pri-mary 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 pro-gression-free survival (PFS; 6.2 vs 4.5 months) also were observed.

The pivotal FLEX (First-Line Erbitux in Lung Can-cer) 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 EGFR-expressing 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-vinorel-bine alone (HR, 0.871; 95% CI, 0.762-0.996; P=0.044). Prespecified subgroup analysis showed that the sur-vival 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 predic-tors 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 com-bined effects. The SWOG (Southwest Oncology Group) 0536 Phase II study combined 4 drugs—cetux-imab, bevacizumab, carboplatin, and paclitaxel—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% inci-dence 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 chemo-therapy. Two additional Phase III studies, INTEREST (Ires-sa NSCLC Trial Evaluating Response and Survival against Taxotere) and IPASS (First-line Iressa versus Carboplatin/Paclitaxel in Asia), compared single-agent biologic ther-apy using the oral EGFR tyrosine kinase inhibitor (TKI) gefitinib (Iressa, AstraZeneca) with traditional chemo-therapeutic 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 biop-sies 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 pri-mary end point was PFS; median PFS was similar in those treated with gefitinib and those treated with car-boplatin-paclitaxel (5.7 vs 5.8 months), but the Kaplan-Meier 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 gefi-tinib and carboplatin-paclitaxel, but gefitinib demon-strated 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 asso-ciated with responsiveness to erlotinib (Tarceva, OSI Pharmaceuticals).14 These findings indicate that genet-ic screening of patients prior to therapy may be war-ranted to allow clinicians to tailor therapy to individual patients. The study results also highlight a need for a par-adigm shift toward molecular profiling in the treatment of advanced NSCLC to improve tolerability of therapy.

Maintenance TherapyDebate continues about delayed (second- or third-

line) 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 chemothera-py in advanced NSCLC (Table).4,15-21 Maintenance che-motherapy 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 dis-ease progression after first-line treatment with 4 cycles of carboplatin-gemcitabine were randomized to receive docetaxel either immediately or at disease progres-sion.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 thera-py 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 plat-inum-based doublet chemotherapy in 1,949 patients with advanced NSCLC. The SATURN trial met its prima-ry end point of PFS, with results showing significant-ly 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 ben-efit was seen in a subset of patients who had EGFR mutations. Based on this information, in April 2010, the FDA approved erlotinib for maintenance treat-ment of patients with advanced or metastatic NSCLC whose disease has not progressed after 4 cycles of


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 plat-inum-based first-line chemotherapy). This trial included 663 patients with advanced NSCLC who did not prog-ress 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, 0.65-0.95; 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 Peme-trexed’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 non–cross-resistant regimens, the ATLAS Phase III trial evaluated bevacizumab with or without erlotinib after completion of chemotherapy with bevacizum-ab for first-line treatment of advanced NSCLC.21 This study, the first to evaluate combination versus single-agent maintenance therapy options, showed significant improvement in PFS in the group receiving combina-tion therapy (4.8 vs 3.7 months; HR, 0.722; 95% CI, 0.592-0.881; P=0.0012).

Biomarkers and TherapyAs discussed above, many of the recent advances

in the treatment of NSCLC have involved the integra-tion of targeted therapeutics and can more accurate-ly define the subset of patients who are most likely to benefit from a given treatment. Thus, it is more impor-tant now than ever before to explore predictors of effi-cacy to help direct the best therapy for each patient. In clinical practice, factors such as smoking history,

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 highlight-ed clearly for the use of pemetrexed in the treat-ment of advanced NSCLC in multiple settings. The large study by Scagliotti et al described above found that patients with nonsquamous tumors had a sur-vival advantage when treated first-line with cispla-tin-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 peme-trexed 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 nonsqua-mous histology.4

One possible explanation for the observed differ-ential efficacy of pemetrexed is that baseline thymi-dylate 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 pre-sented at the ASCO meeting in 2009, significant-ly higher median mRNA and protein TS levels were detected in large cell and squamous cell carcinoma

Table. Selected Trials of Maintenance Therapy in Advanced NSCLC

Clinical Trial Treatment Arms N PFS, mo Median OS, mo

Fidias et al19 GC, then immediate docetaxelGC, then delayed docetaxel

309 5.7 (P=0.001)2.7

12.3 (P=0.0853)9.7

Capuzzo et al20

(SATURN)CT, then ECT, then P

438451

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

1211

Ciuleanu et al4

Pemetrexed + BSCP + BSC

441222

Overall/NSQ/SQ4.3/4.5/2.82.6/2.6/2.6

Overall/NSQ/SQ13.4/15.5/9.910.6/10.3/10.8

Miller et al21

(ATLAS)CT + B, then B + PCT + B, then B + E

768 3.7 (P=0.0012)4.8

NA

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


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 epider-mal 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 Approx-imately 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 asso-ciated 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 erlo-tinib in the SATURN trial, KRAS mutations had no pre-dictive value.20

BROADER GENOTYPE TESTING

With the emergence of EGFR mutations as an impor-tant target for therapy, strategies for treating patients harboring other mutations that make them refracto-ry 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 tyro-sine 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 particular-ly 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 EML4-ALK 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 rearrange-ments, 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.


Adenocarcinoma or nonsquamousAdenocarcinoma or nonsquamous SquamousSquamous

EGFR mutation- positiveEGFR mutation- positive

EGFR mutation- negative or unknownEGFR mutation- negative or unknown

GefitinibErlotinibGefitinibErlotinib

Bevacizumab + chemotherapy doubleta

Bevacizumab + chemotherapy doubleta

Non-bevacizumab chemotherapy doublet (pemetrexed-based)a

Non-bevacizumab chemotherapy doublet (pemetrexed-based)a

Chemotherapy doublet with or without cetuximaba

Chemotherapy doublet with or without cetuximaba

Disease progressionDisease progression

• Salvage therapy• Consider clinical trial• Salvage therapy• Consider clinical trial

Maintenance therapyMaintenance therapy

• Pemetrexeda

• Erlotinib with or without bevacizumab• Docetaxel

• Pemetrexeda

• Erlotinib with or without bevacizumab• Docetaxel

Figure. Proposed algorithm for treatment of NSCLC. a FDA-approved regimens

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

Another active area of research centers on mecha-nisms of resistance to EGFR TKIs, including amplifica-tion of the MET oncogene and secondary mutations in EGFR, such as the T790M mutation. Molecular test-ing for these abnormalities may eventually play a role in treatment selection. A recent Phase II study com-paring 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 thera-py.37 However, patients with a low expression of MET fared worse on combination MET-erlotinib versus erlo-tinib alone, leading to future investigations into the possible interference of METMAb with erlotinib’s effec-tiveness. ARQ 197 is another MET-inhibiting target-ed 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 pla-cebo indicated a greater median PFS in the experi-mental arm (16.1 vs 9.7 weeks), with similar adverse effects between the 2 arms.

On another molecular front, there has been increas-ing interest involving irreversible EGFR inhibitors, main-ly 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-acti-vating 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 stud-ies are under way investigating use of BIBW 2992 in NSCLC patients in other treatment settings.

ConclusionParadigms 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 manage-ment in advanced NSCLC must be considered, evalu-ating 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 tar-geting EGFR, VEGF, and ALK pathways in NSCLC have

demonstrated that different lung cancers respond dif-ferently to therapy. Efforts must continue to be made to understand the biology of individual tumors by empha-sizing tissue-based clinical trials to create patient-spe-cific 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 compar-ing 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 chemo-therapy 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, paclitax-el, cetuximab and bevacizumab followed by cetuximab and bevacizumab maintenance in advanced non-small cell lung can-cer (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 previous-ly 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 carboplatin-paclitaxel 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.

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.

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.

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 double-blind, 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 bevacizum-ab (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–small-cell 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 peme-trexed 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 mes-senger 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.

26. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsive-ness 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 can-cer: 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 associ-ated 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.

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.

31. Morgillo F, Kim WY, Kim ES, Ciardello F, Waun KH, Lee HY. Implica-tion 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.

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 transform-ing 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 lympho-ma 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. Present-ed 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 197-209: a global randomized placebo-controlled phase II clinical trial of erlotinib plus ARQ 197 versus erlotinib plus placebo in previ-ously 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: Personaliz-ing Therapy for Lung Cancer. Cancer Discovery 2011;1:OF42-OF51.


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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 profes-sional 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 work-ing 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 criminal-ized. 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,

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 mari-juana], 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 nau-sea. “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?”

Providing Guidance

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

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 ques-tions. Among the organization’s recom-mendations are the following:

• Develop processes that could pro-vide standardized marijuana to facili-tate research efforts.

• Encourage the Drug Enforcement Administration to eliminate barriers

prohibiting marijuana research, includ-ing 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 meet-ing 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 tak-en 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 pharma-cy 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 phar-macist 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 pharma-cist 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.”

Practice Uncertainties

Among the states that have legal-ized marijuana for medical use, there’s considerable variability regarding spe-cifics, including whether at-home cul-tivation is permitted, as well as which

MARIJUANAcontinued from page 1

‘[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

• see MARIJUANA, page 10

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.


Pain Medicine

Policy 9

medical conditions are covered. Nearly all of the states require the user to carry an identification card. For more state-by-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 appli-cations in mid-April, hospitals can ver-ify 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 monitor-ing 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 prod-uct 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 oth-er 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 rea-son, ASHP officials questioned if medical marijuana would need to be reclassified from Schedule I to Schedule II to facili-tate research.

In the meantime, the clinical uncer-tainties 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.

And we don’t know how it might inter-act 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-

therapy room, Ms. Levy said.When compiling a list of patient

medications, clinicians don’t ask spe-cifically 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 phar-macists 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 spec-ify 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 interac-tions 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 dronabi-nol (Marinol, Unimed Pharmaceuticals, Inc.), an FDA-approved drug therapy that contains tetrahydrocannabinol (THC), the main psychoactive sub-stance 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 medi-cine patients at Moffitt about mari-juana 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 medici-nally, can cause immune suppression

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

‘[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: Scan for More Resources

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

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

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

MARIJUANAcontinued from page 9


Pain Medicine

10 Policy

and increase the risk for infections and even some types of cancer (Eur J Immunol 2010;40:3358-3371).

With some diagnoses, it’s particular-ly 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 anoth-er 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 immuno-suppressive properties, the article cites studies that show that the drug might aggravate underlying psychiatric symp-toms 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 poten-tiation 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 side-bar, page 10).

At ABQ Health Partners, an Albu-querque, N.M.-based system of physi-cian-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—

medical marijuana has been legal in New Mexico since 2007—the clinicians realized that the policy wasn’t neces-sarily 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

prescribe an opioid to someone already using medical marijuana. But it’s a rare circumstance, he stressed. And the doc-tors at the clinic have decided not to pre-scribe marijuana to clinic patients.

“It’s a risk management issue,” he said. “We can’t with any certainty predict the CNS-cumulative clouding effects.”

—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.

What’s Your View?

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?

Contact the editor [email protected]

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• 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.

For more information, please visit Nulecit.com.Important Safety Information• Sodium ferric gluconate complex in sucrose is contraindicated in non iron-defi cient 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 single-dose, 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 painPlease see next page for references and brief summary of full Prescribing Information.

Now AvailableNulecit™

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

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


Pain Medicine

Policy 11

FDA Expands Zostavax Shingles Indication

T he FDA has approved the use of Zostavax (zoster vaccine live,

Merck), a live attenuated virus vaccine, for the prevention of shingles in indi-viduals 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

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 approxi-mately 22,000 people who were aged 50 to 59. Half of the subjects received Zos-tavax and half received a placebo. Study participants were then monitored for at least one year to see if they developed shingles. Compared with placebo, Zos-tavax reduced the risk for developing shingles by approximately 70%.

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 d i s e a s e , i s a rare, potentially life-threatening disorder in chil-dren that causes severe inflamma-tion throughout the body. SJIA is dis-tinguished from other forms of juvenile idiopathic arthritis (JIA) by the promi-nence 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 con-trolled 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

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.

BRIEF SUMMARYSee package insert for full Prescribing Information.

INDICATIONS AND USAGENulecit™ (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.

CONTRAINDICATIONSAll anemias not associated with iron deficiency. Hypersensitivity to Nulecit™ or any of its inactive components. Evidence of iron overload.

WARNINGSHypersensitivity reactions have been reported with injectable iron products. See PRECAUTIONS.

PRECAUTIONSGeneral: Iron is not easily eliminated from the body and accumulation can be toxic. Unnecessary therapy with par-enteral 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 well-controlled 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 num-bers 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 REACTIONSExposure 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, cross-over, 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 post-marketing 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 experi-enced 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, dysp nea/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 reac-tion 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-associ-ated 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 injec-tion. 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 injec-tion. 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 dis order, 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%), hyperten-sion (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.

OVERDOSAGEDosages 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, vomit-ing, 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

Rx Only


FDA Watch

12 Policy

patients aged 2 to 17 years with SJIA, who had inadequate response to or who were unable to take nonsteroidal anti-inflammatory 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 vari-ables, 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 system-ic 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 infec-tion 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 uncom-mon with Actemra and should be moni-tored with regular blood tests. The most common side effects in trial participants with SJIA included upper respiratory tract infection, headache, sore throat and diarrhea.

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 pre-vents McNeil, a subsidiary of Johnson & Johnson, from manufacturing and dis-tributing 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 vio-lations of the Federal Food, Drug, and Cosmetic Act. The act requires drug companies to follow current good man-ufacturing 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 Debo-rah Autor, director of the Office of Com-pliance in the FDA’s Center for Drug Evaluation and Research.

Manufacturing deficiencies at McNeil’s facilities have resulted in several extensive

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) prod-ucts. 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 Litiga-tion and the U.S. Attorney’s Office for the Eastern District of Pennsylvania, requires McNeil to destroy all drugs under its con-trol 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 correct-ed, and to ensure that adequate manufac-turing 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

• see McNEIL-PPC, page 14

PHARMACEUTICAL WASTE.Is your facility at risk?

DANGEROUS

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.

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)

Pyxis®


FDA Watch

Policy 13

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

Agency Approves Ibuprofen-Famotidine Combination

The FDA has approved Duexis (ibu-profen-famotidine, Horizon Phar-

ma), a novel tablet formulation contain-

ing a fixed-dose combination of the nonsteroidal anti-inflam-matory 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 sup-ported by data from the pivotal REDUCE-1 and REDUCE-2 studies, which showed that patients tak-

ing Duexis experienced signifi-cantly fewer upper gastroin-testinal (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

six-month treatment period. The pri-mary 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 demon-strated a statistically significant reduc-tion 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.

New User-Friendly Web-Based Search Engine Launched

As of April 4, the FDA has made searching

for recalls of food, drugs and other products easi-er and faster.

The Food Safety Mod-ernization Act (FSMA), which was signed into law earlier this year 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 con-sulted with stakeholder groups, includ-ing the Center for Science in the Public Interest, Consumers Union, Food Mar-keting 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 infor-mation 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

McNEIl-PPCcontinued from page 13

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FDA Watch

14 Policy

savings generated by reducing adverse events, hospitalizations and emergency department visits would be shared by the ACO. To cal-culate 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 efficien-cies,” said Gloria P. Sachdev, PharmD, clinical assistant professor at Purdue University College of Pharmacy, in West Lafayette, Ind. “Embracing health infor-mation technology is essential.”

Dr. Sachdev said the health IT effort would require hospitals, primary care physician groups and community phar-macies to adopt functionality that per-mits “bidirectional communication. Pharmacy could communicate electron-ically 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.

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 system-wide 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

such as drug carousels to try to maximize our efficiency from a dis-tribution 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 prac-tices 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 clini-cal pharmacotherapy in family medi-cine at Akron General Medical Cen-ter, 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 “prob-ably 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 sum-mer 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 con-tinue the way it is.”

—Bruce Buckley

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Quality Improvement

Policy 15

MCPPN2048.indd 1 5/12/11 5:24:31 PM

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 (ipilim-umab) can reportedly extend the life of the average patient with late-stage mel-anoma 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 fur-ther 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 phas-es 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 mil-lion 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 mel-anoma 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 sur-viving longer, this also means they are receiving medical care longer.

Still, the impact of maintenance thera-py “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, sur-vival and cost remain consistent, the team projects that population growth

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.

Better Cost-Containment Needed

Ali McBride, PharmD, clinical pharma-cy 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 “exor-bitant” 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 legis-lation proposed by the Obama admin-istration that would make it easier for generic companies to enter the mar-ket. 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 devel-opment 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 over-all, 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, not-ed 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.

“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 Colum-bus. Ms. Griffith recalled one pancre-atic 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 particu-larly 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 equiva-lent, 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 Afford-able 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 thou-sands 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

away because they can’t actually pay,” said Dr. McBride.

For infusion therapies, which are cov-ered under Medicare Part B, patients pay 20% of a drug’s price regardless of how high costs go. Many patients have supple-mental 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 [medica-tions] 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 deter-minations target several of the priciest oncology agents, require many to be pre-certified and require specific indications for coverage, sometimes more restrictive than the FDA-approved indications.

NCI REPORTcontinued from page 1 ‘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

‘[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

• see NCI REPORT, page 18

210

180

150

120

90

60

30

0

Do

lla

rs (

Bil

lio

ns)

2010 2020a 2020b

$125

$158

$207

Figure. Cost of cancer care in the United States: 2010-2020.a Constant incidence, survival, cost.

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

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


Drug Costs

Policy 17

“The way that we use these very expen-sive 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 compen-dia, two or more Phase II trials, or one Phase III trial showing efficacy in the specific cancer type. She and her col-leagues know that many effective indica-tions 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 imple-ment 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 help-ing 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 per-sonalized 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 swal-low 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-assis-tance programs (see page 24) and copay assistance foundations, which include funds and medications donated by phar-maceutical 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 pro-vide incentive for doctors to choose therapies based partially on their costs (Health Aff 2011;30:500-509). One pay-ment would cover the costs of drugs and their administration for a predefined

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 propo-sition, it could prove a welcome addi-

tion to the physician’s role. Many oncologists are “unnerved by pric-ing,” said Dr. Howard. “Some may be reluc-tant to prescribe a drug that’s very costly, even if insurers pay.”

—Lynne Peeples

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.

‘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

NCI REPORTcontinued from page 17

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

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 fl exibility when evaluating insulin storage and distribution (fl oor 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 longer-acting insulin, except when used in combination with sulfonylureas in patients with type 2 diabetes.

Humalog Important Safety Information

ContraindicationsHumalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or one of its excipients.

WarningsHumalog 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 lessthan 3 years of age have not been established. There areno adequate and well-controlled clinical studies of the useof Humalog in pregnant or nursing women.

Step up to a range ofinsulin delivery options.

HI69632 0211 PRINTED IN USA ©2011, LILLY USA, LLC. ALL RIGHTS RESERVED.

Scan for ASCO tips on discussing drug costs with patients.


Drug Costs

18 Policy

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Humalog Important Safety Information, continued

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

HypoglycemiaHypoglycemia 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 EffectsOther 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

Humalog Important Safety Information, continued

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

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 Lillyand Company and are available by prescription only.

Humulin® is a registered trademark of Eli Lilly and Company.

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Pharmacy Practice News • June 2011 New Product 19

HUMALOG® INSULIN LISPRO INJECTION (rDNA ORIGIN)BRIEF SUMMARY: Consult package insert for complete prescribing information.

INDICATIONS AND USAGE: Humalog is an insulin analog that is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Humalog has a more rapid onset and a shorter duration of action than regular human insulin. Therefore, in patients with type 1 diabetes, Humalog should be used in regimens that include a longer-acting insulin. However, in patients with type 2 diabetes, Humalog may be used without a longer-acting insulin when used in combination therapy with sulfonylurea agents. Humalog may be used in an external insulin pump, but should not be diluted or mixed with any other insulin when used in the pump. Humalog administration in insulin pumps has not been studied in patients with type 2 diabetes.

CONTRAINDICATIONS: Humalog is contraindicated during episodes of hypoglycemia and in patients sensitive to Humalog or any of its excipients.

WARNINGS: This human insulin analog differs from regular human insulin by its rapid onset of action as well as a shorter duration of activity. When used as a mealtime insulin, the dose of Humalog should be given within 15 minutes before or immediately after the meal. Because of the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an external insulin pump). External Insulin Pumps: When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin. Patients should carefully read and follow the external insulin pump manufacturer’s instructions and the “PATIENT INFORMATION” leaflet before using Humalog. Physicians should carefully evaluate information on external insulin pump use in the Humalog physician package insert and in the external insulin pump manufacturer’s instructions. If unexplained hyperglycemia or ketosis occurs during external insulin pump use, prompt identification and correction of the cause is necessary. The patient may require interim therapy with subcutaneous insulin injections (see PRECAUTIONS, For Patients Using External Insulin Pumps, and DOSAGE AND ADMINISTRATION). Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using an external insulin pump. Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (eg, regular, NPH, analog), species, or method of manufacture may result in the need for a change in dosage.

PRECAUTIONS: General—Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the use of all insulins. Because of differences in the action of Humalog and other insulins, care should be taken in patients in whom such potential side effects might be clinically relevant (eg, patients who are fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to serum potassium level). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins. As with all insulin preparations, the time course of Humalog action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity. Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan. Insulin requirements may be altered during illness, emotional disturbances, or other stress. Hypoglycemia—As with all insulin preparations, hypoglycemic reactions may be associated with the administration of Humalog. Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control. Renal Impairment—The requirements for insulin may be reduced in patients with renal impairment. Hepatic Impairment—Although impaired hepatic function does not affect the absorption or disposition of Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary. Allergy—Local Allergy—As with any insulin therapy, patients may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Systemic Allergy—Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life-

threatening. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient. In Humalog-controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving Humulin R® (N=2969) and 30 patients receiving Humalog (N=2944) (P=.053). Antibody Production—In large clinical trials, antibodies that cross-react with human insulin and insulin lispro were observed in both Humulin R- and Humalog-treatment groups. As expected, the largest increase in the antibody levels during the 12-month clinical trials was observed with patients new to insulin therapy. Usage of Humalog in External Insulin Pumps—The infusion set (reservoir syringe, tubing, and catheter), Disetronic® D-TRON®2,3 or D-TRONplus®2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced and a new infusion site selected every 48 hours or less. Humalog in the external insulin pump should not be exposed to temperatures above 37°C (98.6°F). In the D-TRON®2,3 or D-TRONplus®2,3 pump, Humalog 3 mL cartridges may be used for up to 7 days. However, as with other external insulin pumps, the infusion set should be replaced and a new infusion site should be selected every 48 hours or less. When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin (see INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, For Patients Using External Insulin Pumps, Mixing of Insulins, DOSAGE AND ADMINISTRATION, and Storage). Information for Patients—Patients should be informed of the potential risks and advantages of Humalog and alternative therapies. Patients should also be informed about the importance of proper insulin storage, injection technique, timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose monitoring, periodic hemoglobin A1C testing, recognition and management of hypoglycemia and hyperglycemia, and periodic assessment for diabetes complications. Patients should be advised to inform their physician if they are pregnant or intend to become pregnant. Refer patients to the “PATIENT INFORMATION” leaflet for timing of Humalog dosing (<_15 minutes before or immediately after a meal), storing insulin, and common adverse effects. For Patients Using Insulin Pen Delivery Devices: Before starting therapy, patients should read the “PATIENT INFORMATION” leaflet that accompanies the drug product and the User Manual that accompanies the delivery device. They should also reread these materials each time the prescription is renewed. Patients should be instructed on how to properly use the delivery device, prime the Pen to a stream of insulin, and properly dispose of needles. Patients should be advised not to share their Pens with others. For Patients Using External Insulin Pumps: Patients using an external infusion pump should be trained in intensive insulin therapy and in the function of their external insulin pump and pump accessories. Humalog was tested in the MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested in the Disetronic®2 H-TRONplus® V100 insulin pump (with plastic 3.15 mL insulin reservoir), and the Disetronic D-TRON®2,3 and D-TRONplus®2,3 insulin pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets. The infusion set (reservoir syringe, tubing, catheter), D-TRON®2,3 or D-TRONplus®2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced, and a new infusion site selected every 48 hours or less. Humalog in the external pump should not be exposed to temperatures above 37°C (98.6°F). A Humalog 3 mL cartridge used in the D-TRON®2,3 or D-TRONplus®2,3 pump should be discarded after 7 days, even if it still contains Humalog. Infusion sites that are erythematous, pruritic, or thickened should be reported to medical personnel, and a new site selected. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump. Laboratory Tests—As with all insulins, the therapeutic response to Humalog should be monitored by periodic blood glucose tests. Periodic measurement of hemoglobin A1C is recommended for the monitoring of long-term glycemic control. Drug Interactions—Insulin requirements may be increased by medications with hyperglycemic activity, such as corticosteroids, isoniazid, certain lipid-lowering drugs (eg, niacin), estrogens, oral contraceptives, phenothiazines, and thyroid replacement therapy (see CLINICAL PHARMACOLOGY). Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity or have hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors), angiotensin-converting-enzyme inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (eg, octreotide), and alcohol. Beta-adrenergic blockers may mask the symptoms of hypoglycemia in some patients. Mixing of Insulins—Care should be taken when mixing all insulins as a change in peak action may occur. The American Diabetes Association warns in its Position Statement on Insulin Administration, “On mixing, physiochemical changes in the mixture may occur (either immediately or over time). As a result, the physiological response to the insulin mixture may differ from that of the injection of the insulins separately.” Mixing Humalog with Humulin® N or Humulin® U does not decrease the absorption rate or the total bioavailability of Humalog.

MCPPN2017.indd 1 3/18/11 5:44:00 PM

Given alone or mixed with Humulin N, Humalog results in a more rapid absorption and glucose-lowering effect compared with regular human insulin. Pregnancy—Teratogenic Effects—Pregnancy Category B—Reproduction studies with insulin lispro have been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the average human dose (40 units/day) based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to Humalog. There are, however, no adequate and well-controlled studies with Humalog in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Although there are limited clinical studies of the use of Humalog in pregnancy, published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Careful monitoring of the patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to mothers with diabetes is warranted. Nursing Mothers—It is unknown whether Humalog is excreted in significant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Humalog is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog dose, meal plan, or both. Pediatric Use—In a 9-month, crossover study of prepubescent children (n=60), aged 3 to 11 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 minutes before meals 8.4%, Humalog immediately before meals 8.4%, and Humalog immediately after meals 8.5%. In an 8-month, crossover study of adolescents (n=463), aged 9 to 19 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 to 45 minutes before meals 8.7% and Humalog immediately before meals 8.7%. The incidence of hypoglycemia was similar for all 3 treatment regimens. Adjustment of basal insulin may be required. To improve accuracy in dosing in pediatric patients, a diluent may be used. If the diluent is added directly to the Humalog vial, the shelf life may be reduced (see DOSAGE AND ADMINISTRATION). Geriatric Use—Of the total number of subjects (n=2834) in 8 clinical studies of Humalog, 12% (n=338) were 65 years of age or over. The majority of these were patients with type 2 diabetes. A1C values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Humalog action have not been performed.

ADVERSE REACTIONS: Clinical studies comparing Humalog with regular human insulin did not demonstrate a difference in frequency of adverse events between the 2 treatments. Adverse events commonly associated with human insulin therapy include the following: Body as a Whole—allergic reactions (see PRECAUTIONS). Skin and Appendages—injection site reaction, lipodystrophy, pruritus, rash. Other—hypoglycemia (see WARNINGS and PRECAUTIONS).

OVERDOSAGE: Hypoglycemia may occur as a result of an excess of insulin relative to food intake, energy expenditure, or both. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery.

DOSAGE AND ADMINISTRATION: Humalog is intended for subcutaneous administration, including use in select external insulin pumps (see DOSAGE AND ADMINISTRATION, External Insulin Pumps). Dosage regimens of Humalog will vary among patients and should be determined by the healthcare provider familiar with the patient’s metabolic needs, eating habits, and other lifestyle variables. Pharmacokinetic and pharmacodynamic studies showed Humalog to be equipotent to regular human insulin (ie, one unit of Humalog has the same glucose-lowering effect as one unit of regular human insulin), but with more rapid activity. The quicker glucose-lowering effect of Humalog is related to the more rapid absorption rate from subcutaneous tissue. An adjustment of dose or schedule of basal insulin may be needed when a patient changes from other insulins to Humalog, particularly to prevent premeal hyperglycemia. When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal. Regular human insulin is best given 30 to 60 minutes before a meal. To achieve optimal glucose control, the amount of longer-acting insulin being given may need to be adjusted when using Humalog. The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables. Humalog was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 U/kg regular human insulin or Humalog at abdominal, deltoid, or

femoral sites, the 3 sites often used by patients with diabetes. When not mixed in the

same syringe with other insulins, Humalog maintains its rapid onset of action and has

less variability in its onset of action among injection sites compared with regular

human insulin (see PRECAUTIONS). After abdominal administration, Humalog

concentrations are higher than those following deltoid or thigh injections. Also, the

duration of action of Humalog is slightly shorter following abdominal injection,

compared with deltoid and femoral injections. As with all insulin preparations, the time

course of action of Humalog may vary considerably in different individuals or within the

same individual. Patients must be educated to use proper injection techniques.

Humalog in a vial may be diluted with STERILE DILUENT for Humalog, Humulin N,

Humulin R, Humulin 70/30, and Humulin® R U-500 to a concentration of 1:10

(equivalent to U-10) or 1:2 (equivalent to U-50). Diluted Humalog may remain in

patient use for 28 days when stored at 5°C (41°F) and for 14 days when stored at

30°C (86°F). Do not dilute Humalog contained in a cartridge or Humalog used in an

external insulin pump.

Parenteral drug products should be inspected visually before use whenever the

solution and the container permit. If the solution is cloudy, contains particulate matter,

is thickened, or is discolored, the contents must not be injected. Humalog should not

be used after its expiration date. The cartridge containing Humalog is not designed to

allow any other insulin to be mixed in the cartridge or for the cartridge to be refilled

with insulin.

External Insulin Pumps—Humalog was tested in MiniMed®1 Models 506, 507, and

508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested

in the Disetronic®2 H-TRONplus® V100 insulin pump (with plastic 3.15 mL insulin

reservoir) and the Disetronic D-TRON®2,3 and D-TRONplus®2,3 pumps (with Humalog

3 mL cartridges) using Disetronic Rapid®2 infusion sets. Humalog should not be diluted

or mixed with any other insulin when used in an external insulin pump.

HOW SUPPLIED:

Humalog (insulin lispro injection, USP [rDNA origin]) is available in the following

package sizes (with each presentation containing 100 units insulin lispro per mL

[U-100]):

10 mL vials NDC 0002-7510-01 (VL-7510)

3 mL vials NDC 0002-7510-17 (VL-7533)

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.2 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.

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.

MCPPN2018.indd 1 3/18/11 5:45:31 PM

Louisville, Ky.—Central pharmacy automation is instrumental for estab-lishing a bar-code infrastructure, and results in improved medical practice and good business, according to find-ings presented at the 2011 unSummit for Bedside Barcoding.

“A well-planned deployment of phar-macy automation and dispensing tech-nology improves patient safety, opera-tional efficiency and frees pharmacists to participate more fully in interdis-ciplinary, patient-centric care models and achieve medication-related quality measures,” said Wayne Nye, RPh, phar-macist and pharmacy information sys-tems coordinator at Martha Jefferson Hospital, Charlottesville, Va.

Mr. Nye detailed how achieving bar-code 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 auto-mation 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 signifi-cant improvements in patient safety and efficiency.

Bolstering Existing Systems

Mr. Nye said the bar code readiness project was preceded by earlier tech-nology rollouts. “We first decided to buy a pharmacy robot and were using it just for cart fill with our old phar-macy system,” he said. “In 2002 and 2003, we converted to an integrated clinical software platform with Cerner Millennium, including PharmNet, PowerChart, PathNet and other hospi-tal applications. We then got our robot and the Cerner systems to work togeth-er 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 dispens-ing, automated shelving and packaging, narcotic inventory management, nurs-ing 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 cabi-nets throughout its patient care areas. The facility began using smart pumps in 2008 and medical order imaging in 2009. Moreover, “we had the abil-ity to enter orders either centrally in

the pharmacy or decentrally on nurs-ing 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 out-comes 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 dis-pensing 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 col-lected, ‘I don’t need a weatherman to tell me when it’s raining,’ he quipped. “Order images are now scanned and transmit-ted instantaneously to the pharmacist, as opposed to having to physically trav-el 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 inter-esting challenge, Mr. Nye said. “As with

most organizations, we had to choose between bar code–assisted medication administration [BCMA] or computer-assisted physician order entry systems. We chose to implement BCMA primar-ily because we had a well-established bar-code foundation and we were pre-pared to fully leverage its advantages. Moreover, in the short run, we believed the BCMA safety net offered the great-est immediate benefit to patient safe-ty.” (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 imple-mentation, drug expense was under bud-get by $262,012; drug cost per dose was down 9% and doses per patient-day were up 8%, according to Mr. Nye. In addi-tion, adverse drug reactions were trend-ing 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 spend-ing 152 hours on 673 interventions.

Mr. Nye said the most important thing he learned from this experience is that strong relationships and open commu-nications with both technology vendors and professional colleagues will help ease the transition challenges.

Implementation ‘Pearls’

For hospitals just starting to imple-ment bar coding and safe medication administration, Mr. Nye offered the fol-

lowing “practice pearls”:• Gain support and con-

sensus from invested C-suite executives for goals, timelines and funding for bar-code technology imple-mentation.

• In planning your implementation, understand your organization’s cur-rent state of medication processes—what these processes actually are, and not what these processes are sup-posed 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 medi-cation from the pharmacy and when that medication is administered to the patient. Make everything as safe as pos-sible 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 technol-ogy. Martha Jefferson Hospital, in con-trast, 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

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.

Implementing BCMA Good for Patients and Good for Business

‘In the short run, we believed the BCMA safety net offered the

greatest immediate benefit to patient safety.’—Wayne Nye, RPh

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

Scan for more BCMA lessons learned. Instructions, p. 3


UnSummit

22 Technology

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MCPPN2051.indd 1 5/16/11 6:16:57 PM

IntroductionSpending 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 Pre-scription drugs also contribute substan-tially 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 cov-erage 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 popula-tions of patients.4

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 var-ies and ranges from coupons, discount cards, rebates, and lower copayments to free supplies of prescription drugs.5,6 The criteria for patient eligibility also

vary and generally include income (often a percentage of the poverty lev-el) and insurance status (underinsured o r u n i n s u re d ) . Applications for the PAPs usual-ly 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 Chisholm-Burns, PharmD, professor and head of the Department of Pharmacy Practice and Science at the University of Ari-zona College of Pharmacy, in Tucson, is the founder and executive direc-tor of the Medication Access Program, established to increase access to pre-scription 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. Pharma-ceutical assistance programs have been invaluable for obtaining medications for our patients.”

The value of PAPs for patient access to prescription drugs also has been confirmed by several studies. Con-sistent access to prescription drugs through PAPs has been shown to improve markers of chronic conditions such as type 2 diabetes and dyslipid-emia. Additionally, cost savings to both the patient and the pharmacy have been seen when pharmacists facilitate program enrollment.7-9 In a retrospec-tive review, Trompeter and Havrda compared outcomes for treatment of diabetes between patients with pre-scription insurance and those using PAPs for obtaining prescription drugs.7 Patients using PAPs tended to be old-er and had more medical conditions than those with prescription insurance. Patients using PAPs also demonstrated better control of diabetes. Goal hemo-globin 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 dys-lipidemia who used PAPs for their pre-scription drugs were found to have better

lipid profiles than those using prescrip-tion insurance. For example, patients in the PAP group had lower low-density lipoprotein cholesterol (LDL-C) val-ues (95.8±28.0 mg/dL [mean ±SD]) and higher high-density lipoprotein choles-terol (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 pharmacy-managed medication assistance program using PAPs.8 After enrollment in a medi-cation assistance program, patients had a significant reduction in HbA1C, total cholesterol, low-density lipoproteins, and triglycerides (Table 1). Addition-ally, 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.

Pharmaceutical Assistance Programs

Table 1. Patients’ Disease Indicators Before and After Program Enrollment

Disease Indicator

Mean±SD

P valuePre-Enrollment Post-Enrollment

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


Joan Stachnick, PharmDClinical Assistant ProfessorDrug Information GroupUniversity of Illinois at Chicago College of PharmacyChicago, Illinois

100

80

60

40

20

0

40

67

26

48

112

96

3441

120

100

80

60

40

20

0

Pa

tie

nts

, %

Lip

id V

alu

es,

mg

/dL

Prescription insurance

PAP Group

Reaching Reaching fasting HbA1c goal glucose level goal

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


Drug Costs

24 Operations & Management

Follow-up for the patient is an impor-tant part of using PAPs, as is consisten-cy in pharmacy involvement,” she said.

Adding to the challenge is the com-plexity 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 Medica-tions frequently are sent directly to the patient’s physician’s office, add-ing 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 prescrip-tion drugs or there are different pro-grams 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 spon-sored by not-for-profit organizations as well as by pharmaceutical companies. Most of these resources allow searching by drug name or by pharmaceutical com-pany to identify assistance programs. Some offer links to the online applica-tions. Information on governmental or other public assistance programs also

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 phar-maceutical research companies and provides information on PAPs as well as public and private foundation-spon-sored assistance programs.14 This site

is described as a “single point of entry” for 475 available prescription drug assistance programs. Patients can enter their prescription drugs and person-al information, and the site identifies assistance programs for those medica-tions, 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 pro-grams.15 Developed with funding from the Robert Wood Johnson Foundation,

this site is maintained through dona-tions and company sponsorships. The site includes directories of PAPs and prescription drugs covered under a PAP. The site is searchable for com-panies offering PAPs and for prescrip-tion drugs. Similar to other Web sites, RxAssist has information on govern-mental programs, coupons, and pre-scription drug discount cards. There is no fee to use the Web site.

RxHope is part of the Triplefin group,

an outsourcing company. This site was developed to assist health care provid-ers in the PAP application process.16 Although patients can search the site for programs that include their pre-scription drugs, the physician’s office must complete the application for the patient. RxHope is a professional ser-vice that facilitates the process and tracks PAP applications. RxHope con-tracts 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 not-for-profit organization that lists pre-scription drugs by brand and generic

names, along with lists of pharmaceuti-cal companies offering PAPs, govern-mental 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 main-tain the site are accepted. NeedyMeds also offers a subscription-based soft-ware program to health care provid-ers—PAPTracker—that helps in track-ing PAP applications.

Professional organizations also pro-vide information on PAPs. The Ameri-can Society of Health-System Pharma-cists (ASHP) has compiled information on PAPs under its Practice and Policy Resource Center.17 The ASHP’s Web site provides links to programs such

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.

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 persis-tently high out-of-pocket health care expenses faced by many Americans with chronic condi-tions. Commonwealth Fund. 2009;1303(63):1-14.

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 pri-vate 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’ medica-tion assistance programs: potentially useful but too burdensome to use? South Med J. 2009;102(2):139-144.

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. Pfizerhelpfulan-swers.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 Pharma-cists. Practice and Policy. Resource Centers. Patient Assistance Programs. www.ashp.org/Import/PRACTICEANDPOLICY/Practice-ResourceCenters/PatientAssistancePrograms.aspx. Accessed March 24, 2011.

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 Alaska and Hawaii have separate income 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


Drug Costs

Operations & Management 25

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NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with therisks 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 reportedin 16% (288/1836) of patients treated with intravenous amiodarone. Monitor the initial rate of infusion closely and do not exceed the recommended rate. In somecases, 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 amiodaronefor life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. Treat patients with a known predisposition to bradycardiaor 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/pulselesselectrical 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 andincrease 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 patientstaking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly.

Please see brief summary of Full Prescribing Information on the following pages.

•

•

•

•

•

•

•

MCPPN2052.indd 1 5/19/11 3:28:24 PM

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

The institution of antithyroid drugs, β-adrenergic blockers or temporary corticosteroid therapy maybe necessary. The action of antithyroid drugs may be especially delayed in amiodarone-inducedthyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland.Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated withamiodarone-induced hyperthyroidism.

When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot bediscontinued because it is the only drug effective against the resistant arrhythmia, surgical managementmay be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosisis limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anestheticmanagement require careful planning.

Neonatal Hypo- or HyperthyroidismAmiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone useduring pregnancy is uncommon, there have been a small number of published reports of congenitalgoiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient ofthe potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patientbecomes pregnant while taking NEXTERONE.

HypothyroidismHypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in someseries. This condition may be identified by relevant clinical symptoms and particularly by elevatedserum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine indexvalues may be normal. Manage hypothyroidism by reducing the NEXTERONE dose and consideringthe need for thyroid hormone supplement. However, therapy must be individualized, and it may benecessary to discontinue oral amiodarone in some patients.

5.9 SurgeryPerform close perioperative monitoring in patients undergoing general anesthesia who are onamiodarone therapy as they may be more sensitive to the myocardial depressant and conductiondefects of halogenated inhalational anesthetics.

5.10 Corneal Refractive Laser SurgeryAdvise patients that most manufacturers of corneal refractive laser surgery devices contraindicatecorneal refractive laser surgery in patients taking amiodarone.

5.11 Electrolyte DisturbancesCorrect hypokalemia or hypomagnesemia whenever possible before initiating treatment withNEXTERONE, as these disorders can exaggerate the degree of QTc prolongation and increase thepotential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencingsevere or prolonged diarrhea or in patients receiving concomitant diuretics.

6 ADVERSE REACTIONS6.1 Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observedin the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drugand may not reflect the rates observed in practice.

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

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

Table 4 lists the most common (incidence ≥2%) adverse reactions during intravenous amiodaronetherapy considered at least possibly drug-related. These data were collected in clinical trials involving1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled becausenone of the adverse reactions appeared to be dose-related.

Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone incontrolled 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 ExperienceThe following adverse reactions have been identified during post-approval use of amiodarone. Becausethese reactions are reported voluntarily from a population of uncertain size, it is not always possible toreliably 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

Renal: renal impairment, renal insufficiency, acute renal failure

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

Thyroid: thyroid nodules/thyroid cancer

Vascular: vasculitis

Baxter Healthcare CorporationDeerfield, 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

Table 4: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN

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

Controlled Studies(n=814)

Study Event

Body as a wholeFever

Cardiovascular SystemBradycardiaCongestive heart failureHeart arrestHypotensionVentricular tachycardia

Digestive SystemLiver function tests normalNausea

Body as a whole24 (2.9%)

Cardiovascular49 (6.0%)18 (2.2%)29 (3.5%)

165 (20.2%)15 (1.8%)DigestiveSystem

35 (4.2%)29 (3.5%)


Cardiovascular41 (4.0%)21 (2.0%)26 (2.5%)

123 (12.0%)30 (2.9%)DigestiveSystem

29 (2.8%)43 (4.2%)


Cardiovascular90 (4.9%)39 (2.1%)55 (2.9%)

288 (15.6%)45 (2.4%)

Digestive System64 (3.4%)72 (3.9%)

Open-Label Studies(n=1022)

Total(n=1836)

NEXTERONE (amiodarone HCl) Premixed Injection for intravenous use

Brief Summary of Prescribing Information. See PI for Full Prescribing Information.

1 INDICATIONS AND USAGENEXTERONE is indicated for initiation of treatment and prophylaxis of frequently recurring ventricularfibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory toother therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodaroneis 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 fullprescribing information].

Use NEXTERONE for acute treatment until the patient's ventricular arrhythmias are stabilized. Mostpatients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered forlonger periods if necessary.

4 CONTRAINDICATIONSNEXTERONE 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 PRECAUTIONSNEXTERONE should be administered only by physicians who are experienced in the treatment oflife-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodaronetherapy, and who have access to facilities adequate for monitoring the effectiveness and side effectsof treatment.

5.1 HypotensionHypotension 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 1836patients treated with intravenous amiodarone. Clinically significant hypotension during infusions wasseen most often in the first several hours of treatment and was not dose related, but appeared to berelated to the rate of infusion. Hypotension necessitating alterations in intravenous amiodarone therapywas 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, includingthe following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor the initialrate 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 BlockIn 90 (4.9%) of 1836 patients in clinical trials, drug-related bradycardia that was not dose-relatedoccurred while they were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardiaby slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemakeris required. Despite such measures, bradycardia was progressive and terminal in 1 patient duringthe controlled trials. Treat patients with a known predisposition to bradycardia or AV block withNEXTERONE in a setting where a temporary pacemaker is available.

5.3 Liver Enzyme ElevationsElevations of blood hepatic enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase(AST), and gamma-glutamyl transferase (GGT)] are commonly seen in patients with immediatelylife-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may beelevated in patients who have had recent myocardial infarction, congestive heart failure, or multipleelectrical defibrillations. Approximately 54% of patients receiving intravenous amiodarone in clinicalstudies had baseline liver enzyme elevations, and 13% had clinically significant elevations. In 81% ofpatients with both baseline and on-therapy data available, the liver enzyme elevations either improvedduring therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not acontraindication 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 higherloading dose concentration and much faster rate of infusion than recommended [see Dosage andAdministration (2) in full prescribing information].

In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighedagainst the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONEfor evidence of progressive hepatic injury. In such cases, consider reducing the rate of administrationor withdrawing NEXTERONE.

5.4 ProarrhythmiaLike all antiarrhythmic agents, NEXTERONE may cause a worsening of existing arrhythmias orprecipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associatedwith prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or greater. Although QTcprolongation occurred frequently in patients receiving intravenous amiodarone, TdP or new-onset VFoccurred infrequently (less than 2%). Monitor patients for QTc prolongation during infusion withNEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolongthe QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to asingle agent.

Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. Therehave been reports of QTc prolongation, with or without TdP, in patients taking amiodarone whenfluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly [see DrugInteractions (7) in full prescribing information].

Amiodarone causes thyroid dysfunction in some patients, which may lead to potentially fatalbreakthrough or exacerbated arrhythmias.

5.5 Pulmonary DisordersEarly-onset Pulmonary ToxicityThere have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patientstreated with intravenous amiodarone. Findings have included pulmonary infiltrates and masses onX-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases haveprogressed to respiratory failure or death.

ARDSTwo percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) duringclinical studies involving 48 hours of therapy.

Pulmonary FibrosisOnly 1 of more than 1000 patients treated with intravenous amiodarone in clinical studies developedpulmonary fibrosis. In that patient, the condition was diagnosed 3 months after treatment withintravenous amiodarone, during which time the patient received oral amiodarone. Pulmonary toxicity isa well-recognized complication of long-term amiodarone use (see package insert for oral amiodarone).

5.6 Loss of VisionCases of optic neuropathy and optic neuritis, usually resulting in visual impairment, have beenreported in patients treated with oral amiodarone. In some cases, visual impairment has progressedto permanent blindness. Optic neuropathy and neuritis may occur at any time following initiation oftherapy. A causal relationship to the drug has not been clearly established. Perform an ophthalmicexamination if symptoms of visual impairment appear, such as changes in visual acuity and decreasesin peripheral vision. Re-evaluate the necessity of amiodarone therapy if optic neuropathy or neuritis issuspected. Perform regular ophthalmic examination, including fundoscopy and slit-lamp examination,during administration of NEXTERONE.

5.7 Long-Term UseThere has been limited experience in patients receiving intravenous amiodarone for longer than 3weeks. See package insert for oral amiodarone.

5.8 Thyroid AbnormalitiesAmiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may causeincreased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinicallyeuthyroid patients. Amiodarone is also a potential source of large amounts of inorganic iodine and cancause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment andperiodically thereafter, particularly in elderly patients, and in any patient with a history of thyroidnodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and itsmetabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function testsmay persist for several weeks or even months following NEXTERONE withdrawal.

There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated withamiodarone. In some instances hyperthyroidism was also present [see Adverse Reactions (6.2) in fullprescribing information].

Hyperthyroidism and ThyrotoxicosisHyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may behigher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidismusually poses a greater hazard to the patient than hypothyroidism because of the possibility ofthyrotoxicosis and arrhythmia breakthrough or aggravation, all of which may result in death. Therehave been reports of death associated with amiodarone-induced thyrotoxicosis. Consider the possibilityof hyperthyroidism if any new signs of arrhythmia appear.

MCPPN2053.indd 1 5/19/11 3:31:08 PM

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 “nug-gets.” 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 lis-teners. 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 fol-lowed by an “aha moment,” as each realizes that they have been talking, but not communicating, with one another.

True leadership begins with under-standing. Understanding begins with listening. And listening requires going beyond the spoken words to the unspo-ken. “Hearing” the unspoken requires insight into the heart of the other per-son. 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 organiza-tion 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 every-one 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 dif-ferent 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 lead-ers 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 great-er your potential for improvement.” I remember one time when I gave a lec-ture 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 person-al assessment. Ask your-self what you are good at. Ask others what you do well. Be specific. Then fig-ure out how you can maxi-mize your strengths in the practice of pharmacy. We need to go through this same exercise with our staffs. Successful lead-ers 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

strengths, you might consider encour-aging 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?

Defining Moments of Reality

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 phar-macy 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 appli-cable 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

advantage, don’t compete.We need to base our visions for our

departments on reality—identifying our areas of strength and playing to them.

The People Reflect the Leader

It has been said, “Everything rises and falls on leadership.” Good leaders pro-duce good departments. Poor leadership has a trickle-down effect throughout a department. The leader is responsible.

The more you understand leader-ship, 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 repro-duce 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 learn-ing 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 fol-lowing your lead? As the

Rev. E.V. Hill once stat-ed, “The man who is leading but no one is following, is merely going for a walk.”

‘Active Listening’And Other Leadership Nuggets

“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

See if you can catch yourself so wrapped up in what you are

going to say to someoneduring a conversation

that you haven’t beenlistening to a wordthey said.


Leadership in Action

30 Operations & Management

of physicians surveyed (N=57) would recommend SAMSCA to a colleague1

In this same survey (patient cases; N=150), physicians weresatisfied or very satisfied with SAMSCA 90% of the time1100%

©2011 Otsuka America Pharmaceutical, Inc. February 2011 0711A-2015B

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.

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.

UNMET NEED. FILL IT.

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

15 mgNDC: 59148-020-50

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Unique oral treatment for clinically significant hypervolemic

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Order SAMSCA® (tolvaptan)

MCPPN2006.indd 1 3/15/11 4:47:56 PM

MCPPN2007.indd 1 3/15/11 4:51:26 PM

The use of dietary supplements both to treat disease and for disease pre-

vention 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-Sys-tem Pharmacists (ASHP) has stated that pharmacists, as medication-use experts and as the most accessible members of the health care team, are unique-ly qualified and positioned to counsel patients on the use of dietary supple-ments.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. Addi-tionally, the content of dietary supple-ments is not standardized, therapeutic goals are vague, and evidence of efficacy and safety in most cases is absent and/or

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-

dence-based professional resources. This article reviews herbal products that are commonly used in the United States and provides information regard-ing their effectiveness and their safety.

Dietary supplements are defined in the Dietary Supplement Health and Educa-tion 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 supple-ments often and that almost twice as many have used at least 1 of the estimat-ed 29,000 dietary supplements on the market.4 Out-of-pocket expenditures on dietary supplements and complemen-tary 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. Sur-prisingly, 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

Understanding uses and risks of dietary supplements:

A Teaching Opportunity for PharmacistsM. Chandra Sekar, RPh, PhDAssociate Professor College of PharmacyUniversity of FindlayFindlay, Ohio

vaiyapuri Subramaniam, PharmD, MSAssociate Chief Consultant Pharmacy Benefits Management ServicesDepartment of Veterans Affairs (VA), Washington, DCClinical Affiliate Professor Nova Southeastern University College of PharmacyWest Palm Beach, Florida

Shin Hsien Shen, BS PharmTeam Leader Traditional Chinese Medicine Pharmacy DepartmentChung Gung Memorial HospitalTaipei, Taiwan

Sheila yesquenPharmD CandidateNova Southeastern University College of PharmacyFort Lauderdale, Florida

• see HERBALS, page 34

Table. Commonly Used Herbal Products on the US Market

Herbal Supple-ment Product

Known Uses Safety Profile

GCEApproved

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.


Practice Pearl

Clinical 33

specialty supplements, represent the fastest-growing segment of the over-all supplement product category.6 The demographic profile of the predominant herbal supplement user in the Unit-ed 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 there-fore safe; and finally, an overall disillu-sionment with the medical and pharma-ceutical establishment.

‘Don’t Ask, Don’t Tell’

Despite increased use of these prod-ucts by patients, most health care pro-fessionals continue to choose to remain ignorant, hoping that this trend will reverse itself. Several studies have dem-onstrated 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 medi-cine” believe that herbs and supple-ments 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

about herbal products, they do not press patients on the use of these prepara-tions 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 dif-ferences 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 prod-ucts. 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, phar-macists, pharmacologists, toxicologists, representatives of the pharmaceutical industry, and laypeople, who evaluated the safety and efficacy of phytomedicines. This committee identified several thera-peutically useful herbs and listed them in the German Commission E monographs. These listed herbal products can be pre-scribed 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 refer-ence 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 pharma-cists and other health care profession-als 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 prescrip-tion 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. Tak-ing 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

HERBAlScontinued from page 33

• see HERBALS, page 36


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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 medica-tion stop order or the use of a drug antidote. These signals trigger addi-tional 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 fund-ed 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 pro-cedure-related episodes (109). Hospital-acquired infections (72), pressure ulcers (11), device fail-ures (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 condi-tions 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

reporting system had a sensitivity of 0% and a specificity of 100%.

David C. Classen, MD, associate pro-fessor 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 nei-ther 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 gov-ernment should push for wider adop-tion of the Global Trigger Tool. One way would be to include it in so-called “meaningful use” requirements for elec-tronic medical records. In fact, he and his colleagues have shown that the tool can work with an EMR system to auto-mate 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.

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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 Asso-ciation reported on the FDA advisory regarding kava’s hepatotoxicity.12 This is of particular concern because many patients take acetaminophen and alco-hol, 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 tak-ing kava should be avoided. Kava has pharmacologic effects that are similar to those of benzodiazepines, so patients taking benzodiazepines to treat symp-toms of anxiety or convulsions should avoid kava.13 Although kava already has been banned in Canada but not yet in the United States, pharmacist educa-tion 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 prod-ucts and supplements. Patients also are able to secure these products through the Internet. Ephedra, obtained from the plant ma huang, has been tradition-ally 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 Aristolo-chic acid is a component of several other herbs, including aristolochia, which is used in Chinese herbal medicine. Sever-al 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 edu-cate patients about the significant risks associated with these products.

With the increasing need to enhance the understanding of dietary supple-ments, there are opportunities for

pharmacy schools and universities to implement academic instruc-

tional programs on pharmaceu-tical and therapeutic uses of

dietary supplements and herbal products. A few schools offer online elec-tive courses, such as the University of Findlay’s

Medicinal Herbs course, to pharmacy students.18 Stu-

dents’ interest and evalu-

ation of the course clearly support the idea that pharmacy students and phar-macists have a desire for knowledge with which they can become more empow-ered to counsel patients on this impor-tant 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 supple-ment use by US adults: data from the National Health and Nutrition Examina-tion 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 supple-ment 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: 1999-2010e. http://newhope360.com/NovDec-2010-US-Practitioner-Channel-Supplement-Sales-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, Eisen-berg DM, Phillips RS. Factors associated with dietary supplement use among pre-scription medication users. Arch Intern Med.

2006;166(18):1968-1974.

9. The Complete German Commission E Mono-graphs: 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 hepatotox-icity 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 predispos-ing 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-associat-ed 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 Phar-macy, Findlay, Ohio. On-Line Elective Course on Medicinal Herbs. (Contact person: Chandra M. Sekar, PhD, Associate Professor of Phar-maceutical 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.

REPORTING TOOlcontinued from page 1 ‘Hospitals have no

clue how safe they are,

and neither does the

public, for that matter.’

—David C. Classen, MD

HERBAlScontinued from page 34

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Computerized prescribing and error report-ing 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, 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 Psy-chiatr 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 profes-sor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine, in Baltimore. Everything from indecipherable hand-writing and inaccurate transcriptions, to mis-calculations and administration mistakes, even

An advanced e-learning program offers phar-macists the opportunity to build the skills

needed to be tomorrow’s clinical and man-agement 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 Glo-balHealth Education, an online educational ser-vices firm based in West Palm Beach, Fla. The initiative is an extension of efforts that began in 2008, when the center enrolled its first Phar-macy 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

Psychiatric Medication Error Rates Slashed Via e-Prescribing Initiative

Online Academy Prepares Future Pharmacy Leaders

Salt Lake City—The way a tumor responds to a short course of endo-crine therapy given before sched-uled surgery in women with estrogen receptor (ER)–positive breast can-cer 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

In ER-positive breast cancer …

Presurgical Endocrine Therapy May Be Clue to Tumor Resistance

Salt Lake City—Smokers who develop cancer may think it is too late to improve their health by kicking the habit. That is a danger-ous misconception that caregivers need to correct, according to Jane Pruemer, PharmD, BCOP, profes-sor 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 con-sider 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 effectivestrategies to improve outcomes in

A call to action for the profession

Helping Cancer PatientsQuit Smoking Pays Off


� pharmacypracticenews.com The Pharmacist’s News Source Volume 38 • Number 5 • May 2011 �Hematology/Oncology Pharmacy Edition

in this issue

Leadership in ActionIt shouldn’t be lonely atthe top. 62

Operations & Mgmt

TelepharmacyRural health-system reaps benefits of round-the-clock drug order review. 67

Technology

FDA WatchFinally, a new drug for melanoma approved. 72

Policy

Hem/Onc PharmacyJapan nuclear crisis shakes U.S. drug supply.

14Critical CareStatins in the ICU: ready for prime time? 28Pain MedicinePain contracts: are they really worth the hassle? 52

Clinical

Drug Interactions in Post-Kidney Transplant Patients

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Optimizing Warfarin Therapy Insert after page 38

Educational Reviews

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inner-city Baltimore hospital by more than 80%, report Johns Hopkins researchers.

The findings, published in the March issue of the Journal of Psychiatric Practicethe 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 (chiatr Pract 2011;17:81-88).







•

As 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 prac-tices are now trying to reel them back in, according to the Association of Com-munity Cancer Centers (ACCC).

In the May/June issue of ACCC’s Oncology Issues, the association high-lights a panel discussion of the group’s

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

idea and how it is best imple-mented. “The effort was to edu-cate the membership on what

goes into establishing a dis-pensing pharmacy, includ-ing 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 discus-sion was a follow-up to a 2010 survey on

office-based dispensing conducted by a team led by Mr. D’Amato. The research-ers 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 dis-pensing 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 respon-dents indicated that they were not seek-ing a sigificant profit from drug dispens-ing. 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/Octo-ber edition of Oncology Issues.

A Question of Counseling

David H. Henry, MD, a medical oncol-ogist at the Joan Karnell Cancer Center at Pennsylvania Hospital, in Philadel-phia, 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 phar-macies,” 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 prac-tice. “Nurses can talk to patients about what’s bothering them, how the drug works, and any toxicities or complica-tions 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 con-vinced that the benefits outweigh their

Dispensing Drugs Inside the Cancer Clinic: Who Benefits?

‘We are creating conversations about side effects and what

the patients can expect from their medications. It has been a

differentiator [ for our practice].’—John Hennessy, MBA


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costs. “We don’t have enough information about how oral cancer drugs are being provided from office practices,” said Wil-liam Guss, PharmD, vice president at Aptium Oncology, Inc., in Los Angeles, which manages five comprehensive can-cer programs. “The model varies from dispensing being an added responsibility of existing staff, to the addition of a phar-macist, 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 can-cer drugs with the setting for cancer care” may do “clinical good” if the entire range of challenges is addressed, including medication handling and dis-posal, compliance and adherence, stor-age 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 sup-portive agents such as antidepressants and anti-nausea medications.

With hundreds of oral oncolytics in development, and with Medicare reim-bursement rates for injectable drugs dwindling, the small revenue stream from bringing pharmacy in-house—“just above break-even,” in Dr. Henry’s case—can pro-vide some help for struggling practices.

Weighing the Financial Benefits

The more drugs, the better the prac-tice’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 hospi-tal participating in the 340B [federal drug discount] program, then the hospital’s retail pharmacy, or a contract retail phar-macy, could actually obtain expensive oral cancer drugs at a lower cost than a physician’s office [with an in-house phar-macy service],” noted Dr. Guss.

Timothy Tyler, PharmD, director of pharmacy services for the Comprehen-sive Cancer Center at Desert Regional Medical Center, an Aptium center locat-ed 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 knowl-edgeable pharmacist with training in cancer care, for example, that could be a problem. “While an oncologist likely knows a lot about the drugs they pre-scribe, they might be less aware of poten-tial drug interactions. Pharmacists have always been their “safety net,” he said.

Moreover, any ownership in the phar-macy venture could change a physician’s prescribing behaviors, Dr. Tyler noted.

Sarah Scarpace, PharmD, BCOP, assis-tant dean for pharmacy professional

affairs at Albany College of Pharmacy and Health Sciences, in New York, voiced an additional concern. She said she wor-ries 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 compre-hensive 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 instruc-tion 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

‘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

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In Focus

45Hem/Onc Pharmacy

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 lit-erature that if you are going to have a hypersensitivity reaction with pacli-taxel, it’s usually with the first couple of doses,” said Michael Berger, RPh, PharmD, specialty practice pharma-cist 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 hyper-sensitivity 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 record-ed 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 pre-medication, and zero patients had need for rescue medication. Our 95% con-fidence 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 num-bers of patients, but it was prospec-tive,” Dr. Berger said. “For patients who inquire about the need for premedica-tions, 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

jittery and hyperactive, without neces-sarily putting them at any greater risk for hypersensitivity.

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.”

‘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 spe-cialist 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 univer-sal adoption of this method,” Dr. Kintzel said. “However, the report is useful for providing guidance to clinicians man-aging patients who are tolerating infu-sions of paclitaxel without hypersensi-tivity reactions but are intolerant to the endocrine, anticholinergic, or other side effects of the premedications.”

Laura Michaud, PharmD, manager, clinical pharmacy services at the Uni-versity of Texas MD Anderson Cancer Center in Houston, also offered both congratulations and caution in com-menting on the study.

“I applaud the authors for their will-ingness 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 administra-tion is undertaken.”

—Fran Lowry

Drs. Berger, Kintzel, and Michaud report no relevant conflicts of interest.

Another Look at Paclitaxel Premedication

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.

Is There a Pharmacist In the House?

Ernest R. Anderson Jr., MS, RPh, sys-tem vice-president of pharmacy, Steward Health Care System, in Boston, stressed that if physician offices are consider-ing 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-

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-

macy needs to be locked,” he said.As for the question of optimal staff-

ing, Mr. Hennessy said he worked with his staff pharmacist to develop the pro-gram, 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, phar-macy 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

pharmacy and its increasingly restricted distribution networks.

“More and more cancer drugs—espe-cially oral agents—are part of these net-works and thus have to be dispensed from predetermined sites, such as community pharmacies, or are shipped directly to

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 dis-pense. 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

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.

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 distri-bution networks, Diane Gerards-Benage, CMPE, director of Medical Oncology at Quincy Medical Group, the Cancer Cen-ter at Blessing Hospital in Quincy, Ill., and another ACCC panel participant, suggested a potential solution: A physi-cian 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

‘For patients who inquire about the need for [paclitaxel]

premedications, we feel comfortable offering this

option after two doses.’—Michael Berger, RPh, PharmD

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

education.’—Ernest R. Anderson Jr., MS, RPh

INSIDE JOBcontinued from page 45


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Computerized prescribing and error report-ing 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, 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 Psy-chiatr Pract 2011;17:81-88).






Psychiatric Medication Error Rates Slashed Via e-Prescribing Initiative


Salt Lake City—The way a tumor responds to a short course of endo-crine therapy given before sched-uled surgery in women with estrogen receptor (ER)–positive breast can-cer 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

In ER-positive breast cancer …

Presurgical Endocrine Therapy May Be Clue to Tumor Resistance

Salt Lake City—Smokers who develop cancer may think it is too late to improve their health by kicking the habit. That is a danger-ous misconception that caregivers need to correct, according to Jane Pruemer, PharmD, BCOP, profes-sor 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 con-sider 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 effectivestrategies to improve outcomes in

A call to action for the profession

Helping Cancer PatientsQuit Smoking Pays Off


� pharmacypracticenews.com The Pharmacist’s News Source Volume 38 • Number 5 • May 2011 �Hematology/Oncology Pharmacy Edition

in this issue

Leadership in ActionIt shouldn’t be lonely atthe top. 62

Operations & Mgmt

TelepharmacyRural health-system reaps benefits of round-the-clock drug order review. 67

Technology

FDA WatchFinally, a new drug for melanoma approved. 72

Policy

Hem/Onc PharmacyJapan nuclear crisis shakes U.S. drug supply.

14Critical CareStatins in the ICU: ready for prime time? 28Pain MedicinePain contracts: are they really worth the hassle? 52

Clinical

Drug Interactions in Post-Kidney Transplant Patients

See page 36

Optimizing Warfarin Therapy Insert after page 38

Educational Reviews

• see QUIT SMOKING, page 9

• see DRUG ERRORS, page 71

• see ACADEMY, page 64

New Product

Watson to LaunchNulecit , a generic version of Ferrlecit

See page 43

• see BIOMARKERS, page 23


More Coverage:✜ MTM program a boon to

cancer patients 11✜ Tips for enhancing rituximab

safety, efficacy 12✜ Navigating cancer pain and

drug dependency 22

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

See page 32

Volume 38 • Number 5 • May 2011 �

ASHP

Summ

er Meeting Issue

Preview article, page 6

Come visit us at booth #519

inner-city Baltimore hospital by more than 80%, report Johns Hopkins researchers.

The findings, published in the March issue of the Journal of Psychiatric Practicethe 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 (chiatr Pract 2011;17:81-88).







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