Pharmacy Practice News May 2010

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The Pharmacist’s News Source

pharmacypracticenews.com

Volume ume 37 • Number 5 • May 2010

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With new cancer drugs …

Aggressive Steps Urged For Managing Toxicities During Chemotherapy New Orleans—Knowing the toxicities associated with newly approved agents, monitoring patients closely, and having a contingency plan in place to deal with any problems that may arise are the key ingredients for optimizing outcomes for cancer patients, Cindy L. O’Bryant, PharmD, said during a presentation at the sixth annual meeting of the Hematology/Oncology Pharmacy Association.

“It is important for pharmacists to learn, assess and understand the adverse events [AEs] that are associated with the newly approved medications for use in oncology and hematology patients,” said Dr. O’Bryant, associate professor in the Department of Clinical Pharmacy at the University of Colorado Denver, Aurora. “They need to have a predefined monitoring process, a pretreatment plan when

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see TOXICITIES, page 44

McMahon Publishing

in this issue Up Front

Late-Breaker FDA pushing to cut risks from drug infusion pumps.

4

ASHP, AMA at odds over pharmacists’ scope of practice.

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see INTERFERON, page 39

Millions of Elderly Given Inappropriate Drugs in ED

Operations & Mgmt

Finance How split-billing software can help 340B hospitals maximize savings.

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Leadership in Action Ernie Anderson on what derails workers and managers.

12

Policy

Dietary Supplements Should vitamins and herbs be regulated as OTC drugs?

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Infectious Disease

New Orleans—The question of whether adjuvant high-dose interferon-alfa represents a valid treatment option for patients with resected high-risk melanoma was the subject of a lively debate at the sixth annual conference of the Hematology/Oncology Pharmacy Association (HOPA).

Taking the pro position on this long-standing controversy was Van Anh Trinh, PharmD, BCOP, clinical pharmacy specialist at The University of Texas M.D. Anderson Cancer Center, Houston, who argued that patients with true high-risk disease who cannot participate in clinical trials should “definitely” be offered high-dose interferon-alfa

Risky pain medications among top culprits

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Clinical

No Consensus Reached On High-Dose Interferon For Resected Melanoma

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‘Three strikes’ rule on handwashing boosts compliance.

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Formulary Management

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pproximately 3 million older adults receive prescriptions for at least one potentially inappropriate medication (PIM) in the emergency department (ED) each year, according to researchers at the University of Michigan.

Moreover, 10 medications accounted for 86.5% of PIMs, and two—promethazine and ketorolac—accounted for 40%. Rounding out the top five drugs posing risks to the elderly were propoxyphene, meperidine and diphenhydramine, the investigators reported (Acad Emerg Med 2010;17:231-237).

The results came as a surprise to many pharmacists who specialize in the care of elderly patients.

“Why in the world would any physician prescribe propoxyphene? There’s no literature to show that it’s any more effective than Tylenol,” said Marilyn McEvoy, RPh, CGP, director of pharmacy at Levindale Hebrew Geriatric

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Making the switch to unfractionated heparin pays off.

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Educational Review

Nausea and Vomiting In the Oncology Setting

Insert after page

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see DANGEROUS DRUGS, page 30

Med Reconciliation Rule Released Passage may extend into summer if objections persist

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n response to numerous complaints from hospitals and other organizations that proposed revisions to National Patient Safety Goal (NPSG) No. 8 were overly detailed and burdensome, the Joint Commission in April issued for field review a revised and streamlined version of its hospital medication reconciliation plan.

In some cases, in place of detailed procedures, the new version outlines

goals and leaves implementation largely up to each institution. “The revised NPSG places a spotlight on specific risk-points in the process that are critical and readily achievable,” the Commission said in releasing the new version, now labeled NPSG 03.07.01. Although the comment period for the new version continued through May 11, the process for finalizing the rule may extend

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see RECONCILIATION, page 17

Featured Product Minocin® IV for multidrug-resistant infections.

See page

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

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

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888 TEVA USA • www.tevausa.com

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Up Front 3

Pharmacy Practice News • May 2010

Capsules

surf

Survey: Health Care Reform

MAY 2010

watch

Pharmacy Practice News asked recipients of its e-newsletter to take a survey on the recently passed health care reform legislation. Here are the topline results:

The six most-viewed articles last month on pharmacypracticenews.com: 1.

2.

3.

4.

5.

6.

Reimbursement, Shortages and REMS, Oh My! Medication Storage Tops List of Joint Commission Citations Pharmacy and Emergency Department Collaboration: A Novel Approach Going Wireless With Medication Tracking Bisphosphonates: A Dual Benefit in Breast Cancer?

The Missing Piece in the Pharmacy Practice Model

Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

heard here

Q: Do you support or oppose the recently passed health care reform legislation?

Support: 39%

Oppose: 61%

Here are some of the respondents’ comments: ‘Hopefully, the law will stop the financial drain that hospitals currently face when treating uninsured patients. Also, I hope it will help with seniors’ “donut hole” coverage.’

‘We are starting to see pharmacy practice being driven by the risk

first

‘Did these legislators ever think about holding people accountable in the current system to stop health care fraud? We should make sure that EVERYONE in this country, including the legislators [who passed the health care reform bill], has to live under the same regulations.’

‘One dangerous outcome of this legislation, I fear, is that we will not be able to use optimal medications if the government deems that the cost is too high.’

of noncompliance to regulations versus building

medication use systems that manage the

risks for all patients in the institutions.’’

—David Chen, RPh, MBA

See article, page 36

MCMAHONMEDICALBOOKS.COM

The Book Page

Assuring Continuous Compliance with Joint Commission Standards: A Pharmacy Guide Charles P. Coe, RPh, and John P. Uselton, RPh See page

48

‘Maybe the bill will result in Medicare having tighter regulations and base payments on results-oriented criteria rather than fee-forservice. That could really help control costs.’

‘We should all be thankful that this legislation was passed. Millions of deserving people will finally get the coverage they need. It’s the humane thing to do!’

Visit pharmacypracticenews.com to sign up for the e-newsletter and participate in future surveys.

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Volume 37 • Number 5 • May 2010 • pharmacypracticenews.com

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Robert Barkin, PharmD, Chicago, IL Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY BIOTECHNOLOGY Indu Lew, PharmD, Livingston, NJ

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4 Up Front

Pharmacy Practice News • May 2010

Late Breaker

FDA Seeking Safer Infusion Pumps P harmacists and clinicians are generally pleased with recent FDA efforts to improve the safety and reliability of infusion pumps, including tougher oversight of engineering, software design and manufacturing. Some worry, however, that the FDA’s proposed regulations will also delay the time it takes for improvements and innovations to become commercially available. Others say the proposed regulations do not go far enough, especially in reducing the possibility of user error, which can have disastrous consequences.

“We are in favor of changes that improve the safety of medical devices,” said Stuart Levine, PharmD, informatics specialist at the Institute for Safe Medication Practices. “One thing that concerns me is the length of time it may take for these processes to occur. Even now, FDA has to approve some software changes for smart pumps. Will this [new initiative] result in significant delays?”

On April 26, the FDA announced a comprehensive “infusion pump

improvement initiative” that included proposed strict regulations for manufacturers and practice suggestions for pharmacists and clinicians. The initiative, said Jeffrey Shuren, MD, director of FDA’s Center for Devices and Radiological Health, represents a “major shift” in its approach to medical device safety.

“Instead of responding to problems one

by one, manufacturer by manufacturer, we’re taking comprehensive steps to prevent problems by fostering the development of safer and more effective infusion pumps industry-wide.”

Devices covered by the initiative include external infusion pumps, such as those used to administer insulin infusions (with bolus doses), enteral infusions and patient-controlled analgesia.

It does not include surgically implanted pumps, such as intrathecal pain pumps, or closed-loop, autonomous infusion pump systems.

From 2005 to 2009, FDA received more than 56,000 reports of problems associated with infusion pumps involving more than 500 deaths, 19,000 serious injuries and nearly 35,000 malfunctions. Some of the deaths were due to accidental overdose from clinician error or device malfunction, according to the agency.

The most common problems involved software, human factors (user error), broken components, and alarm and battery failures. As an example, Dr. Shuren noted the problem of “key bounce,” in which a number entered into a keypad is recorded more than once, resulting in overmedication. Many of these problems are due to design defects that are “foreseeable and preventable,” he said.

Under the draft regulations, FDA will require manufacturers to provide detailed design and engineering information in

their premarket submissions, including steps taken to mitigate risks in design, manufacture, maintenance and use. Manufacturers must also test their pumps in hospital and home settings to uncover real-life environmental and user issues, instead of relying on simulated testing.

And for the first time, FDA could inspect manufacturing plants prior to approval.

Pharmacist Appauds FDA Initiative “Pharmacists and other patient safety advocates are clearly not happy with the current state of infusion devices on the market,” said Richard D. Paoletti, BS Pharm, MBA, vice president of radiology, laboratory and pharmacy operations, Lancaster General Health, Lancaster, Pa. “I applaud the FDA for taking action and hope this results in device improvements that reduce harm to our patients,” he told Pharmacy Practice News.

Mr. Paoletti said he also would like the regulations to require, and not just recommend, studies of human factors in patient safety. “As a clinician, I’m most concerned with eliminating user hazard errors,” he said. “One can hope this is [addressed] in the final regulations.”

Although the proposed regulations do not cover surgically implantable pumps, such as intrathecal pain pumps, interventional pain physicians also support the FDA’s efforts. “They have

identified a problem, done an analysis, and are attempting to come up with a systematic response to resolve the problems,” said Standiford Helm, MD, medical director, Pacific Coast Pain Management Center, Laguna Hills, Calif., and executive vice president of the American Society of Interventional Pain Physicians. “We enthusiastically support and applaud their efforts,” he told Pharmacy Practice News.

Representatives of major pump manufacturers, including Baxter Healthcare, Medtronic and CareFusion, said their companies were still reviewing the proposed regulations but supported FDA efforts to improve safety.

To help reduce risks, FDA suggests pharmacists participate in and develop educational activities with other hospital staff to promote the safe use of infusion pumps; work with a multidisciplinary team to develop and implement a plan to monitor incident/occurrence reports about infusion pumps; and collaborate with a multidisciplinary team to plan and implement a staged rollout of new infusion pumps, including analysis of early trends in incidents.

The FDA will host a public workshop on the initiative on May 25-26, in Silver Spring, Md. The public comment period on the proposed regulations closes on July 26.

—Ted Agres

AMA Seeks Limits to Pharmacists’ Scope of Practice P harmacists are challenging a report by the American Medical Association that questions their education, training and ability to provide services that the AMA considers to be reserved solely for physicians.

The “AMA Scope of Practice Data Series: Compendium on Pharmacists” contains “numerous inaccuracies, false statements and mischaracterizations about pharmacy practice and pharmacist education,” according to Henri R. Manasse Jr., PhD, ScD, executive vice president and chief executive officer of the American Society of Health-System Pharmacists (ASHP). “We are chagrined that the AMA would attempt to define, describe and prescribe the scope of practice of pharmacists,” Dr. Manasse wrote in a 24-page response in March.

The AMA issued the report in September 2009 to state and federal legislators and policymakers. It is one of 10 such “information modules” prepared by the AMA Advocacy Resource Center since January 2006. Each module analyzes a “specific limited licensure (non-physician) health care profession”

for the purpose of challenging “unwarranted scope of practice expansions that may endanger the health and safety of patients,” according to Michael D. Maves, MD, AMA executive vice president and chief executive officer.

the potential to lead to independent authority for pharmacists to monitor and modify medication therapy,” Dr. Manasse said. “But that’s what pharmacists do in many collaborative practice agreements, especially in hospitals

‘Bottom line—this is an anachronistic analysis of pharmacy’s role at a time when public policy and patient needs dictate safer and more accountable care.’

—Henri R. Manasse Jr., PhD, ScD The AMA has also issued reports critical of dentists, optometrists, nurse anesthetists, nurse practitioners, audiologists, physical therapists, podiatrists, psychologists and naturopaths, claiming that they “are currently seeking scope of practice [SOP] expansions that may be harmful to the public.”

Doctors See Danger In Collaboration Regarding pharmacists, the AMA “argues that collaborative therapy has

where they have privileges to run clinics in hypertension, antithrombosis or diabetes,” for example.

“Bottom line—this is an anachronistic analysis of pharmacy’s role at a time when public policy and patient needs dictate safer and more accountable care,” Dr. Manasse told Pharmacy Practice News. “It takes a concerted team effort.

Prominent national panels, including the Institute of Medicine, have called for additional team-based care.”

The report has not been publicly

released, but the AMA sent copies to and invited comment from several pharmacy organizations, including ASHP. According to Dr. Manasse, the report focuses on community pharmacists, questioning their education and training and characterizing collaborative drug therapy management changes in that setting “as worrisome incursions into the domain of more highly educated and trained physicians.”

Several other pharmacist organizations, including the American Pharmacists Association (APhA) and the American College of Clinical Pharmacy, have drafted comments. As of press time, the APhA was in the process of assembling the comments to send to the AMA. “A decision on whether or how those comments are made public has yet to be determined and will be made in collaboration with the

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see PRACTICE, page 49

6 Up Front

Pharmacy Practice News • May 2010

Events

Medication safety, informatics and health care policy dominate

ASHP Summer Meeting Heats Up T

he biggest challenge for pharmacists converging on Tampa, Fla., next month for ASHP’s 2010 Summer Meeting & Exhibition will be trying to settle on which of the highly relevant, but competing, educational sessions to attend.

The meeting, scheduled for June 6-9 at the Tampa Convention Center, features an abundance of choices, from five learning community sessions on safe medication use to series presentations on informatics, clinical quality standards and regulatory compliance.

The latest legislative and regulatory developments also will be in the spotlight.

On Sunday, from 12:30 to 1:30 p.m., for example, Susan Dentzer, editor-in-chief of Health Affairs, will address the complexities of the new health care reform law. And at the opening general session Monday 10 to 11 a.m., Connie Chung, award-winning television reporter and former CBS News anchor, will present a journalist’s perspective on the political forces that shaped health care reform, as part of her keynote speech.

On Wednesday from 8 to 10:30 a.m., a “hot topic” session will focus on “Strategizing with the C-Suite on Health Care Reform: Staying Ahead of the Curve.”

Led by Brian Meyer, ASHP director of the Government Affairs Division, the session will include presentations by Ernest Anderson Jr., MS, RPh, system vice president of pharmacy at Caritas Christi Health Care in Boston, Mass., and Beth Roberts, JD, partner in the Washington, DC, law firm of Hogan & Hartson.

Also set for launch at the meeting is a new mentoring program aimed at developing future pharmacy leaders.

The program, said Naomi M. Schultheis, MEd, director of instructional design at ASHP, will “match up experienced mentors with emerging leaders.”

But if any topic dominates the meeting schedule, it is medication safety. Nine sessions directly or indirectly relate to safe medication use. One of the nine sessions, scheduled for Tuesday from 8 to 10 a.m., will describe the development of a smart-pump IV delivery system at Women and Children’s Hospital of Buffalo, New York, that led to a 50% reduction in preventable medication errors.

The initiative won the ASHP Research and Education Foundation’s 2009 award for excellence in medication use safety. Moderating the session will be the Foundation’s executive vice president, Stephen J. Allen, RPh, MS, FASHP. In designing the smart-pump system, an interdisciplinary team reversed the usual process, Mr. Allen said. Instead of having to adapt their policies and procedures to an existing technology, they determined the special needs of their pediatric population first, and then designed the technology to fit. “Their prime focus was on the safety and effectiveness of the system, and they were tremendously successful,” Mr. Allen said.

“This organization serves as a role model,” he continued. “In presenting their story, we want to share the success of their accomplishments, so that other health care professionals … can learn from the approach they took.”

Indirectly related to the medication safety sessions will be a six-part series on informatics totaling more than 14 hours. Three of the informatics sessions will be moderated by Brent Fox, PharmD, PhD, assistant professor at Auburn University Harrison School of Pharmacy, Auburn, Ala. Christopher R. Fortier, PharmD, manager of pharmacy support services and clinical assistant professor at the Medical University of South Carolina, Charleston, will lead the other three sessions.

One of the sessions, led by Dr. Fortier on Wednesday from 10:45 a.m. to 1:15 p.m., focuses on the use of various technologies to improve the safety of oncology medication preparation, dispensing and administration. Another, moderated

by Dr. Fox on Tuesday from 2 to 4:30 p.m., centers on the application of technology to facilitate error reporting. There also will be sessions on the government stimulus program and health information technology (IT); how to achieve the elusive goal of “meaningful use” of electronic health records; project management strategies and how to prioritize technology within organizations; and maximizing operational efficiencies with informatics.

Dr. Fox told Pharmacy Practice News that health IT portions of the economic stimulus package had created “extreme confusion, apprehension and excitement all at the same time. Hopefully, the two sessions—on the stimulus package and meaningful use—will clear up the questions, at least with what we know today, and get people focused on what they can do locally in their institutions to get ready for adoption of these electronic records.”

In Dr. Fortier’s view, “there are really no best practices when it comes to pharmacy informatics, so hopefully these sessions will provide resources for people whatever stage of implementation they are at, whether it is just evaluating the technology, starting up or optimizing. We want people to interact with their colleagues and share experiences—the pitfalls and the lessons learned— and bring [this knowledge] directly back with them to their sites.”

For the first time, the Joint Commission hospital update (Sunday, 10 a.m.-12 p.m.) will be part of the series on regulatory compliance. The two other sessions

Come see us at Booth #219 Be sure to pick up one of our Special Projects and Publications At the ASHP meeting, we’re giving away free copies of a wide variety of medical education, including updates on key cancer therapeutic regimens, the pharmacoeconomics of inhalation agents, GI tract recovery post-surgery, and more.

in the series will focus on managing hazardous waste (Monday, 8-9:45 a.m.) and the various hospital accrediting organizations (Monday, 2-5 p.m.).

The latter session, titled “Do You Det Norske Veritas?” will provide a close look at the newest hospital accrediting body, DNV Healthcare Inc., the American subsidiary of the Norwegian quality assessment organization featured in the session’s title.

“This year, for the first time, we’re going to address the other accrediting agencies” in addition to the Joint Commission, said Patricia C. Kienle, RPh, MPA, FASHP, director of accreditation and medication safety for Cardinal Health Pharmacy Solutions, who will lead the session. “We are also going to be talking about the CMS [Centers for Medicare & Medicaid Services] Hospital Conditions of Participation. That is what all of these accrediting organizations’ standards emanate from.”

Ms. Kienle noted, “there are three organizations permitted by Medicare to accredit hospitals in the United States.

The Joint Commission is the major player, but there are these other two—DNV and American Osteopathic Association— and DNV is the one that is getting a lot

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see ASHP PREVIEW, page 49

8 Clinical

Pharmacy Practice News • May 2010

Events

Hospitalized Patients Still Not Getting Adequate Nutrition Las Vegas—Last November, nearly 500 patients from 38 hospital units participated in the first annual nutritionDay in the United States. Preliminary results from the program, presented at the recent American Society for Parenteral and Enteral Nutrition (ASPEN) Clinical Nutrition Week meeting, suggest that proper nutrition remains an elusive goal for many hospitalized patients.

According to organizers, the goal

of nutritionDay is to document and improve patient nutrition and ultimately reduce complications and medical costs related to malnourishment. The one-day audit of patients’ nutritional status (followed by a re-assessment 30 days later) is modeled on European nutritionDay, a highly successful initiative that is now in its fifth year and involves at least 32 countries.

The preliminary results of the audit underscore the gravity of malnutrition

Premixed Injection in either 4.8% Dextrose or 0.86% Sodium Chloride 5% Dextrose or 0.83% Sodium Chloride Brief Summary of Prescribing Information Cardene I.V. Premixed Injection in 4.8% Dextrose 20 mg in 200 mL (0.1 mg/mL) Each mL contains 0.1 mg nicardipine hydrochloride, 48 mg dextrose hydrous, USP, 0.0192 mg citric acid, anhydrous, USP, and 1.92 mg sorbitol, NF. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 3.7 to 4.7.

Cardene I.V. Premixed Injection in 0.86% Sodium Chloride 20 mg in 200 mL (0.1 mg/mL)

birth weights, neonatal survival, and neonatal weight gain were noted. There are no adequate and well-controlled studies in pregnant women. Cardene® I.V. should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

NURSING MOTHERS: Studies in rats have shown significant concentrations of nicardipine in maternal milk.

Therefore, use in nursing mothers is not recommended.

PEDIATRIC USE: Safety and efficacy in patients under the age of 18 have not been established.

USE IN THE ELDERLY: In clinical studies, no significant difference was observed in the antihypertensive effect of Cardene® I.V. in patients ≥65 years compared to other adult patients.

Clinical studies of nicardipine did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In 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 EXPERIENCES: 244 patients participated in two multicenter double-blind, placebo-controlled trials of Cardene® I.V. Adverse effects were generally not serious and most were expected effects of vasodilation. Some adverse effects required dosage adjustments. Therapy was discontinued in approximately 12% of patients due mainly to hypotension, headache, and tachycardia. The following numbers represent percentage of patients with adverse experiences during the double-blind portion of controlled trials with Cardene® I.V. (n=144) versus Placebo (n=100), respectively.

Each mL contains 0.1 mg nicardipine hydrochloride, 8.6 mg sodium chloride, USP, 0.0192 mg citric acid, anhydrous, USP, and 1.92 mg sorbitol, NF. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 3.7 to 4.7.

Cardene® I.V. Premixed Injection in 5% Dextrose 40 mg in 200 mL (0.2 mg/mL) Each mL contains 0.2 mg nicardipine hydrochloride, 50 mg dextrose hydrous, USP, and 0.0384 mg citric acid, anhydrous, USP. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 3.7 to 4.7.

Cardene® I.V. Premixed Injection in 0.83% Sodium Chloride 40 mg in 200 mL (0.2 mg/mL) Each mL contains 0.2 mg nicardipine hydrochloride, 8.3 mg sodium chloride, USP, 0.0384 mg citric acid, anhydrous, USP, and 3.84 mg sorbitol, NF. Hydrochloric acid and/or sodium hydroxide may have been added to adjust pH to 3.7 to 4.7.

INDICATION AND USAGE: For the short-term treatment of hypertension when oral therapy is not feasible or desirable. For prolonged control of blood pressure, patients should be transferred to oral medication as soon as their clinical condition permits.

CONTRAINDICATIONS: Cardene® I.V. is contraindicated in patients with known hypersensitivity. Cardene® I.V. is also contraindicated in patients with advanced aortic stenosis because part of the effect of Cardene® I.V. is secondary to reduced afterload. Reduction of diastolic pressure in these patients may worsen rather than improve myocardial oxygen balance.

WARNINGS: BETA-BLOCKER WITHDRAWAL: Nicardipine is not a beta-blocker and provides no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of dose of beta-blocker.

RAPID DECREASES IN BLOOD PRESSURE: No clinical events have been reported suggestive of a too rapid decrease in blood pressure with Cardene® I.V. However, as with any antihypertensive agent, blood pressure lowering should be accomplished over as long a time as is compatible with patient’s clinical status.

USE IN PATIENTS WITH ANGINA: Induction or exacerbation of angina has been seen in less than 1% of coronary artery disease patients treated with Cardene® I.V. Increased frequency, duration, or severity of angina has been seen with chronic oral Cardene® therapy.

USE IN PATIENTS WITH CONGESTIVE HEART FAILURE: Cardene® I.V. reduced afterload without impairing myocardial contractility in preliminary hemodynamic studies of CHF patients. However, in vitro and in some patients, a negative inotropic effect has been observed. Exercise caution when using Cardene® I.V., particularly in combination with a beta-blocker, in patients with CHF or significant left ventricular dysfunction.

USE IN PATIENTS WITH PHEOCHROMOCYTOMA: Limited clinical experience exists in these patients; therefore, exercise caution when administering Cardene® I.V. PERIPHERAL VEIN INFUSION SITE: To minimize the risk of peripheral venous irritation, it is recommended that the site of infusion of Cardene® I.V. be changed every 12 hours.

PRECAUTIONS: GENERAL: Blood Pressure: Cardene® I.V. decreases peripheral resistance; monitoring of blood pressure during administration is required. Cardene® I.V., like other calcium channel blockers, may occasionally produce symptomatic hypotension. Caution is advised to avoid systemic hypotension when administering the drug to patients who have sustained an acute cerebral infarction or hemorrhage.

Use in Patients with Impaired Hepatic Function: Nicardipine is metabolized in the liver; exercise caution in patients with impaired liver function or reduced hepatic blood flow; consider use of lower dosages. Nicardipine administered intravenously has been reported to increase hepatic venous pressure gradient by 4 mmHg in cirrhotic patients at high doses (5 mg/20 min). Use Cardene® I.V. with caution in patients with portal hypertension.

Use in Patients with Impaired Renal Function: When Cardene® I.V. was given to mild to moderate hypertensive patients with moderate renal impairment, a significantly lower systemic clearance and higher AUC was observed.

These results are consistent with those seen after oral administration of nicardipine. Careful dose titration is advised when treating renally impaired patients.

DRUG INTERACTIONS: Since Cardene® I.V. may be administered to patients already being treated with other medications, including other antihypertensive agents, careful monitoring of these patients is necessary to detect and promptly treat any undesired effects from concomitant administration.

Beta-Blockers: In most patients, Cardene® I.V. can safely be used with beta-blockers. However, exercise caution when using this combination in CHF patients (see WARNINGS).

Cimetidine: Cimetidine has been shown to increase nicardipine plasma concentrations following Cardene® capsule administration; carefully monitor concomitant use. Data with other histamine-2 antagonists are not available.

Digoxin: Studies have shown that Cardene® capsules usually do not alter digoxin plasma concentrations; however, as a precaution, evaluate digoxin levels when initiating concomitant Cardene® I.V. therapy.

Fentanyl anesthesia: Hypotension has been reported during fentanyl anesthesia with concomitant use of a betablocker and a calcium channel blocker. Even though such interactions were not seen during clinical studies with Cardene® I.V. (nicardipine hydrochloride), an increased volume of circulating fluids might be required if such an interaction were to occur.

Cyclosporine: Concomitant use of Cardene® capsules and cyclosporine results in elevated plasma cyclosporine levels. Monitor cyclosporine plasma levels closely and reduce its dose accordingly.

In vitro interaction: The plasma protein binding of nicardipine was not altered when therapeutic concentrations of furosemide, propranolol, dipyridamole, warfarin, quinidine, or naproxen were added to human plasma in vitro.

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Rats treated with nicardipine in the diet (at doses of 5, 15, or 45 mg/kg/day) for two years showed a dose-dependent increase in thyroid hyperplasia and neoplasia (follicular adenoma/carcinoma). One- and three-month rat studies have suggested that these results are linked to a nicardipine-induced reduction in plasma thyroxine (T4) levels, with resultant increase in plasma levels of thyroid stimulating hormone (TSH). Chronic elevation of TSH is known to cause hyperstimulation of the thyroid. In rats on an iodine deficient diet, nicardipine administration for one month was associated with thyroid hyperplasia that was prevented by T4 supplementation. Mice treated with nicardipine in the diet (at concentrations calculated to provide daily dosage levels of up to 100 mg/kg/day) for up to 18 months showed no evidence of neoplasia of any tissue and no evidence of thyroid changes. There was no evidence of thyroid pathology in dogs treated with up to 25 mg nicardipine/kg/day for one year and no evidence of effects of nicardipine on thyroid function (plasma T4 and TSH) in man. There was no evidence of a mutagenic potential in genotoxicity tests conducted in microbes, mice and hamsters. No fertility impairment was seen in male or female rats administered oral nicardipine doses as high as 100 mg/kg/day (50 times the 40 mg TID maximum recommended human dose [MRHD] in man, assuming a patient weight of 60 kg).

PREGNANCY CATEGORY C: Cardene® I.V. administered at doses up to 5 mg/kg/day and up to 0.5 mg/kg/day to pregnant rats and rabbits, respectively, produced no embryotoxicity or teratogenicity. Embryotoxicity, but not teratogenicity, was seen at 10 mg/kg/day in rats and at 1 mg/kg/day in rabbits. Nicardipine was embryocidal at oral doses of 150 mg/kg/day, given during organogenesis, to pregnant white rabbits but not at 50 mg/kg/day (25 times MRHD). No adverse effects on the fetus were observed when albino rabbits were treated, during organogenesis, with up to 100 mg/kg/day of nicardipine. Pregnant rats receiving oral doses up to 100 mg/kg/day (50 times MRHD) showed no evidence of embryolethality or teratogenicity. However, dystocia and reductions in

among hospitalized patients: • A majority of patients ate less than half of their lunches on nutritionDay. • Nearly one-third had lost almost 10 lb prior to entering the hospital.

• A majority ate less than normal prior to entering the hospital.

• Factors related to undernourishment had a significant impact on hospital resources required for patient care.

• Of patients who died within 30 days, 17% had consumed less than half

Percent of Patients with Adverse Experiences During the Double-Blind Portion of Controlled Trials Cardene® (n=144)

Placebo (n=100)

14.6 0.7 0.7 0.7

2.0 0.0 0.0 0.0

Cardiovascular Hypotension Tachycardia ECG abnormality Postural hypotension Ventricular extrasystoles Extrasystoles Hemopericardium Hypertension Supraventricular tachycardia Syncope Vasodilation Ventricular tachycardia

5.6 3.5 1.4 1.4 1.4 0.7 0.7 0.7 0.7 0.7 0.7 0.7

1.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0

Digestive Nausea/vomiting

4.9

1.0

Injection Site Injection site reaction Injection site pain

1.4 0.7

0.0 0.0

Metabolic and Nutritional Hypokalemia

0.7

0.0

Nervous Dizziness Hypesthesia Intracranial hemorrhage Paresthesia

1.4 0.7 0.7 0.7

0.0 0.0 0.0 0.0

Respiratory Dyspnea

0.7

0.0

Skin and Appendages Sweating

1.4

0.0

Urogenital Polyuria Hematuria

1.4 0.7

0.0 0.0

Adverse Experience Body as a Whole Headache Asthenia Abdominal pain Chest pain

RARE EVENTS: The following events have been reported in clinical trials or in the literature with intravenous use of nicardipine. Body as a Whole: fever, neck pain. Cardiovascular: angina pectoris, atrioventricular block, ST segment depression, inverted T wave, deep vein thrombophlebitis. Digestive: dyspepsia. Hemic and Lymphatic: thrombocytopenia. Metabolic and Nutritional: hypophosphatemia, peripheral edema. Nervous: confusion, hypertonia. Respiratory: respiratory disorder. Special Senses: conjunctivitis, ear disorder, tinnitus. Urogenital: urinary frequency.

Sinus node dysfunction and myocardial infarction, possibly due to disease progression, have been seen in patients on chronic oral nicardipine therapy.

OVERDOSAGE: Several overdosages with orally administered nicardipine have been reported. One adult patient allegedly ingested 600 mg of nicardipine (standard [immediate release] capsules), and another patient, 2160 mg of the sustained release formulation of nicardipine. Symptoms included marked hypotension, bradycardia, palpitations, flushing, drowsiness, confusion and slurred speech. All symptoms resolved without sequelae. An overdosage occurred in a one-year-old child who ingested half of the powder in a 30 mg nicardipine standard capsule. The child remained asymptomatic. Based on results obtained in laboratory animals, lethal overdose may cause systemic hypotension, bradycardia (following initial tachycardia) and progressive atrioventricular conduction block. Reversible hepatic function abnormalities and sporadic focal hepatic necrosis were noted in some animal species receiving very large doses of nicardipine.

For treatment of overdosage, standard measures including monitoring of cardiac and respiratory functions should be implemented. The patient should be positioned so as to avoid cerebral anoxia. Frequent blood pressure determinations are essential. Vasopressors are clinically indicated for patients exhibiting profound hypotension.

Intravenous calcium gluconate may help reverse the effects of calcium entry blockade.

DOSAGE AND ADMINISTRATION: DOSAGE MUST BE INDIVIDUALIZED depending on severity of hypertension and patient response. Monitor blood pressure during and after the infusion; avoid too rapid or excessive reductions in systolic or diastolic blood pressure.

Cardene I.V. Premixed Injection is supplied as a single-use, ready-to-use, iso-osmotic solution for intravenous administration in a 200 mL GALAXY container with 20 mg (0.1 mg/mL) nicardipine hydrochloride in either dextrose or sodium chloride, or with 40 mg (0.2 mg/mL) nicardipine hydrochloride in either dextrose or sodium chloride. Cardene I.V. Premixed Injection should not be combined with any product in the same intravenous line or premixed container. Protect from light; store in carton until ready to use. Protect from freezing. Avoid excessive heat.

See package insert for full prescribing information.

For questions of a medical nature, or to report an adverse event, please call 1-877-207-5802.

Cardene® I.V. is a registered trademark of EKR Therapeutics, Inc. Manufactured by: Baxter Healthcare Corporation Deerfield, IL 60015 USA Marketed by: EKR Therapeutics, Inc. Bedminster, NJ 07921 USA Issued July 2009 CAR09-240

of their lunches on nutritionDay, compared with none of the patients who had eaten at least half of their lunches.

“The first nutritionDay will set a benchmark for where we are today,” said Gail Gewirtz, MS, RD, national project coordinator. “Next time, we would hope to put some policies in place so the malnutrition in a facility declines and we can start to measure that change.”

The second annual U.S. nutritionDay is scheduled for Nov. 4, 2010.

In the United States, said Ms. Gewirtz, 55% to 60% of hospitalized patients are at risk for or suffer from malnutrition, which contributes to poor healing, increased morbidity and mortality and increased costs. According to one analysis of the European initiative, researchers concluded “decreased food intake represents an independent risk factor for hospital mortality” (Clin Nutr 2009;28:484).

‘We have a very hard time recognizing malnutrition in this country and that it has an impact on how well patients respond to treatments that we give them.’

—Jay Mirtallo, MS, RPh

Ms. Gewirtz plans to assemble bestdemonstrated practices from facilities that achieve reductions in the incidence of malnutrition, then use the information to persuade other hospitals to follow suit. European nutritionDay has led to significant improvements in patient nourishment and outcomes, she added.

It is too soon to tell what impact nutritionDay will have on the nutrition policies at participating hospitals. But during a recent visit to one facility in Chicago, Ms. Gewirtz found that the dietitian was excited that physicians were involved in the project and had suggested that dietitians become more involved in patient care. “The physicians are making more time to meet with them and are looking at their profession a little differently than before the preliminary data came out,” she said.

Wake Forest Uses Event To Boost Malnutrition Program Four units at the Wake Forest Baptist Medical Center, Raleigh, N.C., participated in nutritionDay (trauma, general medicine, plastics/wounds and cardiology). The timing of the event paralleled

Clinical 9

Pharmacy Practice News • May 2010

Events the facility’s own initiative, which established diagnostic criteria for patient malnutrition.

“We were already working with medical records to define malnutrition,” according to J. Lynn B. Coley, RD, MEd, LDN, assistant manager, clinical nutrition. “Our clinical nutrition task force took about three months to develop the appropriate criteria,” with the goal of identifying a patient’s nutritional status from the very start of the hospital stay.

For the next nutritionDay, trauma and general medicine will participate again; two other units will replace cardiology

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and plastics/wounds so that the nature of the patients and their lengths of stay will be better suited to the datagathering process.

“We have a very hard time recognizing malnutrition in this country and that it has an impact on how well patients respond to treatments that we give them,” said Jay Mirtallo, MS, RPh, specialty practice pharmacist, Nutrition Support/Surgery at The Ohio State University Medical Center, and director of the MS in Health-System Pharmacy program at The Ohio State University College of Pharmacy, both in Columbus.

“Other than dietitians, most clinicians are not well trained to recognize nutritional problems in patients. It’s always something under their radar.”

Mr. Mirtallo said he was surprised by nutritionDay results showing that such a high proportion of patients had lost so much weight before they were admitted to the hospital: That’s alarming, he said, “because weight loss is probably one of the more significant surrogate markers of outcome.”

Overall, improvements in patient nutrition have been slow, Mr. Mirtallo said. But he expressed confidence that

health care teams gradually will pay more attention to patient nutrition. “If we can highlight the fact that malnourishment correlates with a higher mortality rate, I think people will start acting on it.”

To register for nutritionDay, visit www.nutritionday.org. Participation is free of charge, anonymity is assured and all materials are provided. Participating units will receive a report about their own results plus collective data from all units of the same specialty type.

—Steve Frandzel

10 Operations & Management

Pharmacy Practice News • May 2010

Finance

340B Split-Billing Software a Savior in Mixed-Use Settings Gary Horne Pharmacy Director San Mateo Medical Center San Mateo, Calif.

Part 3 in a Series Part 1 (Nov. 2009): “340B Drug Pricing Program: A Primer.”

Part 2 (Jan. 2010): “How To Sift Through 340B Resources.”

PharmTA Consultant Health Resources and Services Administration, Pharmacy Services Support Center

T

he 340B Drug Pricing Program provides substantial cost savings on the purchase of drugs by qualified hospitals. However, complying with the inventory management requirements of the program can be challenging, which has led some small/rural hospitals not to participate.1 Because the 340B program is limited to outpatient (OP) drugs, inventory compliance can be particularly difficult in mixed-use clinical settings, where both OP and inpatient medications are used. Without specialized billing tools to keep those two pools of patients distinct, hospitals would have to maintain separate inventories to comply with the OP restriction.

Fortunately, there is a way for 340B-eligible hospitals and other facilities to simplify their record keeping: split-billing software applications. These programs can prepare and place drug orders based on medications dispensed to 340B-eligible patients, reducing pharmacy costs and ensuring 340B compliance in the process.

This article will describe how splitbilling applications work, why they are important, and explain the difference between systems used in hospitals that have mixed-use clinical practice areas versus in-house pharmacy and contract pharmacy settings.

Future Topics: Optimizing savings. How to achieve full implementation; dealing with formulary changes.

Contract pharmacy arrangements. In-house versus outside, independent consultants; specialty pharmacy considerations.

Innovations in practice. Alternative Methods Demonstration Projects (AMDP); partnering in the community; patient safety collaboratives.

• Hospitals must maintain auditable records that demonstrate compliance with 340B requirements.

The program statute can be found on the Health Resources and Services Administration (HRSA) Office of Phar-

Interface

macy Affairs (OPA) Web site: http:// www.hrsa.gov/opa/pl102585.htm#602.

The statute is supported by more detailed program guidance through notices published in the Federal Register. These notices address policy and

Interface

Health Systems Inventory Management and 340B As noted, the 340B Drug Pricing Program is limited to covered OP drugs and excludes inpatient medications. But other key provisions of the statute also should be kept in mind when considering participating in the program: • Only the entities (hospitals, longterm care facilities, etc.) outlined in the statute are eligible to participate in the 340B program • 340B participants may not resell or transfer 340B drugs • 340B drugs may not be diverted to ineligible patients • Entities may not cause a manufacturer to pay a Medicaid rebate on a 340B drug • Hospitals may not participate in an OP group purchasing organization (GPO) once enrolled in the 340B program

Drug purchased from WHOLESALER through appropriate account.

Contributed by Lisa Scholz, PharmD, on behalf of the Pharmacy Services Support Center, 2007

Figure. 340B split-billing software concept.

implementation of the 340B program and provide entities with more details on patient eligibility.

There are three particularly informative Federal Register notices for hospitals considering a split-billing solution: 1. The notice addressing patient eligibility, known as the “340B Patient Definition.” This final guidance describes the characteristics of 340B-eligible patients that entities are expected to be able to document. In summary, hospitals should have a relationship with the patient, supported by the existence of a medical record, and hospitals are responsible for the health care services provided to the patient (ftp://ftp.hrsa. gov/bphc/pdf/opa/FR10241996.htm see also http://www.hrsa.gov/opa/patientdefinition.htm).

2. The notice addressing 340B use in OP settings of hospitals, which states that eligible settings must be fully integrated into the hospital and included on the hospital’s Medicare cost report (ftp://ftp.hrsa.gov/ bphc/pdf/opa/ FR09191994.htm).

3. The notice addressing audit and dispute resolution, which states that HRSA or drug manufacturers may audit entities, provides examples of the types of information for audit and lists the processes governing the audit/dispute resolution (ftp://ftp.hrsa.gov/bphc/pdf/ opa/FR12121996.htm).

The statute and all the 340B guidelines establish the need for 340B-eligible facilities to capture and record information, allowing an entity to easily demonstrate accountability for 340B drugs from purchasing to dispensation/ replenishment. As noted, split-billing software provides a means for entities to simplify this record keeping: It can prepare and place orders based on medication dispensing to 340B-eligible patients, and it can improve pharmacy costs and eliminate the need to maintain separate inventories.

Several other restrictions and conditions need to be kept in mind. For example, a hospital participating in 340B, as stated in the 340B statute, must opt out of its GPO contracts for medications administered or dispensed in the OP setting. The GPO exclusion applies to all settings of the hospital where OP drugs are used, including the OP (ambulatory or retail) pharmacy, mixed-use settings such as the emergency department (ED), ambulatory surgery, observation, cardiac catheterization and so on. Therefore, the entity must order drugs used in these settings from a specific 340B account, or another source such as the wholesale acquisition cost (WAC) account, rather than the account associated with GPO pricing.

Operations & Management 11

Pharmacy Practice News • May 2010

Finance Split Billing Defined Split billing really means splitting a purchase order with items for the inpatient setting into the “regular” account and the drugs dispensed in the OP setting to the 340B account. An accumulator records charges of drugs in the OP setting in one “bucket” to be purchased using the 340B account; inpatient setting charges are placed in a second bucket; and other miscellaneous charges go into a third bucket, or trash can, for further review. The entity uses a stockreplenishment model, where items are purchased from the 340B account to replace the items that were used from existing inventory.

As items in the bucket reach quantities equal to purchase package-unit sizes, an order is created to purchase the items using the 340B account. The items purchased must have the same National Drug Code (NDC) of the items administered, so making a decision on which manufacturer to use for multisource product should be considered in formulary selection.

Split billing may be accomplished via manual, or “home-grown,” solutions, or software applications purchased through a vendor or third party. Building one’s own solution may take a great deal of time and expertise; however, in small hospitals this manual approach often is accomplished through a database application (e.g., Excel) charged to outpatients in a spreadsheet, or a database application coupled with reordering when a package size is reached.

Third-party solutions automate the process and are developed for either the traditional OP mixed-use areas or for the retail or contract pharmacy.

Software Application 101 Medications are administered to patients in the mixed-use settings throughout the day. Charge capture for these drugs can be accomplished with a variety of methods and technologies, such as automated dispensing cabinets (ADC), charge entry, order entry and so on. As the charges are accrued and posted, the hospital system will indicate which charges hit the OP account and which were charged to inpatients.

Medications flagged as OP charges accumulate in the split-billing application and a recommended replenishment order, based on this accrual, is automatically generated. Detailed item information allows the buyer to view the order, which can then be edited according to the pharmacy’s needs, before being finalized.

Depending on the particular software, users can generate an upload summary and review exception items—that is, items that do not match valid 340B items, obsolete NDC number, and so on.

An invoice summary tracks and displays

Split-billing software programs are critical in the management of 340B inventory for most eligible facilities, so be sure to build in the cost of the software and related tools in your hospital’s business plan. the amount of money saved on the 340B program.

Emergency Department Application In the ED, most of the medications administered are for outpatients. As charges for these medications are recorded by the hospitals’ charge system, the accumulator adds the items

by NDC number in the OP bucket. As the bucket fills up, the application will then adjust the total to create a purchase of one or more inventory units.

For example, diphenhydramine 50 mg injection is purchased in boxes of 25 vials. When the total number of vials administered to ED patients reaches 25, the application creates an order for one box of 25.

These applications generally are priced as either a subscription, where the entity pays a monthly or annual fee, or as a one-time charge to prepare a solution specifically for the entity.

Most require a one-time setup fee. Entities should remember that the 340B program does not allow for Medicaid duplicate discounts and must be sure to bill appropriately in all situations involving Medicaid. The ongoing savings usually more than pays for the cost of the annual subscription fees. If the eligible facility cannot pay for the application from these savings, then a manual method may make the most sense.

Contract or In-House Pharmacy Open to the Public Covered entities that do not have an in-house pharmacy may wish to partner with a pharmacy in the community to provide pharmacy services. In this case, a “ship to bill to” payment mechanism is established. In this arrangement, the 340B drugs are billed to the eligible facility, but shipped to the contract

pharmacy. A future article will provide a more detailed explanation of contract pharmacy arrangements.

Both in-house and community pharmacy settings share similarities in terms of billing: All medications are dispensed from the pharmacy’s regular inventory and dispensed to 340B-eligible patients.

These are recorded in the appropriate bucket to be purchased using either the eligible facility’s 340B account or the pharmacy’s account.

Eligible patients are provided a card that is used like an insurance card, and the claims processor collects dispensing information to create the purchase order for the eligible facility. The patient then takes the prescription to the in-house pharmacy or pharmacy contracted with the eligible facility to have the prescription filled. Using the information on the card, the prescription is filled, the switch company adjudicates the claim and the patient pays the co-pay or sliding-scale price. The pharmacy benefit manager accumulator keeps track of medications dispensed by NDC number and creates a purchase order to replace the medications dispensed. The pharmacy or entity reviews and transmits the order to the wholesaler, the drugs are shipped to the pharmacy and the bill is paid for by the entity.

In the above strategy, the dispensed medications are typically priced as a feeper-prescription filled and have audit capability.

Choosing a Mixed-Use Strategy Before choosing any strategy for processing 340B prescriptions in mixeduse settings, there are many things to consider and many questions to ask.

The first question should be, “am I compliant with the regulations required for

participation in the 340B purchasing program in my mixed-use settings?” If the answer is “no,” or “I don’t know,” then pursuing a billing software solution may be part of the answer for your hospital.

Not all strategies are equivalent and there are advantages and disadvantages of each. To find the right one, the entity must conduct a thorough internal evaluation of its work flow, systems, budget and other resources before making a final decision. Examples include how much installation and training time will be required, ease of use, compatibility with the wholesaler and other distributors, auditing capabilities, how much time must be devoted to maintenance of files, how obsolete NDC numbers are handled and the total cost to the facility based on the expense of the solution. For more information, contact the U.S. Department of Health and Human Services’ Pharmacy Services Support Center (PSSC) at (800) 628-3297 or via e-mail at PSSC@aphanet.org.

Moreover, in evaluating any splitbilling approach, don’t underestimate the important role that inventory management plays. For hospitals that serve 340B-eligible and noneligible patients— typically termed an open versus closed system—an inventory management system may be beneficial to ensure compliance and eliminate diversion of 340B-purchased drugs.

Calculating Worth Split-billing solutions are critical in the management of 340B inventory for most eligible facilities, so be sure to build in the cost of split-billing software and related tools in the business plan and return-on-investment calculations. Substantial cost savings will still be achieved and it is much easier to plan for these expenditures up front than trying to justify the costs after savings have been realized. It will be one of the best tools to prevent diversion and will save many hours and much frustration when the time comes for an audit.

Conclusion The integrity of the 340B Drug Pricing Program depends on compliance with guidelines that are established by the HRSA’s OPA. The eligible facility is ultimately responsible for ensuring compliance, and failure can potentially result in substantial monetary losses or even exclusion from the program.

Using a split-billing solution to purchase medications used in the mixed-use settings helps the hospital maintain compliance. Use of split-billing solutions in the “retail” environment may provide the best tool to prevent diversion. The audit reports are invaluable for meeting record-keeping requirements or when the eligible facility is audited.

12 Operations & Management

Pharmacy Practice News • May 2010

Leadership in Action

Are You Helping or Hindering Your Staff?

A ccording to Ken Blanchard, in his book, “The Servant Leader,”1 there are two marks of a great leader—succession planning and seeking feedback.

Let’s explore these in light of Reldan Nadler’s “Leaders’ Playbook: How to Apply Emotional Intelligence—Keys to Great Leadership.”2 The No. 1 reason that most workers leave their jobs is because of a lack of appreciation from their bosses. Having been on both sides of that fence, I can attest to the experience of having an unappreciative boss and having a great boss. The real question, however, is what kind of a boss are you?

A debilitating boss, according to Nadler, is one who lacks clarity on direction and expectations, yet criticizes the results. Lack of clarity is debilitating and dysfunctional—it frustrates and sucks the passion out of employees, and leads to a lack of respect from them.

I always tell our managers that we need to treat our employees like volunteers in order to get their best efforts. If we are debilitating bosses, we emotionally deflate our employees, making them feel ineffective, inadequate and weak.

This dramatically affects their confidence and they underperform. So, your action plan should include showing specific appreciation to those employees for their commitment.

Yesterday, my boss asked if I had a good “medication safety story” that she could highlight in an upcoming newsletter. I gave her a fine example from one of our clinical coordinators who had collaborated on the care of a patient’s special insulin therapy needs. My boss was pleased, and I thanked and praised the clinical coordinator for his responsiveness and attention to good patient care.

He appreciated the kind words.

If it is true that most employees leave their jobs due to a debilitating boss, then think of the costs that are incurred. There are the costs of frustrated employees going through the motions, but not feeling motivated enough to give their hearts and souls to their work. Then, there is the high cost of turnover, including recruiting and training. The impact of high turnover rates can be devastating to the entire department—affecting overall productivity and morale.

So what do employees want from their jobs? Most employees want work that is rewarding, challenging and exciting.

Many of us “landed” in the health care industry because we are compassionate, patient-focused caregivers. People want growth opportunities. We want to work toward advanced positions and hone our knowledge and abilities.

The most satisfied employees are those who feel they make a difference in the

lives of patients, directly or indirectly.

I remember taking IV technicians up to the neonatal intensive care unit to show them the neonates for whom they were preparing total parenteral nutrition solutions. They felt a great sense of pride and satisfaction. So here are some questions to ask yourself: • Is there a clear vision of where you are going in your department?

• Is there clarity of expectations for individuals and the team?

• Are there standards of performance?

• Are employees engaged to contribute?

• Do you have a climate that values all individuals?

Nadler states that “Good bosses raise the ‘discretionary efforts’ of the team.”

Discretionary effort is the dedication, loyalty and amount of effort put into a

project or assignment. If you are a good boss, employees will willingly offer their best efforts and aim to please you. Small increases in productivity can have a major impact on your team effort. These behaviors are contagious.

What are the responses of employees if you are a poor boss or your response if you have a debilitating boss?

• Communicate with the boss using conflict resolution skills and stand up to him or her and get your mission accomplished despite a debilitating boss.

• Have enough self-confidence to know you are doing a good job and do not let your boss irritate you.

• Use team-building skills with others to support you and your projects.

• Take the initiative to find another job.

Table. The “Leaders’ Playbook” Derailer Detector DirectReport Employee

You 1. “Smartest person in the room” syndrome: Has to be right all the time, married to own ideas and not open to or distrusting of new ideas 2. Lack of impulse control: Emotionally reactive, volatile, abrasive and follows urges to an unhealthy extreme 3. Drives others too hard: Micromanages and takes over rather than delegates 4. Perfectionism: Sets unrealistic goals; rejects criticism 5. Defensive: Blames others; is inflexible and argumentative 6. Risk-averse: Lacks courage to take risks 7. Failure to learn from mistakes: Same kind of mistakes shows up 8. Lacks insight into others: Can’t read others’ emotions or reactions 9. Doesn’t ask for feedback: Misses opportunities to include others for better decisions 10. Self-promotion: Is attention-seeking; overlooks others’ accomplishments for own recognition 11. Lack of integrity: “Unhonest” with self and then others; omits and minimizes 12. Failure to adapt to cultural differences: Does not change leadership style appropriately 13. Indirect with others: Does not give the hard feedback or make the difficult decisions about people 14. Approval-dependent: Needs too much approval before making decisions 15. Eccentricity: Unpredictable and odd in behavior 16. Mistreats others: Callous, demeaning or discounting to others and their needs 17. Self-interest: Acts in self-interest instead of the interest of the whole organization or larger group 18. Insular: Disregards health and welfare of group outside the responsibility of own organization or team

Adapted from Leslie and Van Velsor (1996), Bryam, Smith and Paese, Grow Your Own Leaders (2002); Kaplan, Beyond Ambition (1991); Dotlich and Cairo, Why CEOs Fail (2002); Kellerman, Bad Leadership (2004); and Lipman-Blumen, The Allure of Toxic Leadership (2005).

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, System Vice President of Pharmacy, Caritas Christi, Boston, Mass.

Mr. Anderson welcomes your input on leadership issues, at ernest.anderson@ caritaschristi.org.

Ernest R. Anderson Jr., MS, RPh

Take the Test Are you interested in learning whether you have tendencies toward being that debilitating boss? Are you willing to take the “Leaders’ Playbook” Derailer Detector? Instructions: Rank yourself and an employee who reports directly to you on the behaviors listed in the Table. The rankings are as follows: 1=almost never; 2=happens once every three months; 3=happens once a month or more often.

Count up the number of 2s and 3s for you and your direct-reporting employee.

If either of you have three or more 2s, that is a warning sign for derailers—that is, employees who limit the potential of the team or organization. Two or more 3s and you and the organization are at risk.

Based on your score, you and your staffers may have some work to do when it comes to creating more positive working relationships. Nadler pinpoints several benefits to such efforts: • Earning the trust of others allows you to communicate more directly, resolve conflicts more easily and enable your team to better follow your lead.

• Empathy skills enable you to build strong relationships, internally and externally. When people feel that you care about them as individuals, they will be more giving and are more likely to be committed to following your leadership.

• Self-confidence enables you to take initiative and achieve goals—despite barriers and obstacles.

Getting Serious I invite you to take the derailer evaluation, identify your weak areas, and then determine how you can change. It may require education and training sessions, plus feedback from your own boss or subordinates and peers. Go back to my last column and complete the rating scale on how to apply emotional intelligence. Making changes is a bit like treating a patient.

First, we have to assess the problem and make a diagnosis, and then we can treat the problem. Doing the self-assessment is hard work, but leads to making improvements that will have enormous impact on yourself and those around you. That’s what good leaders do.

References 1. Blanchard K, Hodges P. The Servant Leader.

Nashville, TN: Countryman; 2003.

2. Nadler R. Leaders’ Playbook: How to Apply Emotional Intelligence—Keys to Great Leadership. Santa Barbara, CA: Psyccess Press; 2006.

14 Policy

Pharmacy Practice News • May 2010

Dietary Supplements Need is there, political will is not

Study Calls for Some Vitamins To Be Regulated as OTC Drugs T

he odds are fairly slim that a new pharmacologist-authored study calling for certain vitamins to be regulated as over-the-counter drugs will meet with legislative success. Even so, experts say the proposal is fully justified based on the continuing, serious danger posed to consumers by current U.S. regulations permitting vitamins to be sold at high dosages, without labels warning of pos-

sible side effects or drug interactions.

“The odds for passage are not good at this point in time,” said Larry Sasich, PharmD, MPH, a longtime consultant to Public Citizen’s Health Research Group who has lately moved to Riyadh, Saudi Arabia, where he is helping to rewrite that country’s food and drug laws.

“We’re going to continue to see fat-soluble vitamins sold in the United States

that have dangerously high potencies and are not labeled properly.”

The new study, in Annals of Pharmacotherapy (2010;44:311-324), came out the same month that Sen. John McCain (R-Ariz.) introduced the Dietary Supplement Safety Act of 2010. The bill would have given the FDA new powers to recall unsafe dietary supplements and to require companies to list all ingre-

Your vision. Our commitment.

Together, we will move healthcare forward.

dients on the labels. By early March, however, Mr. McCain had withdrawn his support for the bill at the urging of Sen. Orrin Hatch (R-Utah), who is from a state where dietary supplements are a major industry.

Despite the slim chances for passage, the new proposals for regulating vitamins as OTC drugs drew accolades from pharmacists who have devoted their careers to the study and use of dietary supplements.

“I’ve said for years that something like this ought to come out,” said Cathy Creger Rosenbaum, PharmD, MBA, RPh, who counsels individuals on healthy lifestyles as alternatives to the need for prescription medications.

“The article nicely outlines the dangers of mega-dosing,” added Dr. Rosenbaum, who also serves as clinical effectiveness and safety officer at Bethesda North Hospital pharmacy, in Cincinnati. “The average person doesn’t know if 3,000% of the RDI [recommended daily intake] for supplements is too much. Somebody needs to help [resolve] that.”

Even Wider Restrictions Urged

Healthcare today. It’s a time of change, of challenge and of great opportunity. At Hospira, creating the future begins with your vision and the goals we share. Goals like making healthcare safer, more efficient and more cost effective. So far, we’ve made great strides forward, like taking over 500 million dollars out of the U.S. healthcare system—all with a single generic specialty injectable.1 And that’s only the beginning. Together, we will move healthcare forward.

Advance with us.

Share your vision of the future with us at www.HospiraAdvanceWithUs.com.

WE LISTEN.

WE THINK.

WE DISCOVER.

W E C R E AT E .

Reference: 1. Data on file. Generic drug savings information. Hospira, Inc.

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

P09-2486B-R1

W E A D V O C AT E .

W E I N V E S T.

Beyond the five vitamins cited in the paper—A, B3 (niacin), B9 (folic acid), D and E—all other vitamins, herbs and dietary supplements should likewise be regulated as OTC drugs, said David J. Kroll, PhD, a natural products cancer pharmacologist who focuses on the discovery of novel compounds from natural sources.

“I think it would make sense for all these supplements to be regulated as OTC drugs,” said Dr. Kroll, professor and chair of the Department of Pharmaceutical Sciences at North Carolina Central University, in Durham. But, he added, “it’s not practical because of existing legislation that says the vitamins displayed on retail shelves are supposed to be used to prevent disease, not for treatment.

One of the criteria for OTC classification is that the patient has to be able to identify an illness and recognize whether or not they’re responding to the agent.

Nobody’s supposed to be taking vitamin A or vitamin E to treat a disease.”

In 2004, Dr. Kroll wrote the first draft of what became the American Society of Health-System Pharmacists’ Statement on the Use of Dietary Supplements (Am J Health Syst Pharm 2004;61:1707-1711), which called for U.S. dietary supplement regulations, including vitamins, to be revised “with the primary goal of providing consumers and health care practitioners with the information they need to use dietary supplements safely and effectively.”

Policy 15

Pharmacy Practice News • May 2010

Dietary Supplements

‘We want people to know about these potential risks, especially when parents are giving their children high doses for long periods of time.’

—Ran D. Goldman, MD

The authors of the new study reviewed adverse events, adverse effects and vitamin–drug interactions between 1966 and 2009, by conducting a MEDLINE/ PubMed search and reviewing four online databases (MedlinePlus, Drug Digest, Natural Medicine Comprehensive Database and the database of the University of Maryland).

“Vitamins have documented adverse effects and toxicities, and most have documented interactions with drugs,” the review found. “While some vitamins (biotin, pantothenic acid, riboflavin, thiamine, vitamin B12, vitamin K) have minor and reversible adverse effects, others, such as fat-soluble vitamins (A, D, E), can cause serious adverse events.

Two water-soluble vitamins, folic acid and niacin, can also have significant toxicities and adverse events.”

The study concluded: “Our recommendation is that vitamins A, E, D, folic acid and niacin should be categorized as over-the-counter medications.

Labeling of vitamins, especially those intended for children and other vulnerable groups, should include information on possible toxicities, dosing, recommended upper intake limits and concurrent use with other products.

Vitamin A should be excluded from multivitamin supplements and food fortificants.”

A Role for Pharmacists The senior author of the research said that although he could not speak to the recommendations’ legislative viability, the findings point up the need for pharmacists and other health care professionals to communicate with patients about their use of vitamins.

“As an emergency physician and a pediatrician and clinical pharmacologist, what’s important for me is that

parents and health care providers talk about these issues,” said Ran D. Goldman, MD, chief of pediatric emergency medicine at British Columbia Children’s Hospital, in Vancouver, Canada.

“Not many of the common adverse events are usually recognized as relating to supplements. We want people to know about these potential risks, especially when parents are giving their children high doses for long periods of time.”

As an example, he noted that vitamin C can decrease the elimination rate of acetaminophen, thereby increasing its half-life. “The mere use of vitamin C has the potential to increase the blood level of acetaminophen and potentially cause adverse events,” he said. “Clinical pharmacists can provide information to parents and to other providers to bridge the gap in recognizing and preventing these kinds of adverse reactions due to vitamins.”

Trade groups representing the dietary supplement industry criticized the study’s findings and methodology.

“The authors have clearly cherrypicked literature to support their position and did not assess the totality of evidence in order to develop their unbalanced recommendation,” said Andrew Shao of the Council for Responsible Nutrition, in a published statement released by the trade group.

Asked to respond to that critique, Dr. Goldman said, “I would suggest reading our published paper and then decide if we cherry-picked literature. All the references are available for anyone to review. The rigorous peer-reviewers of this high-impact journal definitely did not think any cherry-picking was going on, and accepted the paper for publication.”

—Dan Hurley

What’s Your View?

In pre-dialysis CKD anemia

join

the movement

IMPORTANT SAFETY INFORMATION: Venofer® (iron sucrose injection, USP) is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer ® or any of its inactive components, and in patients with anemia not caused by iron deficiency. Hypersensitivity reactions have been reported with IV iron products. Hypotension has been reported frequently in non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving IV iron. Hypotension following administration of Venofer ® may be related to rate of administration and total dose delivered.

In a multi-dose efficacy study in NDD-CKD patients (N=91), the most frequent adverse events ( 5%) whether or not related to Venofer ® administration, were taste disturbance, peripheral edema, diarrhea, constipation, nausea, dizziness, and hypertension.

™

Millions prescribed. Millions treated.

Should vitamins be regulated as OTCs? Are other measures needed to increase their safety? Or are current laws adequate?

Send your feedback to ppneditor@mcmahonmed.com.

Over 9 million patients treated with 180 million units* 1

*100 mg vials and ampules worldwide from 1992 to February 2009.

Reference: 1. Data on file. American Regent, Inc. Shirley, NY.

Please see brief summary of full prescribing information on following pages..

Venofer® is manufactured under license from Vifor (International) Inc., Switzerland. © 2009 American Regent, Inc. Reimbursement and Patient Assistance Program Hotline: 800-282-7712 • Orders or information: 800-645-1706 • venofer.com

=?6;A

@5.?2

?20<::2;1

2 :.69

0<::2;A

Leading anemia management.™

VENFA1 Iss.8/2009

16 Policy

Pharmacy Practice News • May 2010

FDA Watch

Black Box Added to WinRho SDF Label Several cases of intravascular hemolysis reported, some fatal

H

ealth officials have added a black box warning to the platelet deficiency drug Rho(D) immune globulin intravenous (WinRho SDF), following reports that the medication caused a condition in some patients leading to lethal cases of anemia or multiorgan failure.

On March 10, the FDA, WinRho SDF manufacturer Cangene Corporation and WinRho SDF distributor Baxter Health-

care announced that some patients being treated with the drug for immune thrombocytopenic purpura (ITP), a bleeding disorder in which the immune system destroys platelets necessary for blood clotting, died after developing intravascular hemolysis (IVH). IVH, a condition in which hemoglobin separates from red blood cells, can cause severe anemia, multisystem organ failure and respira-

tory distress. Fatal outcomes have occurred, most frequently in patients over age 65 with comorbidities.

A letter to health care professionals posted on the FDA’s Web site states that the boxed warning strengthens earlier warnings about the risk for ITP patients to develop IVH. The companies caution that the drug should not be used

Reference: 1. 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. 2. Data on file. American Regent, Inc., Shirley, NY.

(Table 2 continued)

Brief Summary (See Package Insert For Full Prescribing Information) Therapeutic Class: Hematinic CLINICAL INDICATIONS AND USAGE Venofer® (iron sucrose injection, USP) is indicated in the treatment of iron deficiency anemia in the following patients: • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients receiving an erythropoietin • non-dialysis dependent-chronic kidney disease (NDD-CKD) patients not receiving an erythropoietin CONTRAINDICATIONS The use of Venofer® is contraindicated in patients with evidence of iron overload, in patients with known hypersensitivity to Venofer® or any of its inactive components, and in patients with anemia not caused by iron deficiency.

WARNINGS Hypersensitivity reactions have been reported with injectable iron products. See PRECAUTIONS and ADVERSE REACTIONS. PRECAUTIONS General: Because body iron excretion is limited and excess tissue iron can be hazardous, caution should be exercised to withhold iron administration in the presence of evidence of tissue iron overload. Patients receiving Venofer® require periodic monitoring of hematologic and hematinic parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Iron therapy should be withheld in patients with evidence of iron overload. Transferrin saturation values increase rapidly after IV administration of iron sucrose; thus, serum iron values may be reliably obtained 48 hours after IV dosing. See DOSAGE AND ADMINISTRATION and OVERDOSAGE. Hypersensitivity Reactions: Serious hypersensitivity reactions have been reported in patients receiving Venofer®. No life-threatening hypersensitivity reactions were observed in the clinical studies. Several cases of mild or moderate hypersensitivity reactions were observed in these studies. There are post-marketing spontaneous reports of life-threatening hypersensitivity reactions in patients receiving Venofer. See ADVERSE REACTIONS. Hypotension: Hypotension has been reported frequently in hemodialysis dependent chronic kidney disease patients receiving intravenous iron. Hypotension also has been reported in non-dialysis dependent and peritoneal dialysis dependent-chronic kidney disease patients receiving intravenous iron. Hypotension following administration of Venofer® may be related to rate of administration and total dose administered. Caution should be taken to administer Venofer® according to recommended guidelines. See DOSAGE AND ADMINISTRATION. Carcinogenesis, Mutagenesis, and Impairment of Fertility: No long-term studies in animals have been performed to evaluate the carcinogenic potential of Venofer®.

Venofer® was not genotoxic in the Ames test, the mouse lymphoma cell (L5178Y/TK+/-) forward mutation test, the human lymphocyte chromosome aberration test, or the mouse micronucleus test.

Venofer® at IV doses up to 15 mg iron/kg/day (about 1.2 times the recommended maximum human dose on a body surface area basis) was found to have no effect on fertility and reproductive performance of male and female rats.

Pregnancy Category B: Teratology studies have been performed in rats at IV doses up to 13 mg iron/kg/day (about 0.5 times the recommended maximum human dose on a body surface area basis) and rabbits at IV doses up to 13 mg iron/kg/day (about 1 times the recommended maximum human dose on a body surface area basis) and have revealed no evidence of impaired fertility or harm to the fetus due to Venofer®. There are, however, no adequate and well controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers: Venofer® is excreted in milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Venofer® is administered to a nursing woman.

Pediatric Use: Safety and effectiveness of Venofer® in pediatric patients have not been established. In a country where Venofer® is available for use in children, at a single site, five premature infants (weight less than 1,250 g) developed necrotizing enterocolitis and two of the five expired during or following a period when they received Venofer®, several other medications and erythropoietin. Necrotizing enterocolitis may be a complication of prematurity in very low birth weight infants. No causal relationship to Venofer® or any other drugs could be established.

Geriatric Use: The five pivotal clinical trials did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. No overall differences in safety were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS Adverse Events observed in all treated populations The frequency of adverse events associated with the use of Venofer® has been documented in six randomized clinical trials involving 231 hemodialysis dependent, 139 non-dialysis dependent and 75 peritoneal dialysis dependent-CKD patients; and in two post-marketing safety studies involving 1,051 hemodialysis dependent-CKD patients for a total of 1,496 patients. In addition, over 2,000 patients treated with Venofer® have been reported in the medical literature.

Treatment-emergent adverse events reported by 2% of treated patients with 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 Safety Population) NDD-CKD Oral Iron Adverse Events Venofer® (Preferred Term) (N=139) (N=139) % % Subjects with any adverse event 76.3 73.4 Ear and Labyrinth Disorders Ear Pain 2.2 0.7 Eye Disorders Conjunctivitis 0 0 Gastrointestinal Disorders Abdominal pain NOS* 1.4 2.9 Constipation 4.3 12.9 Diarrhea NOS 7.2 10.1 Dysgeusia 7.9 0 Nausea 8.6 12.2 Vomiting NOS 5.0 8.6 General Disorders and Administration Site Conditions Asthenia 0.7 2.2 Chest pain 1.4 0 Edema NOS 6.5 6.5 Fatigue 3.6 5.8 Feeling abnormal 0 0 Infusion site burning 3.6 0 Injection site extravasation 2.2 0 Injection site pain 2.2 0 Peripheral edema 7.2 5.0 Pyrexia 0.7 0.7 Infections and Infestations Catheter site infection 0 0 Nasopharyngitis 0.7 2.2 Peritoneal infection 0 0 Sinusitis NOS 0.7 0.7 Upper respiratory tract infection NOS 0.7 1.4 Urinary tract infection NOS 0.7 5.0 Injury, Poisoning and Procedural Complications Graft complication 1.4 0 Investigations Cardiac murmur NOS 2.2 2.2 Fecal occult blood positive 1.4 3.6 Metabolism and Nutrition Disorders Fluid overload 1.4 0.7 Gout 2.9 1.4 Hyperglycemia NOS 2.9 0 Hypoglycemia NOS 0.7 0.7 Musculoskeletal and Connective Tissue Disorders Arthralgia 1.4 2.2 Arthritis NOS 0 0

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

Table 3. Most Common Treatment-Emergent Adverse Events Reported in 2% of Patients with NDD-CKD by Dose Group (Multidose Safety Population)

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

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

6.7

0

0

1.8 3.7 6.4 9.2 9.2 5.5

0 6.7 10.0 3.3 6.7 3.3

0.9 0.9 7.3 4.6 0 3.7 2.8 5.5 0.9

0 3.3 3.3 0 0 3.3 0 13.3 0

0 0.9 0 0 0.9

0 0 0 3.3 0

1.8

0

2.8 1.8

0 0

1.8 1.8 3.7 0.9

0 6.7 0 0

0.9 1.8 0 2.8

3.3 3.3 3.3 6.7

(Table 3 continued)

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

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

2.2 0.7 3.6 4.3

3.6 0.7 0 0

6.5 2.9 0.7

1.4 0.7 0.7

2.2 3.6 2.2 1.4 0 0.7

0.7 0.7 0.7 2.2 0 2.2

2.2 1.4

4.3 2.2

6.5 2.2

4.3 0.7

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

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

4.6

3.3

5.5 3.7

10.0 0

0.9 1.8 0

6.7 10.0 0

0.9

6.7

6.4 0.9

6.7 6.7

in patients with autoimmune hemolytic anemia, in patients with pre-existing hemolysis or at high risk for hemolysis, or in patients who are immunoglobulin (Ig) A–deficient and have antibodies against IgA. The warning does not apply to patients taking WinRho SDF for suppression of Rh isoimmunization.

The boxed warning notifies physicians and caregivers of the following: • Patients should be closely monitored in a health care setting for at least eight hours after WinRho SDF administration.

‘It’s challenging—IVH will most often present symptomatology within four hours of the infusion, but patients could have symptoms days or even weeks after receiving the medication.’

—Jerry Siegel, PharmD

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

200 mg (N=109) % 23.9

500 mg (N=30) % 20.0

0 7.3 2.8

0 3.3 0

3.7 2.8 1.8

0 0 6.7

2.8 2.8

6.7 0

0

6.7

*NOS=Not otherwise specified Adverse Events Observed in Non-Dialysis Dependent Chronic Kidney Disease (NDD-CKD) Patients In the pivotal study of 182 NDD-CKD patients, 91 were exposed to Venofer®. Adverse events, whether or not related to Venofer®, reported by 5% of the Venofer® exposed patients were as follows: dysgeusia (7.7%), peripheral edema (7.7%), diarrhea (5.5%), constipation (5.5%), nausea (5.5%), dizziness (5.5%), and hypertension (5.5%). One serious related adverse reaction was reported (hypotension and shortness of breath not requiring hospitalization in a Venofer® patient). Two patients experienced possible hypersensitivity/allergic reactions (local edema/hypotension) during the study. Of the 5 patients who prematurely discontinued the treatment phase of the study due to adverse events (2 oral iron group and 3 Venofer® group), three Venofer® patients had events that were considered drug-related (hypotension, dyspnea and nausea).

Hypersensitivity Reactions: See WARNINGS and PRECAUTIONS. In clinical studies, several patients experienced hypersensitivity reactions presenting with wheezing, dyspnea, hypotension, rashes, or pruritus. Serious episodes of hypotension occurred in 2 patients treated with Venofer® at a dose of 500 mg.

The post-marketing spontaneous reporting system includes reports of patients who experienced serious or life-threatening reactions (anaphylactic shock, loss of consciousness or collapse, bronchospasm with dyspnea, or convulsion) associated with Venofer® administration.

OVERDOSAGE Dosages of Venofer® (iron sucrose injection, USP) in excess of iron needs may lead to accumulation of iron in storage sites leading to hemosiderosis. Periodic monitoring of iron parameters such as serum ferritin and transferrin saturation may assist in recognizing iron accumulation. Venofer® should not be administered to patients with iron overload and should be discontinued when serum ferritin levels equal or exceed established guidelines [1]. Particular caution should be exercised to avoid iron overload where anemia unresponsive to treatment has been incorrectly diagnosed as iron deficiency anemia.

Symptoms associated with overdosage or infusing Venofer® too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Most symptoms have been successfully treated with IV fluids, hydrocortisone, and/or antihistamines.

Infusing the solution as recommended or at a slower rate may also alleviate symptoms.

Preclinical Data: Single IV doses of Venofer® at 150 mg iron/kg in mice (about 3 times the recommended maximum human dose on a body surface area basis) and 100 mg iron/kg in rats (about 8 times the recommended maximum human dose on a body surface area basis) were lethal.

The symptoms of acute toxicity were sedation, hypoactivity, pale eyes, and bleeding in the gastrointestinal tract and lungs.

DOSAGE AND ADMINISTRATION The dosage of Venofer® is expressed in terms of mg of elemental iron. Each mL contains 20 mg of elemental iron.

Most CKD patients will require a minimum cumulative repletion dose of 1,000 mg of elemental iron, administered over sequential sessions, to achieve a favorable hemoglobin response and to replenish iron stores (ferritin, TSAT).

Administration: Venofer® must only be administered intravenously either by slow injection or by infusion.

Recommended Adult Dosage: Non-Dialysis Dependent-Chronic Kidney Disease Patients (NDD-CKD): Venofer® is administered as a total cumulative dose of 1,000 mg over a 14 day period as a 200 mg slow IV injection undiluted over 2 to 5 minutes on 5 different occasions within the 14 day period. There is limited experience with administration of an infusion of 500 mg of Venofer®, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5-4 hours on day 1 and day 14; hypotension occurred in 2 of 30 patients treated.

(See CLINICAL TRIALS, Study D: Non-Dialysis 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 SUPPLIED Venofer® is supplied in 5 mL and 10 mL single dose vials. Each 5 mL vial contains 100 mg elemental iron (20 mg/mL) and each 10 mL vial contains 200 mg elemental iron (20 mg/mL). Contains no preservatives. Store in original carton at 25°C (77°F). Excursions permitted to 15°-30°C (59°-86°F). [See the USP controlled room temperature]. Do not freeze.

Sterile NDC-0517-2340-01 100 mg/5 mL Single Dose Vial Individually Boxed NDC-0517-2310-01 200 mg/10 mL Single Dose Vial Individually Boxed NDC-0517-2340-10 100 mg/5 mL Single Dose Vial Packages of 10 NDC-0517-2310-05 200 mg/10 mL Single Dose Vial Packages of 5 NDC-0517-2340-25 100 mg/5 mL Single Dose Vial Packages of 25 NDC-0517-2310-10 200 mg/10 mL Single Dose Vial Packages of 10 Rx Only REFERENCE: [1] National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease, 2000. Am J Kidney Dis. 37: S182-S238, (suppl 1) 2001.

BS2340 Rev. 10/08 Venofer® is manufactured under license from Vifor (International) Inc., Switzerland.

VENJA Rev 10/2008 © 2008 American Regent, Inc

• A dipstick urinalysis should be performed at baseline, two and four hours after administration, and prior to the end of the monitoring period.

• Patients should be alerted to, and be monitored for, signs and symptoms of IVH, including back pain, shaking chills, fever and discolored urine or hematuria. The absence of these signs and/or symptoms of IVH within eight hours does not indicate that IVH will not occur subsequently.

• If signs and/or symptoms of IVH are present or if IVH is suspected after WinRho administration, posttreatment laboratory work should be performed, including tests for levels of plasma hemoglobin, haptoglobin, lactate dehydrogenase and plasma bilirubin (direct and indirect), as well as urinalysis.

Negative Effect on Prescribing?

Jerry Siegel, PharmD, FASHP, clinical associate professor at the Ohio State University College of Pharmacy, in Columbus, an expert in intravenous immunoglobulin (IVIG) therapy, told Pharmacy Practice News that the boxed warning, although warranted, could turn some physicians off using the drug. The infusion time for the medication is three to five minutes, and he said that most patients receiving it are in and out of their doctors’ offices in

•

see BLACK BOX, page 23

Policy 17

Pharmacy Practice News • May 2010

Joint Commission

RECONCILIATION continued from page 1

into the summer if a consensus is not reached.

Bona E. Benjamin, BS Pharm, director of Medication Use Quality Improvement at the American Society of Health-System Pharmacists’ (ASHP) Practice Development Division, said she believes ASHP will, in general, support the revision because it simplifies requirements while giving organizations flexibility to determine how best to accomplish the goals.

“The best thing about the revised goal is elimination of the lengthy prescriptive set of performance elements, and focusing on areas of risk—when the patient comes into the hospital, when the patient’s current medications are compared to any new ones, and when the patient leaves the hospital,” she said.

For example, the earlier version of the medication reconciliation rule required a number of specific steps for obtaining and documenting the medication list at each transition in care. The new version removes many requirements that are covered in the medication management standards, and emphasizes education of the patient about the importance of managing drug information.

The new version also differs by requiring organizations to measure the effectiveness of their medication reconciliation process. “I’m glad to see that performance improvement is now a part of the goal; it’s a critical element,” Ms. Benjamin told Pharmacy Practice News.

‘This new requirement … may [be] a more complicated goal than its predecessor.’

—Timothy W. Cutler, PharmD dards from the Joint Commission,” Dr. Cutler said.

NPSG No. 8, issued in late December 2008, outlined requirements to “completely reconcile” medication lists that accompany patients as they travel from home through various levels of hospital care and back home. Almost immediately after the safety goal was

issued, however, hospitals and other organizations complained that it was too detailed and would be burdensome to implement. In February 2009, the Joint Commission decided to suspend use of NPSG No. 8 survey scores for accreditation purposes.

Maureen Carr, project director of the Joint Commission’s Division of Standards

and Survey Methods, said the Standards and Survey Procedures Committee will seek to finalize the plan by the end of May, “if it looks like there is general consensus from the field. If not, we will have to consider extending the process,” Ms. Carr told Pharmacy Practice News.

Comments may be submitted at http:// www.jointcommission.org/Standards/ FieldReviews/se_email_feedback.htm —Ted Agres This article previously appeared on www. pharmacypracticenews.com

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While supporting medication reconciliation in general, Dr. Cutler said the process can be “time-consuming, cumbersome and very resource-heavy.”

“I am not sure that well-designed research studies have shown that the resources dedicated to this process are cost-effective. Medication reconciliation is clearly important, but the ‘best practice’ has yet to be described,” Dr. Cutler told Pharmacy Practice News.

One important key may involve integration of information technology so that electronic health information can be shared among various providers and institutions. “Until technology and shared information becomes readily available, I fear institutions will continue to struggle meeting these stan-

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18 Clinical

Pharmacy Practice News • May 2010

Infectious Disease

‘Three Strikes’ Rule Boosts Hand Hygiene Compliance A washed their hands or “gelled” (used hand sanitizer dispensers posted outside each patient room) when entering and leaving patient rooms. Initial surveys showed that the compliance rate was 31%. Soon after, the hospital began a major push to increase hand washing, including lecturing offenders and promoting hand hygiene through screensaver messages on every computer in the hospital.

As a result, the percentage of staff washing hands increased from 31% in December 2007 to 88% in September 2009. It has since leveled off at about 80%, according to a recent Philadelphia Inquirer article, although the aim of the three-card infraction program is to get hospital staff closer to 100%. Spies conduct between 800 and 1,400 observations each month.

Outbreaks of methicillin-resistant Staphylococccus aureus, Clostridium difficile (above) and other severe infectious organisms have prompted some hospitals to adopt aggressive hand-washing protocols for staff.

A Downward Spiral To make the message more personal, Abington’s chief of staff, John J. Kelly, MD, tells the story of patient Catherine “Pat” Zakrzewski, who had knee replacement surgeries at the hospital four years ago. One of her kneecaps later split, requiring her to return to

ICU Study Turns Up Drug-Resistant Germs on Staffers’ Clothing

H

ospitals are well-known sources of drug-resistant bacteria, so it should come as no surprise that the germs might occasionally hitchhike on the clinicians who work there.

Hungarian researchers have found that multidrugresistant pathogens lurk on both the hands and clothing of hospital staff in the intensive care unit (ICU). The researchers even found a positive sample for the particularly problematic microbe, methicillinresistant Staphylococcus aureus, in the pocket of an ICU clinician’s coat.

For the study, Istavan Batai, MD, an anesthesiologist at the University of Pécs, and his colleagues looked for drug-resistant microbes on the hands and hospital coats of 57 ICU staffers at the teaching facility. The researchers found multidrug-resistant strains of Acinetobacter baumannii on seven clinicians, with all but one of the positive samples involving the coats and coat pockets, along with the single positive test for S. aureus. All of the resistant strains matched samples obtained from patients.

Dr. Batai’s group said the study indicates that hospitals trying to control the spread of drug-resistant bacteria must look beyond hand hygiene. Protective aprons and policies to encourage clinicians to change their coats more than once a day might help, they added.

The researchers presented their findings at the 2010 annual meeting of the International Anesthesia Research Society (abstract S-215).

The study is not the first to show that potentially harmful bacteria can be found virtually wherever in the hospital they are sought. In a 2002 article, researchers tested 232 pairs of scissors and found that nearly 80%—particularly those used by nurses or in a communal setting—carried bacteria (Infect Control Hosp Epidemiol 2002;23:147-151). And Japanese researchers reported at the 2006 meeting of the American Society of Anesthesiologists that computer equipment, such as mice and keyboards, in the operating room frequently hosted bacteria, including drug-resistant strains (abstract A948).

—Adam Marcus

‘I don’t think there is a right way or a wrong way to [promote hand hygiene], there are just right ways. It’s all good for the patients.’

—Robert C. Owens Jr., PharmD

the hospital for surgery. While an inpatient, she acquired methicillin-resistant Staphylococcus aureus (MRSA) infection, which led to a downward spiral including removal of her new knee, amputation of a leg and—after a combined 20 surgeries and hospitalizations—her death last April at age 77, the Inquirer reports.

“Almost certainly,” Dr. Kelly told the Inquirer, the infection was carried to her bedside “on the hands of someone in the hospital.”

Mr. Spivak said the hospital has tried several means of increasing hand hygiene com

100

% Compliance

s hospitals around the country stress hand washing as a means of reducing infection, a suburban Philadelphia medical center has kicked it up a notch.

In a new twist to the existing hand hygiene campaign at Abington Memorial Hospital, poor hand-washing habits now could cost staff their jobs. Those observed not washing their hands or using hand sanitizer when entering or leaving patient rooms will be handed index cards noting their noncompliance.

After three infractions, offenders will receive a letter stating that their reappointment—which is required every two years to keep their jobs—is conditional.

Staff members observed adhering to protocol, however, may be given index cards making them eligible for a prize raffle.

“They’re really serious about [hand hygiene],” said Bob Spivak, RPh, a clinical staff pharmacist who has worked at the hospital for about 35 years. “They want everyone to comply.”

About two years ago, the hospital started a program in which employees serving as “spies” observed and reported how often doctors and nurses

pliance, including a “Gel in, gel out” campaign to encourage use of sanitizers, screensaver-based messages and even a promise last year to award every employee a $300 bonus if the hospital met its hand hygiene goal for six months straight. It did, and Mr. Spivak and others received their bonuses.

Hand hygiene rates are announced to employees each month.

“Believe me, it’s ingrained in my head,” Mr. Spivak said.

He said nurses and physicians who enter and leave patient rooms frequently are the most affected. As for the pharmacy, technicians used to go into patient rooms on a regular basis to exchange

88

80 60 40

31

20 0 December 2007

September 2009

Figure. Impact of hand-washing initiative at Abington Memorial Hospital.

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Clinical 19

Pharmacy Practice News • May 2010

Infectious Disease medications, but automated drug dispensing machines located on patient floors mean that happens much less often. Still, there are clinical coordinators who make rounds and are expected to observe hand-washing practices. Occasionally, Mr. Spivak or colleagues may need to mix medications like an epinephrine drip on an inpatient unit and run it into the room.

Even with these stat orders, the pharma-

cists need to remember to stop and use gel on their way into patient rooms, he said.

ID Pharmacist Embraces ‘Observer’ Approach Robert C. Owens Jr., PharmD, codirector of the Antimicrobial Stewardship Program at Maine Medical Center in Portland, said hospitals nationwide are looking at a number of strategies to increase hand-washing compliance. At his own hospital, for example, independent observers planted in the hospital

report those with poor hand hygiene to their department heads, who later pull the staff members aside for conversations. The catch is getting staff to be aware of what they did immediately, instead of approaching them days later when they may have forgotten the surrounding circumstances.

Dr. Owens said he is impressed by Abington’s almost 90% rate of compliance with hand washing. About 34 studies, he noted, conducted over the past 20 years have shown that the median hand hygiene rate nationally is only about 44%. “Yes, it’s that bad, and it’s that

widespread a problem,” he said.

As for whether other hospitals should take similar measures, “I don’t think there is a right way or a wrong way to [promote hand hygiene], there are just right ways,” he said. “It’s all good for the patients.”

As pharmacy is moving toward a more decentralized profession, with pharmacists or pharmacy residents rounding with medical teams or verifying medication orders in patients’ rooms, Dr. Owens noted, hand hygiene policies will more likely affect them.

—Karen Blum

20 Clinical

Pharmacy Practice News • May 2010

Infectious Disease

Brigham Boosts Patient Access to Varicella Vaccinations Las Vegas—Since its launch in March 2007, the pharmacist-managed varicella zoster immunization clinic at Brigham and Women’s Hospital in Boston has administered nearly 2,700 vaccine doses, and, at the current rate of about 100 vaccinations a month, should hit the 3,000 mark by summer, according to a poster presented at the American Society of Health-System Pharmacists (ASHP) Midyear Clinical Meeting.

The increased access that the clinic

provides is important, particularly to older patients, because the vaccine can help protect against the painful cutaneous flare-ups of the varicella zoster (VZ) virus, known as shingles, that often strike many decades after an early bout with chickenpox.

According to the Centers for Disease Control and Prevention (CDC), approximately one million VZ cases occur each year in the United States, the majority after age 60. A common, serious compli-

cation is postherpetic neuralgia, a painful condition that can persist for months or even years after the dermatologic manifestation subsides.

At Brigham and Women’s Hospital (BWH), a pharmacist and nurse staff the twice-monthly, all-day clinic. “In special circumstances where a nurse is not available or in cases where the volume of walk-ins exceeds a wait time of 30 minutes, a second pharmacist may be called on to assist with clinic work flow,”

said Ronelle Stevens, PharmD, senior clinical pharmacist.

To ensure the highest patient access, BWH has located the clinic in the lobby areas at two of its facilities. On the second Tuesday of the month, the pharmacist–nurse team sees patients at the hospital’s ambulatory care satellite in Boston’s Chestnut Hill section. The following Tuesday, the clinic moves to the Cabot Atrium in the hospital’s main campus on Francis Street.

Patients referred by a BWH or partners-affiliated physician can drop by to be vaccinated at any point within a month after receiving a prescription, Dr. Stevens said. For the first year after the clinic opened, visits were by appointment only. The switch to walk-in status two years ago triggered an immediate spike in vaccinations, and, except for three months in 2008 when the clinic closed because of a national vaccine shortage, the higher average patient counts have continued ever since.

‘This observational study exemplifies the positive value that pharmacists in the ambulatory clinic setting provide in the management of patient’s medication therapy.’

—Mark Eggleston, PharmD, MBA The clinic is in operation at a time when pharmacists around the country have been extending their clinical activities to immunization therapy, including the provision of vaccines intended to prevent influenza, pneumonia, hepatitis, diphtheria, tetanus and childhood illnesses such as measles, mumps and rubella.

At the ASHP poster session, Dr. Stevens and colleagues described the results of the first 18 months of the program.

Pharmacist–nurse teams had vaccinated 1,185 BWH patients, ranging in age from 50 to 97. Two-thirds (68%) were women.

The 1% of patients younger than age 60 who were vaccinated required a physician’s assessment and statement that the vaccine was medically necessary to prevent a VZ flare-up. Only one patient experienced a reaction to the vaccine: a mild rash at the injection site.

Since its inception, the vaccination program has continued to enlist additional pharmacists. Fifteen are now qualified to administer the VZ vaccine, according to Dr. Stevens. To meet the

Clinical 21

Pharmacy Practice News • May 2010

Infectious Disease clinic’s criteria, they must be certified in the administration of subcutaneous immunizations and have Basic Life Support (BLS) training.

A Logistical Challenge Vaccinating patients in a medical facility lobby presented something of a logistical challenge because the live attenuated VZ vaccine has to be stored at a temperature of –15 C (5 F) or lower and reconstituted within 30 minutes of administration. The pharmacists solved the problem by using dry ice to keep the vials of vaccine at the proper temperature before reconstituting them with sterile water.

Before a patient receives the vaccine, the pharmacist reviews the physician’s screening form and does a second screening “just to make sure that nothing has occurred between the initial physician visit and the patient’s arrival at the clinic,” Dr. Stevens said. “There is always a chance that they might be on some immunosuppressant agent at that point or on another medication that might interfere with the vaccine’s effectiveness.”

After the vaccination is administered, patients are advised to remain in the clinic for 20 minutes to make sure there are no immediate serious reactions, like shortness of breath or swelling that might indicate anaphylaxis. Afterward, they are counseled to report any longerterm reactions to their primary physician or to the emergency department if their physician is unavailable.

Dr. Stevens said patient reaction to the program has been positive. “We have had positive verbal feedback of satisfaction and letters/electronic communications sent to the Directors of Pharmacy Services and Patient and Family Relations,” she wrote in a follow-up e-mail.

As for the impact on pharmacists’ role as patient care providers, Dr. Stevens noted that “the expanded role of a pharmacist and face-to-face patient care prompts patients to ask more vaccine- and medication-related questions and puts pharmacists at the forefront of building greater trust and serving as another resource to patients.

“A pharmacist-managed vaccination clinic,” she added, “is an alternative means of providing the community with increased access to vaccination and can potentially increase the number and types of patients vaccinated at an institution.”

therapy and in the comprehensive care offered by the health system, while increasing patients’ access to health care.”

He said the BWH vaccination program also is noteworthy because it illustrates the power of collaborative care. “Multidisciplinary care models are now accepted and promoted by the medical community and support the development of pharmacist–physician collaborative care agreements. Pharmacists are important members of the interdisciplin-

ary team and provide the needed expertise in managing complex medication regimens and related disease states.”

Recognizing that value, Dr. Eggleston added, “many states have amended their pharmacy practice acts to allow for expansion of pharmacists’ scope of practice.”

The need for such expansion may be increasing, given recent trends in ambulatory care pharmacy. “This is an area of expected growth and oppor-

NDC

tunities for pharmacists, and has also recently been recognized by the Board of Pharmaceutical Specialties with the institution of the new credential of which ASHP is a lead partner in establishing,” Dr. Eggleston said.

He added that ambulatory care pharmacists are not just making their mark in vaccination programs: “There are numerous benefits documented in the literature,” he noted, in disease areas such as anticoagulation, heart failure, hyperlipidemia, diabetes and asthma.

—Bruce Buckley

Name

Strength

Vial Size

Pack Size

Positive Value of Pharmacists Highlighted Mark Eggleston, PharmD, MBA, director of the Section of Home, Ambulatory and Chronic Care at the ASHP, noted that “this observational study exemplifies the positive value that pharmacists in the ambulatory clinic setting provide in the management of patients’ medication

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

22 Clinical

Pharmacy Practice News • May 2010

Infectious Disease

MRSA Infections Common in PICU Patients M ethicillin-resistant Staphylococcus aureus (MRSA) may pose a bigger threat to hospitalized children than previously recognized.

A new study has found that 6% of children admitted to the pediatric intensive care unit (PICU) of a major U.S. hospital were colonized with community-associated MRSA, which can cause serious and sometimes lethal infections.

“MRSA clearly poses a threat to patients in the PICU,” said first author Prescribing Information as of January 2009.

Aaron M. Milstone, MD, a pediatric infectious disease specialist at Johns Hopkins Children’s Hospital in Baltimore. “Studies have shown that colonization prevalence drives transmission.

The higher the prevalence, the higher the risk for transmission.”

The retrospective cohort study found that of the 1,210 children admitted to the Hopkins Children’s PICU between March 1, 2007 and May 31, 2008, there were 72 colonized with MRSA. For

BREVITAL® SODIUM

3003014B 266

METHOHEXITAL SODIUM FOR INJECTION, USP

For Intravenous Use in Adults For Rectal and Intramuscular Use Only in Pediatric Patients WARNING Brevital should be used only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory (e.g. pulse oximetry) and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a designated individual other than the practitioner performing the procedure should be present to continuously monitor the patient. (See WARNINGS) DESCRIPTION Brevital® Sodium (Methohexital Sodium for Injection, USP) is 2,4,6 (1H, 3H, 5H)-Pyrimidinetrione, 1-methyl-5-(1-methyl-2-pentynyl)-5-(2-propenyl)-, (±)-, monosodium salt and has the empirical formula C14H17N2NaO3. Its molecular weight is 284.29.

The structural formula is as follows: Methohexital sodium is a rapid, ultrashort-acting barbiturate anesthetic. Methohexital sodium for injection is a freeze-dried, sterile, nonpyrogenic mixture of methohexital sodium with 6% anhydrous sodium CH 3 carbonate added as a buffer. It contains not less than 90% and not more than 110% of the labeled O N ONa amount of methohexital sodium. It occurs as a white, freeze-dried plug that is freely soluble in water.

CH 2 CHCH 2 This product is oxygen sensitive. The pH of the 1% solution is between 10 and 11; the pH of the 0.2% soluN tion in 5% dextrose is between 9.5 and 10.5.

CH 3 CH 2C CCH Methohexital sodium may be administered by direct intravenous injection or continuous intravenous drip, intraO CH 3 muscular or rectal routes (see PRECAUTIONS—Pediatric Use). Reconstituting instructions vary depending on the route of administration (see DOSAGE AND ADMINISTRATION).

CLINICAL PHARMACOLOGY Compared with thiamylal and thiopental, methohexital is at least twice as potent on a weight basis, and its duration of action is only about half as long.

Although the metabolic fate of methohexital in the body is not clear, the drug does not appear to concentrate in fat depots to the extent that other barbiturate anesthetics do. Thus, cumulative effects are fewer and recovery is more rapid with methohexital than with thiobarbiturates. In experimental animals, the drug cannot be detected in the blood 24 hours after administration.

Methohexital differs chemically from the established barbiturate anesthetics in that it contains no sulfur. Little analgesia is conferred by barbiturates; their use in the presence of pain may result in excitation.

Intravenous administration of methohexital results in rapid uptake by the brain (within 30 seconds) and rapid induction of sleep.

Following intramuscular administration to pediatric patients, the onset of sleep occurs in 2 to 10 minutes. A plasma concentration of 3 μg/mL was achieved in pediatric patients 15 minutes after an intramuscular dose (10 mg/kg) of a 5% solution. Following rectal administration to pediatric patients, the onset of sleep occurs in 5 to 15 minutes. Plasma methohexital concentrations achieved following rectal administration tend to increase both with dose and with the use of more dilute solution concentrations when using the same dose. A 25 mg/kg dose of a 1% methohexital solution yielded plasma concentrations of 6.9 to 7.9 μg/mL 15 minutes after dosing. The absolute bioavailability of rectal methohexital sodium is 17%.

With single doses, the rate of redistribution determines duration of pharmacologic effect. Metabolism occurs in the liver through demethylation and oxidation. Side-chain oxidation is the most important biotransformation involved in termination of biologic activity. Excretion occurs via the kidneys through glomerular filtration.

INDICATIONS AND USAGE Brevital Sodium can be used in adults as follows: 1. For intravenous induction of anesthesia prior to the use of other general anesthetic agents.

2. For intravenous induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents (such as nitrous oxide in oxygen) for short surgical procedures; Brevital Sodium may be given by infusion or intermittent injection.

3. For use along with other parenteral agents, usually narcotic analgesics, to supplement subpotent inhalational anesthetic agents (such as nitrous oxide in oxygen) for longer surgical procedures.

4. As intravenous anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli (see WARNINGS).

5. As an agent for inducing a hypnotic state.

Brevital Sodium can be used in pediatric patients older than 1 month as follows: 1. For rectal or intramuscular induction of anesthesia prior to the use of other general anesthetic agents.

2. For rectal or intramuscular induction of anesthesia and as an adjunct to subpotent inhalational anesthetic agents for short surgical procedures.

3. As rectal or intramuscular anesthesia for short surgical, diagnostic, or therapeutic procedures associated with minimal painful stimuli.

CONTRAINDICATIONS Brevital Sodium is contraindicated in patients in whom general anesthesia is contraindicated, in those with latent or manifest porphyria, or in patients with a known hypersensitivity to barbiturates.

WARNINGS See boxed Warning.

As with all potent anesthetic agents and adjuncts, Brevital should be used only in hospital or ambulatory care settings that provide for continuous monitoring of respiratory (e.g. pulse oximetry) and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation and personnel trained in their use and skilled in airway management should be assured. For deeply sedated patients, a designated individual other than the practitioner performing the procedure should be present to continuously monitor the patient.

Maintenance of a patent airway and adequacy of ventilation must be ensured during induction and maintenance of anesthesia with methohexital sodium solution. Laryngospasm is common during induction with all barbiturates and may be due to a combination of secretions and accentuated reflexes following induction or may result from painful stimuli during light anesthesia. Apnea/hypoventilation may be noted during induction, which may impair pulmonary ventilation; the duration of apnea may be longer than that produced by other barbiturate anesthetics. Cardiorespiratory arrest may occur.

This prescribing information describes intravenous use of methohexital sodium in adults. It also discusses intramuscular and rectal administration in pediatric patients older than one month. Although the published literature discusses intravenous administration in pediatric patients, the safety and effectiveness of intravenous administration of methohexital sodium in pediatric patients have not been established in well-controlled, prospective studies.

(See PRECAUTIONS—Pediatric Use) Seizures may be elicited in subjects with a previous history of convulsive activity, especially partial seizure disorders.

Because the liver is involved in demethylation and oxidation of methohexital and because barbiturates may enhance preexisting circulatory depression, severe hepatic dysfunction, severe cardiovascular instability, or a shock-like condition may be reason for selecting another induction agent.

Prolonged administration may result in cumulative effects, including extended somnolence, protracted unconsciousness, and respiratory and cardiovascular depression. Respiratory depression in the presence of an impaired airway may lead to hypoxia, cardiac arrest, and death.

The CNS-depressant effect of Brevital Sodium may be additive with that of other CNS depressants, including ethyl alcohol and propylene glycol.

DANGER OF INTRA-ARTERIAL INJECTION—Unintended intra-arterial injection of barbiturate solutions may be followed by the production of platelet aggregates and thrombosis, starting in arterioles distal to the site of injection. The resulting necrosis may lead to gangrene, which may require amputation. The first sign in conscious patients may be a complaint of fiery burning that roughly follows the distribution path of the injected artery; if noted, the injection should be stopped immediately and the situation reevaluated. Transient blanching may or may not be noted very early; blotchy cyanosis and dark discoloration may then be the first sign in anesthetized patients. There is no established treatment other than prevention. The following should be considered prior to injection: 1. The extent of injury is related to concentration. Concentrations of 1% methohexital will usually suffice; higher concentrations should ordinarily be avoided.

2. Check the infusion to ensure that the catheter is in the lumen of a vein before injection. Injection through a running intravenous infusion may enhance the possibility of detecting arterial placement; however, it should be remembered that the characteristic bright-red color of arterial blood is often altered by contact with drugs. The possibility of aberrant arteries should always be considered.

Postinjury arterial injection of vasodilators and/or arterial infusion of parenteral fluids are generally regarded to be of no value in altering outcome. Animal experiments and published individual case reports concerned with a variety of arteriolar irritants, including barbiturates, suggest that 1 or more of the following may be of benefit in reducing the area of necrosis: 1. Arterial injection of heparin at the site of injury, followed by systemic anticoagulation.

2. Sympathetic blockade (or brachial plexus blockade in the arm).

3. Intra-arterial glucocorticoid injection at the site of injury, followed by systemic steroids.

4. A case report (nonbarbiturate injury) suggests that intra-arterial urokinase may promote fibrinolysis, even if administered late in treatment.

If extravasation is noted during injection of methohexital, the injection should be discontinued until the situation is remedied. Local irritation may result from extravasation; subcutaneous swelling may also serve as a sign of arterial or periarterial placement of the catheter.

PRECAUTIONS General—All routes of administration of Brevital Sodium are often associated with hiccups, coughing, and/or muscle twitching, which may also impair pulmonary ventilation.

Following induction, temporary hypotension and tachycardia may occur.

Recovery from methohexital anesthesia is rapid and smooth. The incidence of postoperative nausea and vomiting is low if the drug is administered to fasting patients. Postanesthetic shivering has occurred in a few instances.

The usual precautions taken with any barbiturate anesthetic should be observed with Brevital Sodium. The drug should be used with caution in patients with asthma, obstructive pulmonary disease, severe hypertension or hypotension, myocardial disease, congestive heart failure, severe anemia, or extreme obesity.

Methohexital sodium should be used with extreme caution in patients in status asthmaticus.

Caution should be exercised in debilitated patients or in those with impaired function of respiratory, circulatory, renal, hepatic, or endocrine systems.

Information for Patients—When appropriate, patients should be instructed as to the hazards of drowsiness that may follow use of Brevital Sodium.

Outpatients should be released in the company of another individual, and no skilled activities, such as operating machinery or driving a motor vehicle, should be engaged in for 8 to 12 hours.

Laboratory Tests—BSP and liver function studies may be influenced by administration of a single dose of barbiturates.

Drug Interactions—Prior chronic administration of barbiturates or phenytoin (e.g. for seizure disorder) appears to reduce the effectiveness of Brevital Sodium. Barbiturates may influence the metabolism of other concomitantly used drugs, such as phentyoin, halothane, anticoagulants, corticosteroids, ethyl alcohol, and propylene glycol-containing solutions.

Carcinogenesis, Mutagenesis, Impairment of Fertility—Studies in animals to evaluate the carcinogenic and mutagenic potential of Brevital Sodium have not been conducted. Reproduction studies in animals have revealed no evidence of impaired fertility.

Usage in Pregnancy—Pregnancy Category B—Reproduction studies have been performed in rabbits and rats at doses up to 4 and 7 times the human dose respectively and have revealed no evidence of harm to the fetus due to methohexital sodium. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery—Brevital Sodium has been used in cesarean section delivery but, because of its solubility and lack of protein binding, it readily and rapidly traverses the placenta.

Nursing Mothers—Caution should be exercised when Brevital Sodium is administered to a nursing woman.

Pediatric Use—The safety and effectiveness of methohexital sodium in pediatric patients below the age of 1 month have not been established. Seizures may be elicited in subjects with a previous history of convulsive activity, especially partial seizure disorders. Apnea has been reported following dosing with methohexital regardless of the route of administration used. Studies using methohexital sodium intravenously in pediatric patients have been reported in the published literature. This literature is not adequate to establish the safety and effectiveness of intravenous administration of methohexital sodium in pediatric patients. Due to a variety of limitations such as study design, biopharmaceutic issues, and the wide range of effects observed with similar doses of intravenous methohexital, additional studies of intravenous methohexital in pediatric patients are necessary before this route can be recommended in pediatric patients. (See WARNINGS)

unknown reasons, MRSA was more common in black children, younger children (median age 3 rather than 5 years), and children who had been hospitalized in the preceding year. Threefourths of those who tested positive had no history of MRSA. Patients with MRSA spent more time

Geriatric Use—Clinical studies of Brevital did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. Elderly subjects may commonly have conditions in which methohexital should be used cautiously such as obstructive pulmonary disease, severe hypertension or hypotension, preexisting circulatory depression, myocardial disease, congestive heart failure, or severe anemia. Caution should be exercised in debilitated patients or in those with impaired function of respiratory, circulatory, renal, hepatic, or endocrine systems (see WARNINGS, PRECAUTIONS and ADVERSE REACTIONS). Barbiturates may influence the metabolism of other concomitantly used drugs that are commonly taken by the elderly, such as anticoagulants and corticosteroids. 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 (see PRECAUTIONS-Drug Interactions).

ADVERSE REACTIONS Side effects associated with Brevital Sodium are extensions of pharmacologic effects and include: Cardiovascular—Circulatory depression, thrombophlebitis, hypotension, tachycardia, peripheral vascular collapse, and convulsions in association with cardiorespiratory arrest Respiratory—Respiratory depression (including apnea), cardiorespiratory arrest, laryngospasm, bronchospasm, hiccups, and dyspnea Neurologic—Skeletal muscle hyperactivity (twitching), injury to nerves adjacent to injection site, and seizures Psychiatric—Emergence delirium, restlessness, and anxiety may occur, especially in the presence of postoperative pain Gastrointestinal—Nausea, emesis, abdominal pain, and liver function tests abnormal Allergic—Erythema, pruritus, urticaria, and cases of anaphylaxis have been reported rarely Other—Other adverse reactions include pain at injection site, salivation, headache, and rhinitis For medical advice about adverse reactions contact your medical professional. To report SUSPECTED ADVERSE REACTIONS, contact JHP at 1-866-923-2547 or MEDWATCH at 1-800-FDA-1088 (1-800-332-1088) or http://www.fda.gov/medwatch/.

DRUG ABUSE AND DEPENDENCE Controlled Substance—Brevital Sodium is a Schedule IV drug.

Brevital Sodium may be habit-forming.

OVERDOSAGE Signs and Symptoms—The onset of toxicity following an overdose of intravenously administered methohexital will be within seconds of the infusion. If methohexital is administered rectally or is ingested, the onset of toxicity may be delayed. The manifestations of an ultrashort-acting barbiturate in overdose include central nervous system depression, respiratory depression, hypotension, loss of peripheral vascular resistance, and muscular hyperactivity ranging from twitching to convulsive-like movements. Other findings may include convulsions and allergic reactions. Following massive exposure to any barbiturate, pulmonary edema, circulatory collapse with loss of peripheral vascular tone, and cardiac arrest may occur.

Treatment—To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

Establish an airway and ensure oxygenation and ventilation. Resuscitative measures should be initiated promptly. For hypotension, intravenous fluids should be administered and the patient’s legs raised. If desirable increase in blood pressure is not obtained, vasopressor and/or inotropic drugs may be used as dictated by the clinical situation.

For convulsions, diazepam intravenously and phenytoin may be required. If the seizures are refractory to diazepam and phenytoin, general anesthesia and paralysis with a neuromuscular blocking agent may be necessary.

Protect the patient’s airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.

DOSAGE AND ADMINISTRATION Facilities for assisting ventilation and administering oxygen are necessary adjuncts for all routes of administration of anesthesia. Since cardiorespiratory arrest may occur, patients should be observed carefully during and after use of Brevital Sodium. Age- and size-appropriate resuscitative equipment (ie, intubation and cardioversion equipment, oxygen, suction, and a secure intravenous line) and personnel qualified in its use must be immediately available.

Preanesthetic medication is generally advisable. Brevital Sodium may be used with any of the recognized preanesthetic medications.

Preparation of Solution—FOLLOW DILUTING INSTRUCTIONS EXACTLY. Solutions of Brevital Sodium should be freshly prepared and used promptly. Reconstituted solutions of Brevital Sodium are chemically stable at room temperature for 24 hours.

Diluents—DO NOT USE DILUENTS CONTAINING BACTERIOSTATS. Preferred diluent: Sterile Water for Injection Acceptable diluents: 5% Dextrose Injection (for IV or rectal administration only), 0.9% Sodium Chloride Injection Incompatible diluents: Lactated Ringer’s Injection Dilution Instructions—1% solutions (10 mg/mL) should be prepared for intravenous use. Contents of vials should be diluted as follows: FOR INTRAVENOUS ADMINISTRATION Strength

Amount of Diluent to Be Added to the Contents of the Vial

500 mg

50 mL

For 1% methohexital solution no further dilution needed

2.5 g

15 mL

add to 235 mL for 250 mL total volume

When the first dilution is made with the 2.5 g, the solution in the vial will be yellow. When further diluted to make a 1% solution, it must be clear and colorless or should not be used.

For continuous drip anesthesia, prepare a 0.2% solution by adding 500 mg of Brevital Sodium to 250 mL of diluent. For this dilution, either 5% glucose solution or isotonic (0.9%) sodium chloride solution is recommended instead of distilled water in order to avoid extreme hypotonicity.

For intramuscular administration, contents of the vials should be diluted as follows: FOR INTRAMUSCULAR ADMINISTRATION Strength

Amount of Diluent* to Be Added to the Contents of the Vial

500 mg vial

10 mL

5% Solution (50 mg/mL)

2.5 g vial

50 mL

5% Solution (50 mg/mL)

Methohexital Concentration after Dilution

*Sterile Water for Injection or 0.9% Sodium Chloride Injection only.

For rectal administration, contents of the vials should be diluted as follows: FOR RECTAL ADMINISTRATION Strength

Amount of Diluent to Be Added to the Contents of the Vial

Methohexital Concentration after Dilution

500 mg vial

50 mL

1% Solution (10 mg/mL)

2.5 g vial (larger vial needed)

250 mL

1% Solution (10 mg/mL)

Administration—Dosage is highly individualized; the drug should be administered only by those completely familiar with its quantitative differences from other barbiturate anesthetics.

Adults—Brevital Sodium is administered intravenously in a concentration of no higher than 1%. Higher concentrations markedly increase the incidence of muscular movements and irregularities in respiration and blood pressure.

Induction of anesthesia—For induction of anesthesia, a 1% solution is administered at a rate of about 1 mL/5 seconds. Gaseous anesthetics and/or skeletal muscle relaxants may be administered concomitantly. The dose required for induction may range from 50 to 120 mg or more but averages about 70 mg. The usual dosage in adults ranges from 1 to 1.5 mg/kg. The induction dose usually provides anesthesia for 5 to 7 minutes.

Maintenance of anesthesia—Maintenance of anesthesia may be accomplished by intermittent injections of the 1% solution or, more easily, by continuous intravenous drip of a 0.2% solution. Intermittent injections of about 20 to 40 mg (2 to 4 mL of a 1% solution) may be given as required, usually every 4 to 7 minutes. For continuous drip, the average rate of administration is about 3 mL of a 0.2% solution/minute (1 drop/second). The rate of flow must be individualized for each patient. For longer surgical procedures, gradual reduction in the rate of administration is recommended (see discussion of prolonged administration in WARNINGS). Other parenteral agents, usually narcotic analgesics, are ordinarily employed along with Brevital Sodium during longer procedures.

Pediatric Patients—Brevital Sodium is administered intramuscularly in a 5% concentration and administered rectally as a 1% solution.

Induction of anesthesia—For the induction of anesthesia by the intramuscular route of administration, the usual dose ranges from 6.6 to 10 mg/kg of the 5% concentration. For rectal administration, the usual dose for induction is 25 mg/kg using the 1% solution.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

COMPATIBILITY INFORMATION Solutions of Brevital Sodium should not be mixed in the same syringe or administered simultaneously during intravenous infusion through the same needle with acid solutions, such as atropine sulfate, metocurine iodide, and succinylcholine chloride. Alteration of pH may cause free barbituric acid to be precipitated. Solubility of the soluble sodium salts of barbiturates, including Brevital Sodium, is maintained only at a relatively high (basic) pH. Because of numerous requests from anesthesiologists for information regarding the chemical compatibility of these mixtures, the following chart contains information obtained from compatibility studies in which a 1% solution of Brevital Sodium was mixed with therapeutic amounts of agents whose solutions have a low (acid) pH. Active Potency Volume Physical Change Ingredient per mL Used Immediate 15 min 30 min 1h Brevital Sodium 10 mg 10 mL CONTROL Atropine Sulfate 1/150 gr 1 mL None Haze Atropine Sulfate 1/100 gr 1 mL None Ppt Ppt Succinylcholine chloride 0.5 mg 4 mL None None Haze Succinylcholine chloride 1 mg 4 mL None None Haze Metocurine Iodide 0.5 mg 4 mL None None Ppt Metocurine Iodide 1 mg 4 mL None None Ppt Scopolamine hydrobromide 1/120 gr 1 mL None None None Haze Tubocurarine chloride 3 mg 4 mL None Haze HOW SUPPLIED Store at controlled room temperature (20° to 25°C) (68° to 77°F) [see USP].

Brevital® Sodium Vials*: 500 mg (with 30 mg anhydrous sodium carbonate) are available as follows: 50-mL size, multiple dose—1’s (NDC 42023-105-01) The 2.5 g vials (with 150 mg anhydrous sodium carbonate) are available as follows: 50-mL size, multiple dose—1’s (NDC 42023-106-01)

*In crystalline form.

Rx only Prescribing Information as of January 2009.

Manufactured and Distributed by: JHP Pharmaceuticals, LLC Rochester, MI 48307

in the PICU than noncolonized patients (three vs. two days) and had longer hospital stays (eight vs. five days).

The study, published in the April issue of Emerging Infectious Diseases (2010;16:647655), underscores the potential benefits of screening hospital patients for MRSA and gives a heads-up of sorts to hospital administrators who have argued that universal screening for the bacterium simply isn’t worth the cost—especially when it comes to pediatric patients.

“This study will capture the attention of clinicians,” said Robert C. Owens Jr., PharmD, co-director of the antimicrobial stewardship program at Maine Medical Center in Portland and an advocate of universal screening for MRSA. “Some will say, ‘Wow, I didn’t think MRSA was this big of an issue in peds.’” MRSA often is considered a problem of older people, especially those who have stayed in a long-termcare facility, Dr. Owens noted.

‘Before we know whether [universal MRSA] screening will be cost-effective, we need to better define the outcomes in pediatrics.’

—Aaron M. Milstone, MD Since 2007, Hopkins Children’s has been screening all patients for MRSA on admission and once a week until discharge. No effort is made to “decolonize” PICU patients who test positive, although doctors consider colonization status in picking antibiotic regimens for other conditions, such as sepsis or pneumonia, according to Dr. Milstone.

Patient screening for MRSA is mandatory in some states, but screening protocols vary widely from hospital to hospital and state to state.

Many hospital administrators reportedly have been wary of implementing universal screening protocols. Cost is a major factor—the cost of hiring additional staff or installing automated equipment to process the additional cultures, according to Dr. Owens.

Reimbursement experts say that the cost of universal screening may someday be offset if MRSA infections are ever included in a list of hospital-acquired conditions (HACs) that now carry reduced

Clinical 23

Pharmacy Practice News • May 2010

Infectious Disease reimbursement under the Centers for Medicare & Medicaid Services’ “neverevent” policy.

Under that policy, which took effect in 2009, Medicare does not pay additional health care costs for HACs that the agency considers “could reasonably have been prevented” through adherence to evidence-based guidelines.

Although there are specific hospitalacquired infections included in this list, the organism(s) causing the infection has not been specified.

A representative for CMS said the agency has no plans to add MRSA to the

‘Universal screening could prove that a patient who needed treatment for a post-admission MRSA actually had been colonized with MRSA prior to admission.

—Robert C. Owens, PharmD “never events” list.

The question of whether universal screening makes sense doesn’t only hinge on finances: Dr. Milstone said it ultimately depends on patient outcomes. “We know that adults who acquire MRSA in the ICU have up to a 25% chance of getting an infection in the hospital, but we still don’t know how bad it is for a child

to acquire MRSA in the hospital,” he said.

“Before we know whether screening will be cost-effective, we need to better define the outcomes in pediatrics.”

Previous studies that looked at whether MRSA screening cuts infection rates yielded uneven results. A Swiss study (JAMA 2008;299:1149-1157) found that screening did not reduce the rate of noso-

comial infections in surgical patients.

But a multihospital study conducted in the United States found that universal screening reduced the rate by five infections per 10,000 patient-days (Ann Intern Med 2008;149:409-418).

Each year, 94,000 people develop invasive MRSA infections, 19,000 of which are fatal, according to a JAMA study (2007;298:1763-1771). Community-associated MRSA accounts for 86% of these infections (compared with about 60% of PICU patients in the Hopkins study).

—David W. Freeman

POLICY

FDA Watch

BLACK BOX continued from page 16

less than an hour. He predicted that physicians may think if they don’t monitor patients for at least eight hours and follow the checklist, and a patient becomes ill, they could be subject to litigation.

The warning has more stringent monitoring instructions and “significantly impacts the ease and convenience of using this predominantly outpatient product,” noted Dr. Siegel.

“It’s challenging—IVH will most often present symptomatology within four hours of the infusion, but patients could have symptoms days or even weeks after receiving the medication,” he said. “It requires teaching the patient what to look for. Fever, chills, etc., are relatively normal, but if they get more severe back pain or blood in the urine, they need to call their doctor. But not many people have urine tests at home that detect occult blood, so they would have to watch for darkening of the urine as a symptom.”

In lieu of WinRho SDF, physicians could turn to intravenous Ig or to platelet-stimulating medications such as romiplostim (Nplate, Amgen) or eltrombopag (Promacta, Glaxo SmithKline), said Dr. Siegel.

In a prepared statement, Baxter spokeswoman Laura Jacobs said, “WinRho is an important treatment option for many ITP patients, and we expect that it will continue to play an important role in the treatment of this disease. Patient safety is Baxter’s first priority, and we have communicated the revisions to the WinRho label, so health care professionals and patients can make informed decisions regarding clinical care.”

Cases of IVH associated with the drug were first reported in 2002, in adolescents with Epstein-Barr virus, Dr. Siegel noted. By 2006, the FDA had issued a warning that physicians should look for signs of IVH in patients with ITP. He noted that the exact mechanism causing IVH in WinRho SDF–treated patients has not yet been determined.

—Karen Blum

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24 Policy

Pharmacy Practice News • May 2010

Books in Focus

Beyond Avandia: The Curious Disconnect Why have lowered glucose levels and death rates in type 2 diabetes not matched up?

By Dan Hurley

researcher, Professor Wilhelm Falta, published a paper in German describing what he considered to be two types of diabetes: insularer, or insulin-sensitive, and insulinresistenter, or insulin-resistant. But with no effective way to treat insulin resistance, deaths due to diabetes continued to climb.

The First Breakthrough

Adapted from Diabetes Rising: How a Rare Disease Became a Modern Pandemic, And What To Do About It. By Dan Hurley.

Published by Kaplan Publishing, 2010.

H

eard about the top-selling diabetes drug that, despite lowering blood glucose levels, failed to stem the disease’s steadily rising death toll?

Sure, you’ve heard about rosiglitazone (Avandia, GlaxoSmithKline), including the latest report on the front page of The New York Times (Feb. 19) revealing that, in a confidential memo, two FDA officials recommended pulling the drug from the market due to an increased risk for heart attacks.

But Avandia is only the latest drug prescribed to individuals with type 2 diabetes that showed a curious disconnect between the lowering of glucose levels and death rates. Like Avandia, the other agents initially were heralded as great breakthroughs, and then became mired in controversy as long-term statistics began to tell another story.

Pharmacists and physicians who treat and counsel patients with diabetes would do well to learn the curious, colorful and all-too-often forgotten history of diabetes treatments, if they hope to avoid repeating them.

The first great disappointment, most astonishing at the time, was insulin. In 1923, the year after insulin’s discovery, the death rate from diabetes in New York City was 22.9 per 100,000 residents. By 1926, the city’s death rate had inched up to 25 per 100,000, climbing to 29 per 100,000 in 1932. The trend was so puzzling that articles appeared in the Times with headlines like “Toll of Diabetes Is Rising Rapidly” and “Diabetes Mortality Up 58% in 30 Years.”

Some took the rise to mean that insulin, far from being a cure, was not even an effective treatment. Some doctors even refused to prescribe it.

The first attempt to make sense of the mystery came in 1931, when a Viennese

An unexpected breakthrough came in spring 1942, in the French Mediterranean city of Montpellier, when the privations of war forced residents to eat rotting or contaminated meat and seafood. The resulting cases of typhoid fever were treated by Dr. Marcel Janbon of the Montpellier Medical School with one of the miraculous new sulfa drugs that had revolutionized the treatment of bacterial infections. But the sulfa drug he chose, an experimental one known simply as 2254 RP, turned out to cause some severe side effects of its own: convulsions and coma.

Fabrik von Heyden, identified one called BZ 55, or carbutamide. Its research efforts collapsed with the ruins of the Third Reich, when Dresden became part of East Germany. It took until 1952 for a sample of carbutamide to be smuggled across the Iron Curtain into West Germany, where it was tested and brought onto the German market in 1956. Further testing in the United States revealed rare but fatal side effects that resulted in its discontinuation.

But in 1957, the Upjohn Company brought another sulfonylurea onto the U.S. market. The result was a pharmaceutical juggernaut that would transform the very definition of diabetes.

Making Lemonade Orinase, as the drug was called, offered a tricky marketing challenge for Upjohn. The company had brought in top researchers from across the United States, including some from the Joslin Clinic, to test Orinase on more than

‘Here we are, 50 years after the initial introduction of antidiabetic agents. And although cardiovascular disease is the cause of death in 75% of diabetics, there exists no well-designed, adequately powered, comparative effectiveness trials evaluating macrovascular outcomes for diabetes drugs.’

—Steve Nissen, MD Dr. Janbon asked Auguste Loubatières, a physiologist at the medical school, to look into the matter.

Loubatières had been studying protamine zinc insulin, and he suspected that the side effects caused by 2254 RP were the result of severely low sugar levels, the kind that could be caused by taking too much insulin. On June 13, 1942, Loubatières gave 2254 RP to a dog, and sure enough, tests showed that the dog’s blood glucose level dropped dramatically.

Loubatières and Janbon kept up their experiments throughout the war, eventually concluding that the drug worked by spurring what they called a “lazy” pancreas into producing more insulin.

But once the Nazis had rolled into Montpellier and learned of the work, Germany’s pharmaceutical giants sought to exploit the results with other sulfa drugs. A Dresden firm, Chemische

5,000 patients. What they found would have disappointed a less ambitious drug company: Orinase didn’t work for most people with diabetes who already took insulin; all it did was stimulate a functioning pancreas to work a little harder.

Those in whom Orinase worked best, it turned out, were precisely those in whom insulin injections had traditionally been considered unnecessary: older diabetics with a mild, early form of the disease. Still, with no signs of serious side effects, and on the strength of an extraordinary 10,580-page application document, Orinase won FDA approval.

Taking what some would consider a lemon, the Upjohn marketing department began selling lemonade. As described in exquisite detail by Harvard physician-historian Jeremy A. Greene in Prescribing by Numbers: Drugs and

the Definitions of Diseases (Johns Hopkins University Press, 2007), Upjohn succeeding in convincing doctors that these mild cases, often undiagnosed, needed to be found and treated. The odd thing was that people with socalled “hidden” diabetes, or “prediabetes,” had none of the symptoms that had defined the disease for millennia. A promotional film made by Upjohn and described in Dr. Greene’s book attacked the problem head-on, asking “how do we convince people who do not feel sick, do not feel that they are patients,” to begin taking a drug for a disease they never knew they had?

It’s not that Upjohn was creating a disease category out of thin air: Most of these patients with early diabetes would, in fact, progress to full disease over time, and they did have increased risks for developing the long-term complications associated with diabetes. And although there was no clear evidence, the logical assumption that lowering sugar levels should lower their long-term risks for complications was hard to refute. Maybe the drug would even prevent their diabetes from becoming more severe.

And so in 1958, Orinase was being taken by 320,000 of the estimated 1.5 million patients diagnosed with diabetes in the United States.

Close on the heels of Orinase, another sulfonylurea hit the U.S. market, Diabinese, launched by Pfizer & Co., with an unprecedented 24-page advertising insert in the Journal of the American Medical Association. Almost simultaneously, a third drug came out, not from pharmaceutical giants like Upjohn or Pfizer but from a little-known firm with scant experience in selling drugs, U.S. Vitamin Corporation. Seymour L. Shapiro, a chemist at the company who had diabetes himself, had chemically tinkered with a drug tested and discarded back in the 1920s, synthalin, in hopes of eliminating the toxic side effects. He came up with one called phenformin, later sold under the trade name DBI. It seemed to have no side effects beyond causing nausea or diarrhea in some people, which usually could be relieved by lowering the dose. Like Orinase and Diabinese, it worked only in older, heavier patients with diabetes. (Such patients were now said to have “adult-onset” diabetes, as opposed to “juvenile” diabetes.) But unlike its competitors, which usually caused weight gain, phenformin often led to weight loss. It even reduced cholesterol levels!

By the time the conservative crewcuts

•

see BEYOND AVANDIA, page 26

Please see us at Booth #513 at the ASHP Show in Tampa, FL

26 Policy

Pharmacy Practice News • May 2010

Books in Focus vide an adequate basis” for warning consumers about the possible cardiovascular risks associated with sulfonylureas, the Orinase label states. Yet most physicians continued to prescribe them, and pharmacists to dispense them, if not with the same enthusiasm they had felt for the drugs when they had first entered the market.

BEYOND AVANDIA continued from page 24

of the Eisenhower era had given way to mop-tops and go-go boots, the defeat of diabetes appeared well in hand. Doctors were happy to have so many choices for treating their patients; patients were happy to have pills rather than being stuck between a rock (insulin syringes) and a hard place (draconian diets); and the drug companies were happy to be making money while doing good.

And then something called the UGDP hit the fan.

The UGDP Firestorm On May 20, 1970, the results of the largest diabetes study yet conducted were leaked, unofficially and before being published in a medical journal or presented at a medical meeting, by the Dow Jones newswire. The next morning, a longer article about the study appeared in The Washington Post.

The University Group Diabetes Program (UGDP) had been started 10 years earlier to do what no drug company had: track the long-term death rates of diabetics on pills, insulin or diet alone.

The findings were shocking: During eight years of follow-up, 26 of 204 patients (12.7%) on Orinase had died of heart disease, compared with 10 of 205 patients (4.9%) who had been given a placebo. Individuals taking insulin, on the other hand, had a risk for death due to heart disease that was no higher than patients managing their diabetes by diet alone. The results were significant enough that the leaders of the UGDP had decided to stop the Orinase portion of the study early.

The reaction was swift and cataclysmic. As Dr. Greene said in Prescribing

by Numbers, “All hell broke loose.” An estimated 800,000 Americans, he notes, “were taking Orinase every day for mild (asymptomatic) diabetes, largely on the premise that the pill reduced their longterm risk for diabetic complications and heart disease.” Leading diabetes specialists at Joslin and the American Diabetes Association (ADA) expressed outrage—not at drug manufacturers but at the press, for daring to report the study before it had been presented at the annual meeting of the ADA in June, and at the academics who had designed it, whom they accused of sloppy statistical work. The medical equivalent of a soap opera played itself out before a perplexed and whipsawed public.

On June 8, the FDA sent a letter to physicians noting that sulfonylureas “could no longer be given simply on the grounds that they might help and could do no harm.” A week later, the ADA responded by saying it saw no need to abandon the use of oral medications.

The American Medical Association

Rezulin’s Residue

(AMA), on the other hand, supported the FDA’s cautious view. That fall, a group of 34 leading diabetes specialists led by Robert F. Bradley, MD, medical director of the Joslin Clinic, held a press conference known as the “Boston Tea Party,” in which they denounced the views of the FDA and AMA. Dr. Bradley went so far as to call the UGDP study “worthless.”

In October 1970, the ADA reversed itself, saying it now agreed with the AMA and the FDA that Orinase should be taken only by individuals with adultonset diabetes in whom diet had failed and insulin was unacceptable or impractical. In December, Dr. Bradley and his Boston Tea Party, now going under the more dignified name of “Committee for the Care of the Diabetic,” deplored the warning letter the FDA had mailed out to physicians, saying it had “damaged the welfare of a million diabetic patients” and was guilty of “unprecedented interference with the practice of medicine.”

In May 1971, phenformin was dragged into the debate. The UGDP had studied it, too, and only now were the results available: 26 of 204 patients (12.7%) on phenformin died of heart disease, compared with two of 64 patients (3.1%) given a placebo. That same month, the FDA announced its intention to require all pills sold for diabetes to include a special warning on the label about the apparent increased risk for death due to heart disease. Faced with a harsh response from Dr. Bradley and his growing group of followers, who filed a lawsuit to prevent the action, the agency reconsidered.

By 1975, with an astonishing 1.5 million people now taking pills for diabetes, the FDA again proposed to require stern warnings on the labels, saying the drugs “may be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin.” An investigator from the National Institutes of Health, brought in to help review the statistical evidence for or against the pills, estimated that they were causing 10,000 to 15,000 deaths per year.

Yet that spring, the chief executive officer of the AMA permitted Upjohn to use a letter he wrote minimizing the risks associated with the drugs, even though the AMA’s journal had published a study confirming those risks.

Why were the very specialists who should have been defending the health and welfare of individuals with diabetes instead defending the drugs? Because the drugs really did lower blood sugar levels, and the patients really did like them. It is impossible to exaggerate how resistant most grown men and women, then as now, are to following strict diets, or how much they dislike the prospect of taking shots. And there was some evidence that by lowering sugar levels, the pills did lower the risk for damage to the eyes and other organs, if not the heart.

On a deeper level, however, the dynamics between those defending and those attacking the pills were ultimately determined by the kind of evidence, and the kind of government, in which they believed. On one side of the UGDP battlefield stood those who swore by the results of large studies and believed that government should protect and defend the people’s well-being. Among the defenders of this view were the FDA, academics, and consumer-protection groups like the Health Research Group formed by Ralph Nader’s Public Citizen. On the other side stood practitioners (urged on by self-interested manufacturers) who placed their faith in their own hands-on experience with patients, and whose libertarian politics deemed the FDA and other would-be regulators as interlopers.

Not until 1984 did the battle over Orinase reach an uneasy truce—in part because Upjohn’s patent rights were finally expiring. That year, Orinase and other sulfonylureas were required by the FDA to carry, in boldface, a “SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY” on the labeling information that comes with every prescription. To this day, although controversies remain about the interpretation of the UGDP, the study’s findings nevertheless “pro-

Not surprisingly, when a bumper crop of new sugar-lowering drugs started to hit the market in the 1990s—the golden age of development for type 2 drugs— physicians, pharmacists and patients grabbed them with both fists. First came the approval in 1994 of metformin, a chemical cousin of phenformin (banned in 1977 due to rare but potentially fatal side effects). Metformin was considered especially valuable because it did not cause hypoglycemia and tended to result in weight loss rather than weight gain.

Sold under the brand name Glucophage (Bristol-Myers Squibb), it eventually became the best-selling drug for type 2 diabetes. Glucophage is a mainstay of treatment to this day, still considered by many physicians to be the safest and most effective pill to prescribe to newly diagnosed patients.

The next big drug to hit the market, Rezulin (troglitazone), was vaunted as a potential blockbuster by its maker, Warner-Lambert, and given fast-track approval by the FDA in January 1997. It caused modest weight gain and worked directly against insulin resistance in the muscles, meaning that the body actually needed less insulin to maintain normal sugar levels. By that fall, however, dozens of patients taking Rezulin were hospitalized with liver ailments; some of them died. The liver toxicity proved enough to convince regulators in Britain to ban the drug on Dec. 1 of that year, but in the United States, the FDA decided that a warning to doctors to check patients’ liver function was a sufficient response.

In March 1999, however, the FDA acknowledged that 43 cases of liver failure, including 28 deaths, had been linked to Rezulin. That same month, David J. Graham, MD, a senior epidemiologist at the agency, called Rezulin among the most dangerous drugs on the market. Still, the leadership of the FDA defended it.

In January 2000, Robert I. Misbin, MD, a senior medical officer at the FDA who had previously supported approval of the drug, began calling for its withdrawal from the U.S. market in private e-mails to his colleagues. When his correspondence was published two months later in The Los Angeles Times (in a series of articles that eventually won the Pulitzer for investigative

•

see BEYOND AVANDIA, page 28

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Chemotherapy-Induced Nausea and Vomiting: Guideline Summary and Clinical Challenges LISA A. THOMPSON, PHARMD Assistant Professor

CINDY L. O’BRYANT, PHARMD, BCOP Associate Professor Department of Clinical Pharmacy School of Pharmacy University of Colorado Denver Aurora, Colorado

C

hemotherapyinduced nausea and vomiting (CINV)

can significantly impact patient care and quality of life (QoL), resulting in potential complications of electrolyte disturbances, decreased functional ability, weight loss, anorexia, esophageal tears, and treatment noncompliance.1

CINV results in higher health care resource utilization, including hospital admissions and outpatient visits.2 Although substantial progress has been made in the treatment and prevention of CINV over the past 2 decades, this patient-focused treatment complication remains an important issue.

In addition to the emetic risk of the chemotherapy regimen, CINV risk factors include patient characteristics such as female gender, high levels of anxiety, age younger than 50 years, and a history of CINV with previous chemotherapy.

The pathogenesis of CINV is multifactorial, involving release of multiple emetic transmitters, such as dopamine, serotonin, and substance P, that stimulate emesis by binding receptors in the gastrointestinal

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

tract and central nervous system.3,4 The approved antiemetics work by binding to the receptors of these pro-emetic neurotransmitters, thus preventing the emetic stimulus.

Antiemetic Information Today’s oncology practitioners have many antiemetic agents at their disposal. One of the most frequently used classes of antiemetic drugs is the serotonin (5-HT3) receptor antagonists. Three first-generation agents and 1 second-generation agent are available (Table 1). The class is well tolerated, with constipation and headache as the most common adverse effects. Although the 5-HT3 receptor antagonists have relatively few drug–drug interactions, it is important to use caution in patients receiving

P H A R M A C Y P R A C T I C E N E W S • M AY 2 0 1 0

1

other QTc-interval prolonging agents.

Corticosteroids are among the oldest agents used in prevention of CINV, and they remain a backbone of therapy. They are highly effective at preventing delayed CINV and they increase the effects of other antiemetic agents. Due to ease of dosing and experience with its use, dexamethasone is the preferred corticosteroid for antiemetic regimens. Common adverse effects of shortterm use of dexamethasone include hyperglycemia, hypertension, and agitation (with higher doses); longterm use may result in immunosuppression.

The neurokinin (NK1) antagonists are the newest class of medications for CINV. Aprepitant (Emend, Merck), the first drug in this class, is used with a corticosteroid and a 5-HT3 receptor antagonist to prevent CINV associated with high-risk regimens. Aprepitant a major substrate of cytochrome P450 (CYP) 3A4, has clinically significant drug–drug interactions with strong CYP 3A4 inhibitors, moderate-strong CYP 3A4 inducers, and other substrates of CYP 3A4. Fosaprepitant (Emend, Merck), the IV prodrug of aprepitant, also is used in combination with a corticosteroid and a 5-HT3 receptor antagonist for patients receiving high-risk CINV regimens; fosaprepitant may be given on day 1, followed by oral aprepitant on days 2 and 3. Although this adds another option for route of administration, drug–drug interactions still must be considered and addressed.

Historically, dopamine antagonists were one of the first agents to show benefit in preventing CINV. However, effective prevention requires high doses of these agents and their efficacy is limited by an increased incidence of extrapyramidal reactions associated with these drugs at these doses. The development of 5-HT3 receptor antagonists has shifted the role of dopamine antagonists from primary prevention and treatment to the management of breakthrough or refractory nausea and vomiting.

Guideline Summary There are multiple guidelines for prevention and treatment of CINV. The 4 used most regularly are those of the American Society of Clinical Oncology (ASCO),5 the European Society for Medical Oncology (ESMO),6 the Multinational Association of Supportive Care in Cancer (MASCC),7 and the National Comprehensive Cancer Network (NCCN).1 These clinical practice guidelines are summarized in Table 2. The guidelines classify IV chemotherapy products by potential into high (>90%), moderate (30%-90%), low (10%-30%), and minimal (<10%) risk groups.

ACUTE

AND

DELAYED NAUSEA

AND

VOMITING

Acute and delayed CINV are defined by the onset of nausea and/or vomiting (N/V)—up to 24 hours and more than 24 hours up to 5 days, respectively. Antiemetic regimens for the prevention of acute and delayed CINV should include treatment on day 1 followed by days 2 and 3, if appropriate per the guidelines. An NK1 antagonist, a 5-HT3 receptor antagonist, and a corticosteroid are

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recommended to prevent acute CINV in patients treated with high-risk chemotherapy regimens, with continued use of the NK1 antagonist and corticosteroid to prevent delayed CINV. A 5-HT3 receptor antagonist and corticosteroid are recommended on day 1 to prevent acute CINV for moderate-risk regimens. As noted in the guidelines, an NK1 antagonist is recommended for select moderaterisk regimens (eg, anthracycline plus cyclophosphamide).

A 5-HT3 receptor antagonist, corticosteroid, or NK1 antagonist (with or without a corticosteroid) should be continued on days 2 and 3 of the moderately emetogenic regimen. A corticosteroid on day 1 only is recommended for regimens with a low risk for CINV, and minimal-risk regimens do not require routine prophylaxis.

BREAKTHROUGH NAUSEA

AND

VOMITING

Breakthrough or refractory CINV can occur at any point in a treatment cycle, despite adequate therapy for acute and delayed CINV. Clinical recommendations advise that the emetic risk of the regimen be reevaluated and therapy adjusted through the addition of an agent with a different mechanism of action, such as a dopamine antagonist or an NK1 antagonist (if not already used). Other principles of management include scheduling antiemetics instead of using them on an asneeded basis and assessing the patient for other potential causes of nausea and vomiting.

ANTICIPATORY NAUSEA

AND

VOMITING

Anticipatory N/V can occur hours to days before chemotherapy and are estimated to occur in up to 29% and 11% of patients receiving chemotherapy, respectively.8 As anticipatory N/V is considered a learned response due to classical conditioning (ie, Pavlovian response), the clinical guidelines stress the importance of preventing an initial episode of CINV by using appropriate antiemetic regimens. In this setting, behavioral interventions are effective and are a primary treatment modality. Techniques that may be used include hypnosis, systematic desensitization, relaxation techniques, and distraction. Due to their anxiolytic effects, benzodiazepines such as lorazepam and alprazolam also play a role in the management of anticipatory N/V.

RADIATION-INDUCED NAUSEA

AND

VOMITING

The risk for developing radiation-induced nausea and vomiting (RINV) is primarily dependent on the treatment administered, including both the location of the radiation field and the dose and pattern of fractionation.5,7,9 The clinical practice guidelines for prevention of RINV are summarized in Table 3. A 5-HT3 receptor antagonist and corticosteroid should be administered prior to highly emetogenic radiation therapy. Patients undergoing moderately emetogenic radiation therapy should receive a 5-HT3 receptor antagonist. Routine prophylaxis is not recommended for mildly or minimally emetogenic radiation therapy, although patients should have breakthrough medications (such as a 5-HT3 receptor antagonist or dopamine antagonist) available.

Table 1. Characteristics of Commonly Used Antiemetic Agents

Drug

Place in Therapy

How Supplied

Common Adverse Drug Events

Dose

Drug–Drug Interactionsa

Other Notes

Neurokinin Antagonists Aprepitant/ Fosaprepitant (Emend, Merck)

High-risk regimens

Casopitant (Rezonic, Glaxo SmithKline)

Pending FDA approval

PO, IV

PO: 125 mg, day 1; 80 mg, days 2-3 IV: 115 mg, day 1, followed by 80 mg PO days 2-3

Fatigue, hiccups, weakness

Strong CYP 3A4 inhibitors, moderatestrong 3A4 inducers, major 3A4 substrates

Caution with severe hepatic impairment (Child-Pugh class C)

Neutropenia, alopecia, fatigue, leukopenia, anemia, constipation

3A4 substrates, inhibitors, inducers

Potentially single-dose regimen

Headache, constipation, diarrhea, fatigue

Not clinically significant

Cross-react with others in class, risk for QTc prolongation with dolasetron, granisetron, and ondansetron (highest with dolasetron); palonosetron is secondgeneration agent

Serotonin Antagonists Dolasetron (Anzemet, Sanofi-aventis)

High- and moderate-risk regimens

PO, IV

PO: 100 mg, day 1; as indicated, days 2-3 IV: 1.8 mg/kg or 100 mg, day 1; as indicated, days 2-3

Granisetron

PO, IV, transdermal

PO: 1 mg, day 1; 1-2 mg as indicated, days 2-3 IV: 0.01 mg/kg (max 1 mg), day 1 Transdermal: patch applied at least 24 h before chemotherapy; remove ≥24 h but ≤7 d after chemotherapy

Not clinically significant

Ondansetron

PO, IV, ODT tablets

PO: 24 mg, day 1; 8 mg bid as indicated, days 2-3 (high-risk) or 8 mg bid, day 1; as indicated, days 2-3 (moderate-risk) IV: 8 mg or 0.15 mg/kg once

Strong 3A4 inducers

Palonosetron (Aloxi, Eisai)

PO, IV

PO: 0.5 mg once IV: 0.25 mg once

Not clinically significant

PO, PO solution, IV

High-risk regimens: 12 mg, day 1; 8 mg, days 2-4 Moderate-risk: 8-12 mg, days 1-3 Low risk: 8 mg PO, day 1

Corticosteroids Dexamethasone

High-, moderate- and low-risk regimens

Mood disturbance, hyperglycemia, HTN, immune and adrenal suppression with prolonged use

Moderatestrong 3A4 inhibitors and inducers, 3A4 substrates

If given with aprepitant, administer 12 mg instead of 8 mg

continued on next page

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Table 1. Characteristics of Commonly Used Antiemetic Agents continued Place in Therapy

Drug

How Supplied

Common Adverse Drug Events

Dose

Drug–Drug Interactionsa

Other Notes

Dopamine Receptor Antagonists Haloperidol

Adjunctive

PO, PO solution, IV

PO: 1-2 mg q4-6h PRN

Dystonia, QTc prolongation, drowsiness, confusion

Moderatestrong 2D6 and 3A4 inhibitors and inducers

Metoclopramide High-, moderate- and low-risk regimens

PO, PO solution, IV

PO/IV: 10-40 mg q4-6h PRN

Dystonia, drowsiness, fatigue, restlessness, diarrhea

Not clinically significant

Prochlorperazine

PO, IV, suppository

PO/IV: 10 mg q4-6h PRN (max dose 40 mg/d) PR: 25 mg q12h

Not clinically significant

PO, PO syrup, IV, suppository

PO/IV/PR: 12.5-25 mg q4-6h PRN

Sedation, somnolence, extrapyramidal symptoms, tardive dyskinesia, urinary retention, anticholinergic effects, reports of QTc prolongation

Adjunctive

Promethazine

Clinical Challenges MULTIPLE-DAY REGIMENS Many patients receive multiday treatment regimens for the treatment of their cancer. It is important that these patients receive appropriate CINV prevention and treatment on all days they are receiving chemotherapy. For moderate to highly emetic regimens, a 5-HT3 receptor antagonist and dexamethasone is recommended. Aprepitant or fosaprepitant can be added if significant delayed CINV has been associated with the regimen. Another treatment option would be the granisetron transdermal patch (Sancuso, Strakan), which is approved for use in chemotherapy regimens of up to 5 days in length.

ORAL CHEMOTHERAPY Management of CINV in patients receiving oral chemotherapy is critical to patient adherence. The number of new oral anticancer therapies approved and in development is increasing. Select oral agents, including temozolomide, busulfan (Myleran, GlaxoSmithKline), etoposide, and cyclophosphamide (≥100 mg/m2 per day), require prophylactic therapy for CINV that typically consists of a 5-HT3 receptor antagonist.1,7 Prophylactic therapy should be administered 30 to 60 minutes prior to the oral chemotherapy dose to ensure adequate

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Moderatestrong CYP 2B6 and 2D6 inhibitors and inducers

Decrease dose by 50% for ClCr <40

IV should be given through a free-flowing IV catheter to prevent extravasation and tissue necrosis

serum concentrations. Because oral therapies may be continued for many days, it is important to consider the toxicities of antiemetic medications in addition to their efficacy. When oral chemotherapy is being used in addition to parenteral chemotherapy, CINV prophylaxis for the parenteral agent should be given in addition to therapy required for prevention of CINV secondary to the oral agent.

The majority of approved oral chemotherapy agents fall within the low- to minimal-emetic risk categories and do not typically require prophylactic therapy, although the patient should have breakthrough N/V medication available. The NCCN guidelines suggest administering metoclopramide or prochlorperazine prior to the first dose, then as needed thereafter during treatment.1 Adjuvant agents such as proton pump inhibitors, histamine 2-receptor antagonists, and lorazepam should be considered. CINV can significantly affect a patient’s ability to be compliant with oral chemotherapy, so swift action to control CINV should be taken.

Economic Considerations There has been much discussion in the literature regarding the most cost-effective means of preventing CINV. As mentioned previously, CINV also can significantly increase health care resource utilization. A recent

Table 1. Characteristics of Commonly Used Antiemetic Agents

Drug

Place in Therapy

How Supplied

Adjunctive

PO

Common Adverse Drug Events

Dose

Drugâ&#x20AC;&#x201C;Drug Interactionsa

Other Notes

Cannabinoid Dronabinol

PO: 5-10 mg q3-6h or 5-15 mg/m2 q4-6h

Abnormal thinking, euphoria, paranoia, somnolence, appetite stimulation

Not clinically significant

Anticipatory: 0.5-2 mg PO tid beginning the night before through day of treatment

Sedation, somnolence, impaired cognition, abnormal coordination, depression, irritability, memory impairment, lightheadedness, xerostomia, constipation, appetite changes and weight gain/ loss

Moderatestrong 3A4 inhibitors and inducers

Caution in elderly patients

Benzodiazepines Alprazolam

AnticiPO, PO patory, solution, adjunctive ODT

Lorazepam

PO, IV

PO/IV: 0.5-2 mg q4-6h PRN Anticipatory: give night before and morning of treatment

Adjunctive

PO

PO: 2.5-5 mg bid

Somnolence, extrapyramidal symptoms, insomnia, dizziness, constipation, weight gain, xerostomia, weakness

Moderatestrong 1A2 inhibitors and inducers

Use in elderly patients being treated for dementia associated with increased mortality

Adjunctive

PO, PO elixir, IV

PO/IV: 25-50 mg q4-6h PRN

Anticholinergic effects, sedation, somnolence, blurred vision, disturbed coordination, tachycardia, palpitations, irritability, paradoxical excitement

Major 2D6 substrates

Useful for treatment of dystonic reactions due to dopamine antagonists

Not clinically significant

Atypical Antipsychotic Olanzapine

Antihistamine Diphenhydramine

bid, twice daily; CrCL, creatinine clearance; CYP, cytochrome P450; HTN, hypertension; ODT, orally disintegrating tablets; PO, orally; PRN, as needed; tid, three times a day a

clinically significant CYP-enzyme drugâ&#x20AC;&#x201C;drug interactions.

Based on prescribing information and references 1 and 5.

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5

Table 2. Guideline Summary: ASCO, ESMO, MASCC, NCCN Emetic Risk Category

Antiemetic Regimen

Higha

Day 1: NK1 antagonist + 5-HT3 receptor antagonist + corticosteroidb Days 2 and 3: NK1 antagonist + corticosteroidb (ASCO, NCCN recommend continuing corticosteroid on day 4)

Moderatea

Day 1: 5-HT3 receptor antagonist + corticosteroidb ± NK1 antagonistc Days 2 and 3: 5-HT3 receptor antagonist or corticosteroidb or NK1 antagonistc ± corticosteroidb

Lowa

Day 1: Corticosteroidb or metoclopramided or prochlorperazined Days 2 and 3: No routine prophylaxis

Minimal

No routine prophylaxis

Anticipatory

Use of best initial therapy + behavioral therapy if needed + lorazepam or other benzodiazepines beginning day –1 ± behavioral techniquese

Multiple-day regimens

Day 1: Acute management per above recommendations based on risk category Days 2 and 3: Delayed management per above recommendations based on risk category

Breakthrough • • • •

Re-evaluate emetogenic risk of regimen to ensure appropriate prophylaxis Add 1 agent from a different drug class (see Table 1) to current regimen Use medications around-the-clock, not as needed Consider adjunctive therapies (see Table 1)

ASCO, American Society of Clinical Oncology; ESMO, European Society for Medical Oncology; H2RA, histamine-2 receptor antagonist; MASCC, Multinational Association for Supportive Care in Cancer; NCCN, National Comprehensive Cancer Network; PPI, proton pump inhibitor a

Consider addition of lorazepam ± H2RA or PPI starting on day 1 per NCCN guidelines; bDexamethasone preferred; cFor select patients, eg, anthracycline + cyclophosphamide; dNCCN only; eHypnotherapy, acupuncture, acupressure, etc.

Based on references 5-7.

retrospective review of hospital database information for patients receiving highly and moderately emetogenic chemotherapy noted that delayed CINV was responsible for the majority of health care visits associated with CINV.4 The mean costs of these visits ranged from $900 (emergency department visit) to $5,300 (hospitalization). This represents the potential for significant cost savings and emphasizes the financial impact of developing and initiating appropriate CINV prophylaxis in a patient receiving emetogenic chemotherapy.

New Directions Olanzapine is an atypical antipsychotic that antagonizes multiple neurotransmitters involved in the pathogenesis of CINV. It has an effect on dopamine, serotonin, α-adrenergic, muscarinic, and histamine receptors.10 It has been studied in combination with

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a 5-HT3 receptor antagonist and dexamethasone in the acute setting and in combination with dexamethasone or alone in the delayed setting. In a study of 30 patients who received either a highly or moderately emetogenic regimen, the drug demonstrated a 100% and 80% complete response for acute and delayed CINV, respectively.10 In a larger study (N=229) of patients receiving highly or moderately emetogenic regimens, olanzapine resulted in better QoL and lessdelayed CINV compared with standard antiemetic therapy, but it did not have an effect on acute CINV.11 Casopitant (Rezonic, GlaxoSmithKline) is an NK1 antagonist in development that is pending approval by the FDA. Like aprepitant, it has been studied in combination with a 5-HT3 receptor antagonist and dexamethasone. The results from Phase II and III studies conducted with casopitant in moderately and highly

Table 3. Treatment Recommendations for RINV Level of Radiation Emetogenicity (Area of Treatment) Recommended Therapy Highly emetogenic (total body irradiation)

5-HT3 receptor antagonist + corticosteroid

Moderately emetogenic irradiation (upper abdomen)

5-HT3 receptor antagonist

Low emetogenic (lower thorax regions, pelvis, cranium-radiosurgery, craniospinal)

Rescue with a 5-HT3 receptor antagonist if patient experiences N/V followed by a 5-HT3 receptor antagonist before future radiation

Minimally emetogenic (head and neck, extremities, cranium, breast)

Rescue with a dopamine antagonist or 5-HT3 receptor antagonist

N/V, nausea and/or vomiting; RINV, radiation-induced nausea and vomiting Based on references 5, 7, and 9.

emetogenic regimens, showed a complete response of 73% to 86% for delayed CINV and no difference in response for acute CINV.12 An improvement in QoL has been observed in patients who received highly emetogenic regimens.12,13 Casopitant differs from aprepitant in that it has the potential for one-time dosing, but the 2 agents are similar with respect to their drug窶電rug interaction profile.

Conclusion Appropriate CINV prophylaxis in patients receiving emetogenic chemotherapy is critical. Effective, cost-conscious prevention of CINV can improve QoL, patient compliance, and treatment outcomes as well as foster appropriate consumption of medical resources.

Newer antiemetics have significantly improved the control of acute N/V but have had less impact in the delayed setting. Continued research and the development of new antiemetics likely will lead to improved outcomes for patients.

The recommendations in the major antiemetic guidelines are comparable and are represented in this review of CINV and RINV. It is important to realize that although these guidelines provide highly supported treatment plans they should be considered general recommendations. An individual risk assessment should be performed, the emetogenicity of a regimen identified, and an individualized treatment plan developed for each patient receiving chemotherapy or radiation therapy to achieve optimal CINV outcomes.

References 1.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Antiemesis v.1.2010. http://www.nccn. org/professionals/physician_gls/f_guidelines.asp. Accessed April 16, 2010.

2. Burke TA, Wisniewski T, Ernst FR. Resource utilization and costs

associated with chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy administered in the US outpatient hospital setting. Support Care Cancer. 2010 [Epub ahead of print], PMID: 20101417.

3. Herrstedt J. Antiemetics: an update and the MASCC guidelines applied in clinical practice. Nat Clin Pract Oncol. 2008;5(1):32-43, PMID: 18097455.

4. Trigg ME, Higa GM. Chemotherapy-induced nausea and vomiting: antiemetic trials that impacted clinical practice. J Oncol Pharm Pract. 2010 [Epub ahead of print], PMID: 20085961.

5. Kris M, Hesketh PJ, Somerfield M, et al. American Society of Clinical Oncology Guideline for Antiemetics in Oncology: Update 2006. J Clin Oncol. 2006;24(18):2932-2947, PMID: 16717289.

6. Herrstedt J, Roila F, ESMO Guidelines Working Group.

Chemotherapy-induced nausea and vomiting: ESMO clinical recommendations for prophylaxis. Ann Oncol. 2009; 20(suppl 4):156-158, PMID: 19454442.

7. Antiemetic Guidelines. Multinational Association of Supportive Care in Cancer 2008; www.mascc.org. Accessed March 21, 2010.

8. Morrow GR, Roscoe JA, Kirschner JJ, Hynes HE, Rosenbluth RJ. Anticipatory nausea and vomiting in the era of 5-HT3 antiemetics. Support Care Cancer. 1998;6(3):244-247, PMID: 9629877.

9. Roila F, Hesketh PJ, Herrstedt J, et al. Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol. 2006;17(1):20-28, PMID: 16314401.

10. Navari RM, Einhoarn LH, Loehrer PJ Sr. A phase II trial of olanzapine, dexamethasone, and palonosetron for the prevention of chemotherapy-induced nausea and vomiting: a Hoosier oncology group study. Support Care Cancer.

2007;15(11):1285-1291, PMID: 17375339.

11. Tan L, Lui J, Lui X, et al. Clinical research of olanzapine for prevention of chemotherapy-induced nausea and vomiting.

J Exp Clin Ca Res. 2009;28:131-137, PMID: 19775450.

12. Ruhlmann C, Herrstedt J. Casopitant: a novel NK1-receptor antagonist in the prevention of chemotherapy-induced nausea and vomiting. Ther Clin Risk Manage. 2009;5(2):375-384, PMID: 19536319.

13. Gridelli C, Haiderali AM, Russon MW, et al. Casopitant improves the quality of life in patients receiving highly emetogenic chemotherapy. Support Care Cancer. 2009 Oct 31. [Epub ahead of print], PMID: 19882176.

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7

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STRONG. FROM THE START.

FOR A SUCCESSFUL CINV PREVENTION STRATEGY FROM THE FIRST CYCLE When patients experience acute chemotherapyyeir induced nausea and vomiting (CINV) during their first cycle of chemotherapy, they may have an increased risk of CINV on subsequent days and in subsequent cycles.1-3 ALOXI®: A single IV dose lasts up to 5 days after MEC4,5* The only IV 5-HT3 antiemetic specifically approved for prevention of both acute and delayed CINV associated with MEC6* Can be used with multiple-day chemotherapy regimens mens6† * Moderately emetogenic chemotherapy. † Based on sNDA approval in August 2007, the restriction on repeated dosing of ALOXI (palonosetron HCl) injection within a 7-day interval was removed.

Indication ALOXI® (palonosetron HCl) injection 0.25 mg is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information • ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components • Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%) Please see the following brief summary of prescribing information.

REFERENCES: 1. The Italian Group for Antiemetic Research. Dexamethasone alone or in combination with ondansetron for the prevention of delayed nausea and vomiting induced by chemotherapy. N Engl J Med. 2000;342:1554-1559. 2. Hickok JT, Roscoe JA, Morrow GR, et al. 5-hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet Oncol. 2005;6:765-772. Epub September 13, 2005. 3. Cohen L, de Moor CA, Eisenburg P, Ming EE, Hu H. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503. Epub November 14, 2006. 4. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 5. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 6. ALOXI® (palonosetron HCl) injection full prescribing information.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.

Distributed and marketed by Eisai Inc. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL448-A 08/09

www.ALOXI.com

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Pharmacy Practice News • May 2010

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BEYOND AVANDIA continued from page 26

reporting), Dr. Misbin was threatened with dismissal.

The same series of articles soon revealed that another FDA medical officer, John L. Gueriguian, MD, had originally been in charge of reviewing the drug in 1996, and had recommended that it be rejected due to concerns that it could harm the liver and the heart. Dr. Gueriguian, it turned out, had been removed from the assignment following pressure from WarnerALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI is indicated for: • Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses • Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy.

Instructions for I.V. Administration ALOXI is supplied ready for intravenous injection.

ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.

CONTRAINDICATIONS ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information ] WARNINGS AND PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT 3 receptor antagonists.

ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates reported in practice.

In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron.

Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1).

Table 1: Adverse Reactions from ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=633) (N=194) Headache 60 (9%) 34 (8%) 32 (16%) Constipation 29 (5%) 8 (2%) 12 (6%) Diarrhea 8 (1%) 7 (2%) 4 (2%) Dizziness 8 (1%) 9 (2%) 4 (2%) Fatigue 3 (< 1%) 4 (1%) 4 (2%) Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%) Insomnia 1 (< 1%) 3 (1%) 3 (2%) In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study.

In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy: Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear.

Dermatological: < 1%: allergic dermatitis, rash.

Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia.

Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and flatulence.

Lambert; his recommendation against approval had been struck from the official FDA record and withheld from an advisory committee. Furthermore, a St. Louis physician who had supervised some of the early clinical trials for Warner-Lambert was now charging that the company had “deliberately omitted reports of liver toxicity and misrepresented serious adverse events experienced by patients in their clinical studies.”

When the FDA finally announced on March 21, 2000, that it was banning Rezulin, the numbers racked up during its General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-like syndrome.

Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy.

Metabolic: 1%: hyperkalemia, < 1%: electrolyte fluctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia.

Musculoskeletal: < 1%: arthralgia.

Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia.

Psychiatric: 1%: anxiety, < 1%: euphoric mood.

Urinary System: < 1%: urinary retention.

Vascular: < 1%: vein discoloration, vein distention.

Postmarketing Experience The following adverse reactions have been identified during postapproval use of ALOXI. 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.

Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.

DRUG INTERACTIONS Palonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically significant drug interactions with palonosetron appears to be low.

Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.

In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not significantly altered (AUC: no change, Cmax: 15% increase).

A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no significant pharmacokinetic interaction.

In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.

Palonosetron did not inhibit the antitumor activity of the five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/ kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed.

Labor and Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown.

Nursing Mothers It is not known whether palonosetron is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

three years on the market were impressive, on two very different levels. On one hand, it had earned Warner-Lambert $2.1 billion; on the other, it was suspected in 391 deaths. Even so, by then, two other drugs, Actos (pioglitazone, Takeda) and Avandia (rosiglitazone, GlaxoSmithKline), had already been approved under the same fast-track process that had led to Rezulin’s approval.

Back to the Future Today, people with type 2 diabetes have a mind-boggling array of 18 different sugar-lowering drugs and three combination

Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established.

Geriatric Use Population pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients.

Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated.

Renal Impairment Mild to moderate renal impairment does not significantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects.

Dosage adjustment is not necessary in patients with any degree of renal impairment.

Hepatic Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment.

Race Intravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized.

OVERDOSAGE There is no known antidote to ALOXI. Overdose should be managed with supportive care.

Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fixed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed.

Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.

PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions for Patients • Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information].

• Patients should be instructed to read the patient insert.

Rx Only Mfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.

Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677. © 2009 Eisai Inc. All rights reserved. Printed in USA. AL449 08/09

products from which to choose. What they have not had is clear and convincing proof that any of these products protect against the development of heart disease, the leading complication of diabetes, or that using them aggressively to achieve tight control of their sugar levels would extend their lives.

That began to change on June 14, 2007, when Steven Nissen, MD, chairman of cardiovascular medicine at the Cleveland Clinic, published an analysis of Avandia in The New England Journal of Medicine. By combining data from previously published studies, as well as from databases maintained by the FDA and the drug’s manufacturer, GlaxoSmithKline, Dr. Nissen found that, compared with patients not taking the drug, type 2 diabetes patients taking Avandia had a 43% increased risk for heart attack and a 64% increased risk for death due to cardiovascular causes.

The response was an uncanny restaging of the UGDP farce.

First came the outrage of endocrinologists, who pointed out that a metaanalysis cannot provide convincing proof of anything, because it mashes up previous studies into a hash. Dr. Nissen, in fact, agreed with his critics, arguing only that the study pointed out the need for carefully constructed, randomized trials to resolve the matter one way or the other. The FDA, he said, needed to begin requiring that all diabetes drugs be studied for their effects on the heart.

Then came the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study, designed by the National Heart, Lung and Blood Institute to determine whether near-normal sugars would not merely prevent complications of the eyes, kidneys and nerves, but would actually prevent heart attacks and stroke in those considered at high risk for such complications. The study was huge, involving more than 10,000 individuals with type 2 diabetes, and it was supposed to run for more than five years. Patients in the tight-control group aimed to keep their hemoglobin (Hb) A1c levels below 6, meaning that their sugar levels would be in the nondiabetic range. To achieve that, some had to test their sugar levels as often as eight times a day and take up to three sugar-lowering medications.

But 18 months before it was to have been completed, researchers stopped the study early after finding exactly the opposite of what they had expected: 257 patients in the tight-control group had died, compared with 203 in the standard-treatment group, a statistically significant difference. The president of the American College of Cardiology (ACC) called the findings “confusing and disturbing.” After all, the guidelines of both the ADA and the American Association of Clinical Endocrinologists called for

Policy 29

Pharmacy Practice News • May 2010

Books in Focus keeping sugars as low as possible—a strategy that now appeared to increase the risks for heart attack and death.

Some comfort came later that year, when another large study, known as ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation; presented at the International Diabetes Federation Congress, Nov. 20, 2009), found no increased risk for death or heart attack in tight-control patients with average HbA1c of 6.5, compared with the standard-control group with an average HbA1c of 7.3. Then again, ADVANCE found no benefit either for tight control on the risk for death or heart attack. A third study, the VADT (Veterans Affairs Diabetes Trial), likewise found no benefit of tight control in reducing the risk for heart attack, stroke or other cardiovascular events; the only demonstrable effect of tight control, VADT found, was an increase in the risk for hypoglycemia.

In contrast, the UKPDS (UK Prospective Diabetes Study) found that 10 years after patients had completed the type 2 study, those who had been on the tightcontrol regimen had a 15% lower risk for suffering a heart attack and a 13% lower risk for dying of any cause, than those on standard control. Those who had taken metformin had enjoyed even greater benefits of tight control: a 33% lower risk for heart attack and 27% lower risk for death due to any cause.

Still, the negative results of the ACCORD, ADVANCE and VADT studies could not be ignored. By summer 2008, it was clear that something was amiss with the FDA’s approach of approving so many drugs for type 2 diabetes based solely on their ability to lower blood sugars, without demanding proof of their effects on heart disease and overall life expectancy. In early July, the FDA scheduled a meeting of its diabetes drug advisory committee to consider the matter.

develop beyond current therapies that will improve health outcomes.”

Dr. Nissen then tweaked the endocrinologists in the room by coining a name for a “disorder” that he called “glucosecentricity.” “It’s the irrational belief that lowering blood sugar using virtually any pharmacological means will produce a reliable reduction in adverse outcomes. I think what we’ve learned in the last year is that that’s not correct. And so we’ve got to move beyond a glucose-centric approach. We have drugs to lower blood sugar. You know, people are not dying out there because we can’t figure out

how to lower their blood sugar. We have 10 classes of drugs to lower blood sugar.

We need ways to lower blood sugar that reduce complications.”

On Dec. 17, 2008, the FDA announced a new policy, effective immediately, requiring that before any new drug for type 2 diabetes is approved, evidence must be presented that the agent will not increase the risk for heart attacks, strokes or other cardiovascular events.

Questions remain about many of the drugs already on the market. But a glimmer of hope was seen in March of this year, during the ACC meeting in Atlanta,

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Glucose-centricity It took until after lunch on the first day for Dr. Nissen, who had started the whole brouhaha with his meta-analysis of Avandia, to make the case that cardiovascular testing of diabetes drugs was not only sensible and practical but also long overdue.

“Here we are, 50 years after the initial introduction of anti-diabetic agents,” Dr. Nissen said. “And although cardiovascular disease is the cause of death in 75% of diabetics, there exists no well-designed, adequately powered, comparative effectiveness trials evaluating macrovascular outcomes for diabetes drugs. We have a knowledge gap. There are certainly many ways to lower blood sugar. What we really need to know are what agents improve health outcomes, and what agents can we

when researchers presented promising reports on the potential ability of nateglinide (Starlix, Novartis) and valsartan (Diovan, Novartis) to prevent cardiovascular events in diabetics.

Whether that promise will be chewed up and spat out by the same buzzsaw that has hit so many other drugs marketed to patients with type 2 diabetes is anybody’s guess. But now that researchers are at least looking for ways to prevent cardiovascular morbidities in type 2 diabetes, perhaps it is not unduly optimistic to believe that a corner has been turned.

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30 Clinical

Pharmacy Practice News • May 2010

Medication safety

DANGEROUS DRUGS continued from page 1

Center and Hospital in Baltimore. In 2009, the FDA required the drug’s manufacturers to strengthen label warnings about the risk for overdose.

Perhaps equally puzzling is the fact that so many of the prescribing clinicians in the study were seemingly ignorant of the Beers criteria and other tools for identifying and avoiding inappropriate medication use in nursing homes. To pharmacists, the Beers criteria is old news. Many physicians, in contrast, apparently don’t even know it exists—including the lead author of the study, William Meurer, MD, assistant professor of emergency medicine and neurology at the University of Michigan, in Ann Arbor.

Dr. Meurer said he only learned of the Beers criteria in 2008 at an emergency medicine conference, and subsequently used it to define PIMs in his study. When he analyzed the results, he noted, “I quickly realized that the list of available medications for these patients needs serious paring.”

Robust Data Set Dr. Meurer and his colleagues extracted data on ED visits from the 2000-2006 National Hospital Ambulatory Medical Care Survey, then extrapolated the data to the entire U.S. population. The sample group included adults age 65 and older

‘Why in the world would any physician prescribe propoxyphene? There’s no literature to show that it’s any more effective than Tylenol.’

—Marilyn McEvoy, RPh, CGP who were treated in the ED and discharged. Out of an estimated 116 million ED visits, approximately 19.5 million (16.8%) involved one or more PIMs. The rate of PIMs was most strongly tied to the total number of medications administered or prescribed during an ED visit.

Other variables also were predictive of a higher level of PIMs. They were more likely to occur at rural hospitals outside of the Northeast and at for-profit hospitals; when a staff physician (and not a resident or intern) treated patients; when the patients presented with an injury; and with the combination of female sex and an age of 65 to 74 years. Over the study period, there was a small but significant decrease in the proportion of visits associated with a PIM. The study did not explore the impact of drug interactions. But what the study did show is that “some medications are

not recommended for older adults, regardless of the situation in which they’re being used,” Dr. Meurer said. “For many of these drugs, there are better alternatives that don’t impair cognition and balance, that pose lower risks for respiratory arrest and other adverse events, and that have shorter half-lives. It’s not entirely clear why we as medical providers as a group are still using [PIMs].”

pharmacists to the ED—a practice that is slowly gaining adherents in the nation’s hospitals. Kyle Weant, PharmD, BCPS, clinical pharmacy specialist in emergency medicine/ critical care, University of Kentucky HealthCare, in Lexington, said that his profession excels at avoiding the types of potential drug errors that were uncovered in Dr. Meurer’s study.

In fact, for all of the top five drugs identified in the study, suitable sub-

‘You’re talking about physicians who may have been prescribing these drugs for many years before the [Beers] criteria came out.

Long-term prescribing habits can be hard to break.’

—Allen Vaida, PharmD Beers Overlooked It is also not clear why the Beers criteria seemed to be so overlooked by the prescribing clinicians in Dr. Meurer’s study. Geriatrician Mark Beers conceived the Beers criteria in 1991 to define inappropriate medication use in nursing homes. It has undergone two updates, most recently in 2003. Although the criteria are based on expert consensus rather than firm outcomes data, and aren’t the perfect tool for assessing drug risk (http:// www.pharmacypracticenews.com/ fwd/14858.htm), they have become a valuable guide for decisions regarding medications for older adults.

According to the Institute for Safe Medication Practices (ISMP), the Beers criteria are widely known for identifying drugs that may increase the likelihood of adverse events in elderly patients. “It’s gained [adherents] in the last few years because of an emphasis on patient falls that may be due to medications, especially in acute care and nursing homes,” said Allen Vaida, PharmD, BSc, executive vice president, ISMP. In fact, Dr. Vaida speculated that the lower number of PIMs associated with residents and interns in the study is a result of wider dissemination of the Beers criteria, and its incorporation in medical training curriculum.

“You’re talking about physicians who may have been prescribing these drugs for many years before the criteria came out,” he said. “Long-term prescribing habits can be hard to break.”

“It’s been shown repeatedly that prescribers tend to adhere to certain patterns that they adopt early on, and it’s pretty hard to change them,” Ms. McEvoy added.

Aggressive Intervention Urged Dr. Meurer said that the scope of the problem warrants aggressive intervention. One tactic is to assign dedicated

stitutes exist, Dr. Weant stressed. He added that many pharmacists consider some of the identified drugs, such as propoxyphene, ineffectual and others, like meperidine, very dangerous in elderly patients.

“That’s why we can be such valuable members of the health care team in the ED,” Dr. Weant said. “We really are the drug experts, and we’re trained to help our physician colleagues avoid problems with these types of medications.”

In 2006, the University of Kentucky became the first hospital in the state to provide full-time clinical pharmacist services in the ED, according to Dr. Weant, who documented the impact of the change in a study accepted for publication in the American Journal of Health System Pharmacists. He concluded that adding two ED pharmacists resulted in an increase in medication error reporting of nearly 15 times compared with that seen when there were no ED pharmacists. The findings led to changes in medication distribution, order sets and the implementation of targeted education initiatives at his institution.

“The ED is an environment where there is a lot of emphasis placed on physicians to turn over patients quickly,” Dr. Weant said. “They’re overwhelmed by the number of patients who show up at the door, so there’s tons of pressure to get them in, get them treated, send them home or get them admitted to a service, and move on to the next station.”

The presence of pharmacists in the ED has heightened awareness among prescribers regarding medication errors, Dr. Weant added. “They’re more likely to stop and say ‘hey, let’s slow down and make sure we are doing this right.’”

A growing number of hospitals are seeing the benefits of adding pharmacists to the ED team, according to Dr. Vaida. “It’s a slow process that’s happening most frequently in large academic centers with

ED visits involving one or more potentially inappropriate medications Total ED visits

16.8%

Figure. ED Visits, 2000-2006 National Hospital Ambulatory Medical Care Survey. busy emergency departments with the financial resources to support them.”

Smaller hospitals that lack the finances to hire an ED pharmacist can redouble efforts to educate physicians and nurses. “It comes down to educating practitioners and other health care professionals that we can’t care for all patients the same,” Dr. Weant said. “We can’t treat the 18-year-old who falls and breaks a leg the same as we treat an older population.”

Some options include in-service programs, lectures at grand rounds and morbidity and mortality conferences and presentations at nursing meetings. All of those activities can be coordinated by the hospital pharmacy without significant expense, Ms. McEvoy said.

“Simply informing practitioners about the Beers criteria may dramatically decrease PIM administration to older adults in the ED,” added Dr. Meurer. He also suggested systemic fixes, such as computerized systems that warn clinicians when a PIM is prescribed, or the development of distinct ED-specific prescribing criteria.

Dr. Meurer said he would also welcome regulatory intervention. That’s unlikely to happen soon, he admitted, because drug companies could persuasively argue that there’s no robust or systematic evidence demonstrating actual harm caused

by PIMs. But he also pointed out that although it is reasonable to conclude PIMs will not cause problems inevitably for every patient, they undoubtedly increase the risk for adverse events.

“It’s very difficult to get a feel for how big the problem is in terms of actually hurting people,” he said. “But if there are safer alternatives to potentially harmful prescriptions, I don’t know why we need to wait for that information before we change our own practices.”

—Steve Frandzel

32 Clinical

Pharmacy Practice News • May 2010

Medicaton Safety

(Patient Safety) Checklist, Please C hecklists in medicine are all the rage, with books by Atule Gawande and Peter Pronovost just two recent examples of high-profile tomes advocating the tool as a simple and effective way to protect patients from harm.

But can checklists help hospitals prevent medication errors? Some experts think so.

“A pharmacy practice checklist could be transforming,” said John Poikonen, PharmD, director of clinical informat-

ics at UMass Memorial Medical Center, Worcester.

Checklists increase safety and reduce risk for errors because they force health care providers to follow appropriate safety precautions, said Sharon Enright, RPh, MBA, president of Envision Change in Richmond, Va. “Human memory is fallible. Our knowledge base is vast and growing every day and too complex for the human mind to manage—particularly for a process

like medication use, which is complex beyond the norm,” Ms. Enright said.

Dr. Gawande, a well-known surgeon and essayist, and Dr. Pronovost, an intensive care specialist, have been instrumental in developing checklists used for other areas of patient care, particularly in operating suites and intensive care units (ICUs). Studies have shown that a checklist can reduce deaths in surgical patients by as much as half (N Engl J Med 2009;360:491-499). And a simple five-

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

BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE Flebogamma® 5% DIF is indicated for replacement therapy in primary (inherited) humoral immunodeficiency disorders.

DOSAGE AND ADMINISTRATION The usual dose of Flebogamma® 5% DIF for replacement therapy in primary humoral immunodeficiency diseases is 300 to 600 mg/kg body weight administered every 3 to 4 weeks.

An in-line filter with a pore size of 15 to 20 microns is recommended for the infusion.

Antibacterial filters (0.2 micron) may also be used. Discard unused contents and administration devices after use.

The infusion of Flebogamma® 5% DIF should be initiated at a rate of 0.01 mL/kg body weight/minute (0.5 mg/kg/minute). If, during the first 30 minutes, the patient does not experience any discomfort, the rate may be gradually increased to a maximum of 0.10 mL/kg/minute (5 mg/kg/minute).

For patients judged to be at risk for developing renal dysfunction or considered to be at increased risk of thombotic/thromboembolic events, it may be prudent to limit the infusion rate to a maximum rate less than 0.06 mL/kg body weight/minute (3 mg/ kg/minute). Reduction in dose, concentration, and/or rate of infusion in patients at risk of acute renal failure, which includes patients over 65, has been proposed in the literature in order to reduce the risk of acute renal failure.

CONTRAINDICATIONS Flebogamma® 5% DIF should not be administered to individuals with a history of severe or anaphylactic reactions to blood or blood-derived products. Patients with severe selective IgA deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction. Anaphylaxis can occur using Flebogamma® 5% DIF even though it contains low amounts of IgA (typically < 50 μg/mL). Such patients should only receive intravenous immune globulin with utmost caution and in a setting where supportive care is available for treating life-threatening reactions. If patients are known to be intolerant to any component of Flebogamma® 5% DIF, such as sorbitol (i.e., intolerance to fructose), they should not receive the product.

WARNINGS Immune Globulin Intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Flebogamma® 5% DIF does not contain sucrose.

See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure.

Flebogamma® 5% DIF is made from human plasma. As with all plasma derived products, the risk of transmission of infectious agents, including viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated. The risk that such products will transmit an infectious agent has been greatly reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses.

ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Biologicals at 888-GRIFOLS (888-474-3657).

All patients, but especially individuals receiving Flebogamma® 5% DIF for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks, may be at risk for the development of inflammatory reactions characterized by fever, chills, nausea, and vomiting. Careful monitoring of recipients and adherence to recommendations may reduce the risk of these types of events.

Appropriate supportive care, including immediate access to epinephrine injection, should be available for the management of acute anaphylactic reactions.

step checklist—in which hand washing is the first step—has been shown to reduce rates of catheter-related bloodstream infections by up to 66% in emergency rooms and ICUs (BMJ 2010;340:c309).

But in the pharmacy field, standardized checklists are not broadly used. The specialty has introduced formal safety precautions like error reporting systems, best practices, bar-code medication administration and toolkits to eliminate use of error-prone abbreviations. But

PRECAUTIONS General: Any vial that has been entered should be used promptly. Partially used vials should be discarded and not saved for future use because the solution contains no preservative.

Do not use if turbid. Solution that has been frozen should not be used.

Ensure that patients are not volume-depleted before the initiation of the infusion of IGIV. Renal Function: Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure.

Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma® 5% DIF and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered.

For patients judged to be at risk for developing renal dysfunction, it may be prudent to reduce the amount of product infused per unit time by infusing Flebogamma® 5% DIF at a maximum rate less than 0.06 mL/kg (3 mg/kg) body weight/minute.

Aseptic Meningitis Syndrome: An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with IGIV treatment. The syndrome usually begins within several hours to 2 days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic milliliter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high-dose (e.g., > 1.0 g/kg body weight) and/or rapid-infusion IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.

Hemolysis: Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis. Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration [See ADVERSE REACTIONS]. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis [See PRECAUTIONS: Laboratory Tests].

Thrombotic Events: Thrombotic events have been reported in association with IGIV (See ADVERSE REACTIONS).

Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [See PRECAUTIONS: Laboratory Tests].

Transfusion-Related Acute Lung Injury (TRALI): There have been reports of non-cardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1 to 6 hours after transfusion.

Patients with TRALI may be managed by using oxygen therapy with adequate ventilatory support. IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum [See PRECAUTIONS: Laboratory Tests].

Information For Patients: Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (which may suggest kidney damage) to their physicians.

It is recommended that the lot number of the vials used be recorded when Flebogamma® 5% DIF is administered.

Laboratory Tests: Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed before the initial infusion of Flebogamma® 5% DIF in patients judged to have a potential increased risk for developing acute renal failure and again at appropriate intervals thereafter.

Clinical 33

Pharmacy Practice News • May 2010

Medication Safety

‘It’s time to stop talking about doing something about heparin and actually do something.’

—John F. Mitchell, PharmD

checklists like the ones Drs. Gawande and Pronovost propose are different from most protocols used in pharmacy.

The checklists are quick, formalized

steps that must be checked off as a health care practitioner acts. Done properly, they also provide hospitals and health care systems with a way to measure and report key patient safety performance indicators. Checklist supporters also say that they make health care providers and patients better aware of safety precautions.

Signs of Uptake Industry leaders said they plan to start moving soon on pharmacy checklists.

Following infusion of Flebogamma® 5% DIF, there may be a transitory rise of various antibody titers that may result in misleading positive results in serological testing.

Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

If TRALI is suspected, appropriate tests should be performed for the presence of antineutrophil antibodies in both the product and patient serum.

Pregnancy Category C: Animal reproduction studies have not been performed with Flebogamma® 5% DIF. It is also not known whether Flebogamma® 5% DIF can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Flebogamma® 5% DIF should be given to a pregnant woman only if clearly needed.

Drug Interactions: Antibodies in Flebogamma® 5% DIF may interfere with the response to live viral vaccines, such as measles, mumps, and rubella. Physicians should be informed of recent therapy with Immune Globulin Intravenous (Human) so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months from the time of IGIV administration.

Pediatric Use: The above mentioned clinical trial with Flebogamma® 5% DIF enrolled only a very limited number of children (0) and adolescents (3) with primary humoral immune deficiency, a number insufficient to fully characterize and establish the efficacy and safety in pediatric patients.

Geriatric Use: Subjects over 65 are at increased risk of renal failure with IGIV treatment. For these subjects, and for any other subjects at risk of renal failure, the infusion rate of Flebogamma® 5% DIF should be limited to < 0.06 mL/kg/min (3 mg/kg/min).

Adverse Reactions Increases of creatinine and blood urea nitrogen (BUN) have been observed as soon as 1 to 2 days following infusion of IGIV. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment. Types of severe renal adverse reactions that have been seen following IGIV therapy include: acute renal failure, acute tubular necrosis, proximal tubular nephropathy, and osmotic nephrosis.

Certain severe adverse reactions may be related to the rate of infusion. The recommended infusion rate [See DOSAGE AND ADMINISTRATION] must be closely followed. Patients must be closely monitored and carefully observed for any symptoms throughout the infusion period. Adverse reactions may occur more frequently when a high infusion rate is used, the treatment is the initial exposure to immunoglobulin, the immunoglobulin product has been changed to that of a different manufacturer, or there has been a long interval (more than 8 weeks) since the previous infusion. Slowing or stopping an infusion usually results in the prompt disappearance of symptoms.

Post-Marketing: The following adverse reactions have been identified and reported during the postapproval use of IGIV products.

Respiratory

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

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

Because post-marketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product.

Such is also the case with literature reports authored independently.

Adverse events were reported in a study of 46 individuals with primary humoral immunodeficiency diseases receiving infusions every 3 to 4 weeks of 300 to 600 mg/kg body weight. Forty-three (94%) subjects experienced at least 1 adverse event

Ms. Enright said she and colleagues are discussing a new project in which pharmacists will identify the practices best suited to a checklist. As yet, the group has no conclusive plans. But they hope “to move on this quickly.”

Pharmacy “is the poster child for the checklist approach,” she said. “Pharmacy is so applicable to this concept because it is such a complex and complicated care delivery process.”

Setting up checklists is no easy task. It involves pinpointing the critical moments when checklists could be helpful, identifying the key steps—and not too many

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

Table 1. Adverse Events Occurring with an Incidence of > 15% Adverse Event

Number of AEs

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

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

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

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

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

Table 2. Summary of Infusions with Mild, Moderate, and Severe TreatmentRelated Adverse Events Severity of AE Mild Moderate Severe

No. Infusions 58 25 1

Adjusted % a with AE 7.9 3.6 0.1

Confidence Intervalb 10.4 4.9 0.3

a. Adjusted % = average of the % of infusions with a treatment-related adverse event for each individual subject. b. The 95% upper bound for the adjusted % of infusions for which at least 1 treatmentrelated adverse event was reported was derived by using the t-statistic.

The number and percent of subjects with treatment-emergent rises in AST or ALT are in Table 3.

Table 3. Number (%) of Subjects with Treatment-Emergent Rises in AST or ALT (N = 46) Laboratory Test AST ALT

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

n 3 1

% 6.5 2.2

a. ULN = upper limit of normal.

None of these subjects had a concomitant treatment-emergent rise in total bilirubin.

Reported adverse reactions with Flebogamma® 5% DIF and other IGIV products include: headache, chills, fever, shaking, fatigue, malaise, anxiety, back pain, muscle cramps, abdominal cramps, blood pressure changes, chest tightness, palpitations, tachycardia, nausea, vomiting, cutaneous reactions, wheezing, rash, arthralgia, and edema, often beginning within 60 minutes of the start of the infusion.

Rarely, Immune Globulin Intravenous (Human) can induce a severe fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with IGIV. In the case of shock, the current standard medical treatment for shock should be implemented.

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steps—that need to be taken, getting staff on board, validating the checklists and continually following progress to ensure improvement. Dr. Pronovost said the process must be carried out with strict adherence to research principles.

So far, some formal checklists exist for pharmacy. Pharmacydirectors.com has published a 12-step checklist for inspecting the medication storage area.

The checklist is available online. The American Society of Health-System Pharmacists (ASHP) published some checklists in its practice guidelines, such as checklists for the initial setup of anti-neoplastic drugs and for preparing and labeling such drugs.

“Certainly, in the hospitals, there are many instances where there would be a place for a checklist—in particular with use of heparin. It’s time to stop talking about doing something about heparin and actually do something,” said John F. Mitchell, PharmD, previously the medication safety coordinator for the Department of Pharmacy Services, University of Michigan Health Systems, who has been recognized by the Institute for Safe Medication Practices for his work.

But checklists also pose problems, he said. It’s one thing to set up a quick checklist for hand washing; it’s difficult to implement a checklist for medication orders that pass through several health care practitioners. “There are many, many hand-offs. How many checklists would there have to be? How would you do that?” he said.

Bedside May Be a Good Place To Start Dr. Mitchell suggested that the patient bedside might be the most appropriate place for a medication checklist. “It’s the last place you can check and the last place for an error to be prevented.

That’s where it would be great to have a checklist but it would require a total commitment by the hospital.”

Checklists alone will not make patients safe, Dr. Pronovost said. Hospital staff also must commit to changing the culture of hospitals.

“Errors come from bad teamwork and a toxic hospital culture, something that is endemic to the entire health care system,” he said in an interview.

“Checklists are useful but they’re not Harry Potter’s wand.”

Bona Benjamin, director of medication-use quality improvement at the ASHP, agreed. “Improving care is not as simple as handing a checklist to the doctors and nurses,” she said. “Pharmacists should facilitate the use of checklists by becoming active members of the team that delivers care and sharing accountability with the team for patient outcomes. That’s a major culture change.”

—Christina Frangou

34 Clinical

Pharmacy Practice News • May 2010

Formulary Management

Making the Switch to Unfractionated Heparin Pays Off Editor’s Note: In March 2009, staff at the Saint Barnabas Health Care System’s Community Medical Center in Toms River, N.J., undertook a pharmacy-driven therapeutic interchange in which low-dose unfractionated heparin (UFH) was substituted for enoxaparin (Lovenox, Sanofi-aventis) as the formulary-preferred method of delivering venous thromboembolism (VTE) prophylaxis. This interchange, which saved the institution $500,000 annually without compromising patient outcomes, is detailed below.

Robert T. Adamson, PharmD Corporate Vice President of Clinical Pharmacy

Indu Lew, PharmD Corporate Vice President of Education and Research

Elena Beyzarov, PharmD Director of Medical Communications at Ideas, a Saint Barnabas affiliate Saint Barnabas Health Care System West Orange, New Jersey

O

ur therapeutic switch initiative was prompted by a need to contain hospital expenditures associated with high-cost medications such as low molecular weight heparins (LMWHs), as well as by recently updated consensus guidelines by the American College of Chest Physicians for preventing VTE. In these guidelines, low-dose UFH received the same 1A recommendation as LMWH and fondaparinux for VTE prophylaxis in oncology patients, acutely ill/high-risk medical patients and critical care patients. What follows is an account of Saint Barnabas Community Medical Center’s experience with implementing the new protocol.

Most pharmacists attending general medical rounds can attest to the importance of protecting clot-prone hospitalized patients from VTE. Risk factors such as immobility, advanced age, surgery, trauma and cancer are notoriously common among hospitalized patients and make for a perfect storm of pro-coagulation. Almost all hospitalized patients have at least one of these risk factors for VTE, and approximately 40% have three or more risk factors.1 Considering that VTE occurs 150 times more often in hospitalized patients than in non-hospitalized patients,2 prevention is essential. Without thromboprophylaxis, the incidence of hospital-acquired deep venous thrombosis (DVT) is approximately 10% to 40% among medical or general surgical patients and 40% to 60% following major orthopedic surgery.

Thrombotic complications are a major cause of in-hospital morbidity

and mortality, with pulmonary embolism (PE) accounting for 5% to 10% of all inpatient deaths.3-5 Early mortality rates of 3.8% and 38.9% in patients experiencing DVT and PE, respectively, have also been reported.4 An estimated 75% of all fatal PEs occur in medical patients, who account for 60% of all hospital admissions.3 At our institutions, VTE prophylaxis is always at the forefront of care, especially because the Joint Commission considers this to be a safety goal.

The use of LMWHs in preventing and treating thrombotic complications has grown exponentially over the last decade as a result of accumulating safety and efficacy data and clinicians’ increased comfort level with their use. However, LMWHs are associated with substantially higher costs compared with UFH. Therefore, hospital expenditures have increased dramatically, prompting institutions to evaluate LMWHs for potential therapeutic interchange. Health care systems are under unprecedented pressure to contain costs, particularly when it comes to medications. With an aging population, expanded indications for thromboprophylaxis in nonsurgical patients and the introduction of more expen-

sive new agents, the stakes are high when choosing the most cost-effective anticoagulant.

Financial incentives and the American College of Chest Physicians’ updated pulmonary guidelines compelled our staff at Saint Barnabas to reevaluate VTE prophylaxis. Whenever national guidelines pertaining to any disease state are updated or revised, we review them thoroughly to ensure that our own institution-based guidelines and protocols reflect the most current standard of care. When we reviewed the 2008 guidelines, we realized that low-dose UFH received the same 1A recommendation as LMWH and fondaparinux for VTE prophylaxis in oncology, critical care and acutely ill or high-risk medical patients.1 A 1A recommendation is traditionally based on the highest quality of evidence and a strong level of confidence regarding risks and benefits. Indeed, randomized studies supporting the 1A recommendation have shown no significant difference between LMWHs and lowdose UFH with regard to DVT and bleeding rates.1 After closely assessing the potential financial implications of changing our thromboprophylaxis (enoxaparin 40 mg daily) to low-dose

UFH (5,000 units q8h), we decided to pilot a pharmacy-driven initiative using low-dose UFH as the formularypreferred method instead.

Getting Buy-In Rolling out the initiative was no simple task. As with any major therapeutic interchange, consensus from key players within the hospital was critical. Physicians needed reassurance that the new therapy would not affect rates of DVT, PE and heparin-induced thrombocytopenia (HIT). Nurses had to comply with a new schedule of three daily injections instead of one. As the nursing schedule at Community Medical Center is divided into three eight-hour shifts per 24-hour period, nursing staff anticipated that each nurse would have to administer only one injection daily.

Physicians were concerned about the possibility of HIT with UFH. A rare yet devastating complication associated with venous and arterial thrombosis, HIT is generally less likely to occur with LMWHs than with UFH. But thromboprophylaxis with low-dose UFH in nonsurgical patients is associated with a statistically low risk for HIT, a risk similar to that of LMWHs.

•

see SWITCH, page 47

0.003

3

0.014

0.013

0.002

2

1.28 1.1 0.001

1

Cohort 1

Cohort 2

Figure 1. Pulmonary embolism rates per 1,000 patient-days.

Cohort 1

Cohort 2

Figure 2. Heparin-induced thrombocytopenia rates per 1,000 patient-days.

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Important Safety Information GELFOAM PLUS should not be used in closure of skin incisions, because it may interfere with the healing of the skin edges. GELFOAM PLUS should not be placed intravascularly, because of the risk of embolization.

GELFOAM PLUS is not recommended for use other than an adjunct for hemostasis.

GELFOAM PLUS contains thrombin, which is made from human plasma. It may carry the risk of transmitting infectious agents, e.g., viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent.

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GELFOAM PLUS is not recommended in the presence of infection. There have been reports of fever associated with the use of Gelfoam Sterile Sponge, without demonstrable infection.

FLOSEAL [Hemostatic Matrix] Indications FLOSEAL is indicated in surgical procedures (other than ophthalmic) as an adjunct to hemostasis when control of bleeding by ligature or conventional procedures is ineffective or impractical.

Important Safety Information FLOSEAL must not be injected into blood vessels, or allowed to enter blood vessels. Do not apply in the absence of active bleeding. Extensive intravascular clotting and even death may result.

Do not use FLOSEAL in the closure of skin incisions because it may interfere with the healing of the skin edges.

Do not use FLOSEAL in patients with known allergies to materials of bovine origin.

FLOSEAL is made from human plasma. It may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

The maximum swell volume of approximately 20% is achieved within about 10 minutes. Excess FLOSEAL (material not incorporated in the hemostatic clot) should be removed from the site of application using gentle irrigation.

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36

Hem/Onc Pharmacy

Pharmacy Practice News • May 2010

In Focus

Concern Revving Up Over REMS P

harmacists, oncologists and other practitioners are expressing concern over how they will comply with requirements imposed by FDA’s Risk Evaluation and Mitigation Strategy (REMS) program for erythropoietin-stimulating agents (ESAs).

Under the long-awaited program unveiled in February, physicians and hospitals have one year to register, undergo training and be certified in order to continue prescribing and dispensing ESAs to cancer patients. Those who fail to comply by March 2011 will be barred from accessing ESAs.

tion for the Safe Use of ESAs) requires that physicians register with Amgen; complete a specific training module on ESA usage; discuss the risks, benefits and approved usage of ESAs with each patient before beginning treatment; and document this discussion with written acknowledgment from both doctor and patient. Health care providers must reenroll in the program every three years.

Hospitals dispensing ESAs must also designate someone to “assume the authority and responsibility” to internally coordinate and oversee the institution’s program. The hospital “designee”

‘Pharmacy has the opportunity to take a leadership role in shaping [REMS] programs to seek more balanced, standardized processes.’

—Timothy R. Franson, MD

“Most REMS [requirements] to this point have been for agents and classes of agents indicated for limited patient populations. This is the first one that’s impacting pharmacists and clinicians to such an extent,” said Bridget C. Fowler, PharmD, clinical pharmacy manager at Dana-Farber Cancer Institute’s Department of Pharmacy, in Boston. “Some providers may just decide not to prescribe ESAs,” she told Pharmacy Practice News.

In April 2008, the FDA required Amgen Inc., to establish and oversee a REMS program for ESAs, which include epoetin alfa (Procrit, Centocor Ortho Biotech; Epogen, Amgen) and darbepoetin alfa (Aranesp, Amgen). The program was instituted in response to studies that found ESAs caused tumors to grow faster and resulted in earlier deaths in certain cancer patients (http://www.pharmacypracticenews. com/fwd/9554.htm).

Evaluation of ESAs “has been an ongoing and intensive process since 2004, involving a series of public meetings, labeling changes and a required Medication Guide,” said Richard Pazdur, MD, director of FDA’s Office of Oncology Drug Products. “This new risk management program will help ensure that patients and their health care professionals have fully considered the benefits and risks of using ESAs.” The REMS program requires that health care professionals give all patients receiving ESAs the FDA-approved Medication Guide containing information about the drugs’ risks and benefits.

For cancer patients, a separate REMS APPRISE program (Assisting Providers and Cancer Patients with Risk Informa-

viders and institutions to be trained, certified and held strictly accountable for implementation,” said Timothy R. Franson, MD, senior vice president at B&D Consulting in Washington, D.C., and a former regulation and drug safety specialist at Eli Lilly & Co. The program is further “confounded,” he said, by new enforcement powers recently granted to FDA to assess civil monetary penalties for compliance failures. “This could be a very real concern for manufacturers and practitioners,” Dr. Franson told Pharmacy Practice News.

Oncologists are also unhappy about the additional requirements. “Oncologists continually struggle to provide highquality cancer care in the face of dwindling resources and growing administrative burdens,” according to the American Society of Clinical Oncology in a recent statement to its members. “While ASCO supports efforts to raise risk awareness

we will have to scan them into our electronic systems,” said Niesha Griffith, RPh, pharmacy director at Arthur G. James Cancer Hospital, Ohio State University, in Columbus.

Additional time-consuming activities are likely if a medication order arrives without the necessary paperwork. “While it may take only 10 minutes for the physician to print out the form and talk with the patient, when the order is sent to the hospital, if the sheet doesn’t accompany the order, the amount of time it will take to track it down will be much more than 10 minutes,” said David Chen, RPh, MBA, director of Pharmacy Practice Sections at the American Society of Health-System Pharmacists (ASHP).

And although individual pharmacists are not required to register and be APPRISE-certified, they also will not have access to the hospital’s master list to verify which physicians are registered, Dr. Fowler said. “The pharmacists will have to go through one central person who is the designee, and that’s not terribly user-friendly,” she explained.

Responsibility Without Authority The FDA was granted authority to impose REMS programs on drug companies following enactment of the FDA Amendments Act in September 2007.

Ever since, pharmacists have been wary about the cost and complexity of managing diverse REMS requirements. “Hospitals are incurring all the costs of risk management, but they are not reimbursed for those services,” Mr. Chen said. “This is another example of unintended side effects from restrictive drug (often the pharmacy manager) is responsible for the hospital’s compliance. This entails completing a separate training module, compiling a list of everyone at the hospital who prescribes ESAs to cancer patients, maintaining proof that each one has enrolled in APPRISE, and archiving the written acknowledgments from every cancer patient who receives ESAs. “Failure of the staff to comply with enrollment requirements will lead to suspension of access to ESAs for your hospital,” Amgen warned.

In private-practice settings, the registration and acknowledgment forms are required to be faxed or mailed to a third-party call center that oversees and monitors compliance.

A ‘Daunting Burden’ The REMS for ESA use represents a “daunting burden at the bedside” because it “requires health care pro-

‘Hospitals are incurring all the costs of risk management, but they are not reimbursed for those services. This is another example of unintended side effects from restrictive drug distribution systems.’

—David Chen, RPh and promote patient safety, we strenuously object to duplicative requirements that further diminish time and resources available for patient care.”

Impact on Pharmacists Pharmacists are particularly concerned about the bookkeeping and time management burdens APPRISE will place on them, especially because the system is paper-based. “Most hospitals and physician practices are moving toward electronic medical records. If we want the REMS forms to be electronic,

distribution systems.”

Perhaps most significantly, APPRISE “puts the pharmacist in the middle of collecting and validating the information; it’s putting the pharmacist in the role of a compliance officer instead of a clinician,” he added. “We are starting to see pharmacy practice being driven by the risk of noncompliance to regulations versus building medication use systems that manage the risks for all patients in the institutions.”

Ms. Griffith concurred. “I am not sure

•

see ESA REMS, page 38

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38

Hem/Onc Pharmacy

Pharmacy Practice News • May 2010

In Focus

ESA REMS continued from page 36

the hospital pharmacy director is best to sign for the hospital enrollment because they don’t have any authority over the physicians who are expected to comply.

We cannot make them enroll, but then we are not permitted to give them the drugs if they don’t. It puts us in a very tenuous position.”

The hospital’s responsibility, she added, shouldn’t rest solely with pharmacy.

“You have to engage risk management [lawyers], Medication Safety and Qual-

‘[The] hospital pharmacy director … cannot make [physicians enroll in the REMS program for ESAs], but then we are not permitted to give them the drugs if they don’t. It puts us in a very tenuous position.’

—Niesha Griffith, RPh

ity Committees, the P&T [pharmacy and therapeutics] Committee, as well as medical and nursing staffs that will be impacted by the program,” Ms. Griffith said. “It’s not just pharmacy—it’s a

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CMS Weighs the Evidence The REMS is the latest in a series of restrictions imposed by federal agen-

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PATIENT SAFETY

cies on ESAs. In March 2007, the FDA ordered black box warnings to be added to labeling for ESAs and subsequently limited initiation to patients with hemoglobin levels of 10 g/dL or lower. In July 2007, the Centers for Medicare & Medicaid Services (CMS) issued a national coverage determination (NDC) denying ESA reimbursement for any anemia of cancer unrelated to chemotherapy. CMS also tied initiation to hemoglobin levels lower than 10 g/dL (hematocrit <30%) and for a maximum of eight weeks.

CMS is expected later this year to issue a final prospective payment system decision that would “bundle” payments for dialysis services, ESAs and lab tests, potentially further eroding ESA use. CMS has expressed interest in issuing an NDC for ESA use in patients with chronic kidney disease (CKD). (The APPRISE program does not apply to ESAs used for anemia in patients with CKD and other noncancer conditions.)

In March, the agency convened an advisory panel to weigh the evidence on the use of ESAs to manage anemia in CKD patients in both dialysis and predialysis populations. Members of the Medicare Evidence Development & Coverage Advisory Committee (MEDCAC) generally agreed that increased heart risks have been demonstrated when hemoglobin is targeted to 12 g/dL and higher, but noted that when targeted to less than 12 g/dL ESAs can improve patient-perceived quality of life. The panelists said additional clinical trials were needed to identify the optimal range between 9 and 12 g/dL and for specific patient groups.

“There’s too great a gap between what we’ve observed in practice and what we know” about ESAs, said panel chair Clifford Goodman, a vice president at The Lewin Group, a health care policy consultancy in Falls Church, Va., that was contracted for the meeting. The panel’s recommendations are not binding, but “CMS will carefully consider the MEDCAC panel’s recommendations,” said Louis B. Jacques, MD, director of the agency’s Coverage & Analysis Group, without elaborating.

An additional problem with the REMS program, said Dr. Franson, is that the benefits of requiring “burdensome administrative processes” have not yet been validated in terms of risk reduction.

“One would hope that over time, the data from initial REMS programs will aid the design of future risk mitigation efforts, and that patients will truly be beneficiaries of these interventions,” Dr. Franson said. “In such a formative stage, pharmacy has the opportunity to take a leadership role in shaping such programs to seek more balanced, standardized processes.”

—Ted Agres

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Pharmacy Practice News • May 2010

In Focus (J Clin Oncol 1997;15:2351-2358). The drug alone cost $37,000 in 1996 U.S. dollars. Added to that was $6,200 in administration costs; $4,000 for induction; and $200 per month for maintenance, including central line insertion, lab monitoring, office visits and toxicity management.

Furthermore, there is no denying that high-dose IFN toxicities can be substantial and affect many organ systems, Dr. Trinh said. Side effects include flu-like symptoms, myelosuppression, neuropsychiatric disorders and hepatotoxic-

INTERFERON continued from page 1

(IFN-alfa), if they are willing to accept the associated toxicity.

Taking the opposite view was Jaime Anderson, PharmD, oncology clinical pharmacist, also at the M.D. Anderson Cancer Center, who countered that there are so many negative issues associated with high-dose IFN in this setting, including extreme toxicity, high cost and lack of benefit in terms of overall survival (OS), that its use cannot be justified.

Dr. Trinh told HOPA attendees that the FDA granted approval of adjuvant high-dose IFN for resected high-risk melanoma in 1995, based on the results of the “landmark” Eastern Cooperative Oncology Group (ECOG) 1684 (E1684) trial (J Clin Oncol 1996;14:7-17). Despite this approval, many clinicians remain skeptical about the treatment’s effectiveness, she said. “That’s why we are reviewing the pros and cons of this regimen.”

•

PREVNAR 13™ NOW RECOMMENDED BY ACIP*1

‘Only once full disclosure [regarding efficacy and toxicity] has been made can patients make an informed decision.’

THE CPT® CODE IS 90670†

—Myke R. Green, PharmD E1684 enrolled 287 patients with either thick (>4 mm) primary tumors or positive regional nodes which were recurrent or detected on elective lymph node dissection (ELND). After recovery from surgery, patients were randomized to receive either observation alone or one year of high-dose IFN, which consisted of one month of intravenous induction with IFN at 20 million units (MIU)/m2 five times per week for four weeks, followed by a maintenance phase with subcutaneous IFN 10 MIU/m2 three times per week for 48 weeks.

The primary end points of E1684 were relapse-free survival and OS. At a median follow-up of 6.9 years, the relapse-free survival rate for highdose IFN was 37% compared with 26% for observation. The median relapse-free survival duration was 1.72 years for highdose IFN compared with 0.98 year for observation (P=0.002).

The five-year OS rate was 46% for IFN versus 37% for observation, and the median OS duration was 3.82 years versus 2.78 years for observation (P= 0.02).

The survival improvements with high-dose IFN did not come free, noted Dr. Trinh, citing a study by Hillner et al

see INTERFERON, page 40

Prevnar 13™ provides coverage against 13 serotypes, including 19A, which is the leading cause of invasive pneumococcal disease in children less than 5 years of age in the United States2,3 • The ACIP recommends Prevnar 13™ for routine vaccination of children 2 months through 59 months of age1 For the full ACIP recommendation, please visit www.cdc.gov/mmwr. *Advisory Committee on Immunization Practices. †

CPT is a registered trademark of the American Medical Association (AMA).

INDICATION FOR PREVNAR 13™

• Prevnar 13™ is a vaccine approved for use in children 6 weeks through 5 years of age (prior to the 6th birthday) • Prevnar 13™ is indicated for active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F IMPORTANT SAFETY INFORMATION FOR PREVNAR 13™

• Severe allergic reaction (eg, anaphylaxis) to any component of Prevnar 13™, Prevnar ® (Pneumococcal 7-valent Conjugate Vaccine [Diphtheria CRM197 Protein]), or any diphtheria toxoid–containing vaccine is a contraindication to the use of Prevnar 13™ • Prevnar 13™ does not provide 100% protection against vaccine serotypes or protect against nonvaccine serotypes • Immunocompromised children or children with impaired immune responsiveness due to the use of immunosuppressive therapy may have reduced antibody response to active immunization • Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including Prevnar 13™, to infants born prematurely should be based on consideration of the individual infant’s medical status and the potential benefits and possible risks of vaccination • The most commonly reported serious adverse events were bronchiolitis (0.9%, 1.1%), gastroenteritis (0.9%, 0.9%), and pneumonia (0.9%, 0.5%) for Prevnar 13™ and Prevnar®, respectively • The most commonly reported solicited adverse reactions (≥20%) in US clinical trials with Prevnar 13™ were redness, swelling and tenderness at the injection site, fever, decreased appetite, irritability, increased sleep, and decreased sleep Please see Brief Summary of Prescribing Information on reverse side.

For more information about Prevnar 13 ™, please visit www.prevnar13hcp.com, or call 1-800-666-7248.

References: 1. Centers for Disease Control and Prevention. Licensure of a 13-valent pneumococcal conjugate vaccine (PCV13) and recommendations for use among children — Advisory Committee on Immunization Practices (ACIP), 2010. MMWR. 2010;59:258-261.

2. Prevnar 13™ (Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein]) Prescribing Information, Wyeth Pharmaceuticals Inc. 3. Hicks LA, Harrison LH, Flannery B, et al; for Active Bacterial Core Surveillance Program of the Emerging Infections Program Network. Incidence of pneumococcal disease due to non–pneumococcal conjugate vaccine (PCV7) serotypes in the United States during the era of widespread PCV7 vaccination, 1998–2004. J Infect Dis. 2007;196:1346-1354.

NOW Manufactured by Wyeth Pharmaceuticals Inc. 266704-01

© 2010 Pfizer Inc.

Marketed by Pfizer Inc. All rights reserved.

April 2010

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Hem/Onc Pharmacy

Pharmacy Practice News • May 2010

In Focus

INTERFERON continued from page 39

ity, which can be fatal if liver function is not monitored closely. Grade 3 or greater adverse events are very common, occurring in 78% of patients. Half of patients require dose reductions or delays, and in 23%, treatment has to be discontinued due to toxicity (J Clin Oncol 2002; 20:3703-3718).

“Because high-dose interferon is costly and toxic, it is important to make sure that the survival benefit is truly worth it,” she said.

‘In this E1690 trial, there were no treatment-related deaths in the high-dose interferon arm, but the toxicity was still pretty phenomenal and rivaled what was seen in the ECOG 1684 study, where 78% of patients had grade 3 or worse toxicities.’

—Jaime Anderson, PharmD Citing the study by Hillner et al, Dr. Trinh said that the incremental cost of high-dose IFN at seven years, which was estimated based on the results

BRIEF SUMMARY: These highlights do not include all the information needed to use Prevnar 13™ safely and effectively. Before prescribing, please consult the full Prescribing Information for Prevnar 13™.

INDICATIONS AND USAGE: Prevnar 13™ is a vaccine approved for use in children 6 weeks through 5 years of age (prior to the 6th birthday). Prevnar 13™ is indicated for active immunization for the prevention of invasive disease caused by Streptococcus pneumoniae serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F. Prevnar 13™ is also indicated for the prevention of otitis media caused by Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F. No otitis media efficacy data are available for serotypes 1, 3, 5, 6A, 7F, and 19A. DOSAGE AND ADMINISTRATION: For intramuscular injection only. Do not inject intravenously, intradermally, or subcutaneously.

Vaccine Schedule for Infants and Toddlers – Prevnar 13™ is to be administered as a 4-dose series at 2, 4, 6, and 12-15 months of age.

Vaccine Schedule for Unvaccinated Children ≥7 Months of Age – For children who are beyond the age of the routine infant schedule and have not received Prevnar® (Pneumococcal 7-valent Conjugate Vaccine [Diphtheria CRM197 Protein]) or Prevnar 13™, Prevnar 13™ is to be administered as a 3-dose series beginning at 7-11 months of age; a 2-dose series beginning at 12-23 months of age; and as a single dose at 24 months through 5 years of age (prior to the 6th birthday).

The immune responses induced by this catch-up schedule may result in lower antibody concentrations for some serotypes, compared to antibody concentrations following 4 doses of Prevnar 13™ (given at 2, 4, 6, and 12-15 months of age). In children 24 months through 5 years of age, the catch-up schedule may result in lower antibody concentrations for some serotypes, compared to antibody concentrations following 3 doses of Prevnar 13™ (given at 2, 4, and 6 months of age). The clinical relevance of these lower antibody responses is not known.

Prevnar 13™ Vaccine Schedule for Children Previously Vaccinated With Prevnar® (Streptococcus pneumoniae serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) – Children who have received 1 or more doses of Prevnar® may complete the 4-dose immunization series with Prevnar 13™. Children 15 months through 5 years of age who have received 4 doses of Prevnar® may receive 1 dose of Prevnar 13™ to elicit immune responses to the 6 additional serotypes.

The immune responses induced by this Prevnar 13™ transition schedule may result in lower antibody concentrations for the 6 additional serotypes (types 1, 3, 5, 6A, 7F, and 19A) compared to antibody concentrations following 4 doses of Prevnar 13™ (given at 2, 4, 6, and 12-15 months of age). The clinical relevance of these lower antibody responses is not known.

DOSAGE FORMS AND STRENGTHS: Prevnar 13™ is a suspension for intramuscular injection available in 0.5-mL single-dose pre-filled syringes.

CONTRAINDICATIONS: Severe allergic reaction (eg, anaphylaxis) to any component of Prevnar 13™, Prevnar®, or any diphtheria toxoid–containing vaccine.

WARNINGS AND PRECAUTIONS: Management of Allergic Reactions or Other Adverse Reactions – Before administration of any dose, all precautions should be taken to prevent allergic or any other adverse reactions. This includes a review of the patient’s immunization history for possible sensitivity to the vaccine or similar vaccines and for previous vaccination-related adverse reactions in order to determine the existence of any contraindication to immunization with Prevnar 13™ and to allow an assessment of risks and benefits. Epinephrine and other appropriate agents used for the control of immediate allergic reactions must be immediately available should an acute anaphylactic reaction occur following the administration of the vaccine.

Limitations of Vaccine Effectiveness – Prevnar 13™ may not protect all individuals receiving the vaccine. Prevnar 13™ will not protect against Streptococcus pneumoniae serotypes that are not in the vaccine or serotypes unrelated to those in the vaccine. It will also not protect against other microorganisms. This vaccine does not treat active infection.

Protection against otitis media is expected to be substantially lower than protection against invasive disease. In addition, because otitis media is caused by many organisms other than the 7 serotypes of Streptococcus pneumoniae included in the indication, protection against all causes of otitis media is expected to be lower than for pneumococcal otitis media caused by these 7 vaccine serotypes.

The duration of protection from immunization is not known.

Altered Immunocompetence – Data on the safety and effectiveness of Prevnar 13™ when administered to children in specific groups at higher risk for invasive pneumococcal disease (eg, children with congenital or acquired splenic dysfunction, HIV infection, malignancy, or nephrotic syndrome) are not available.

Children in these groups may have reduced antibody response to active immunization due to impaired immune responsiveness. Vaccination in high-risk groups should be considered on an individual basis.

The use of pneumococcal conjugate vaccine does not replace the use of 23-valent pneumococcal polysaccharide vaccine (PPV23) in children ≥24 months of age with sickle cell disease, asplenia, HIV infection, chronic illness, or who are otherwise immunocompromised.

Premature Infants – Apnea following intramuscular vaccination has been observed in some infants born prematurely. Decisions about when to administer an intramuscular vaccine, including Prevnar 13™, to infants born prematurely should be based on consideration of the individual infant’s medical status and the potential benefits and possible risks of vaccination.

of E1684, was $32,600 per life-year saved. “This is totally comparable to other recognized medical interventions, such as hemodialysis, which

ADVERSE REACTIONS: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect the rates observed in practice. As with any vaccine, there is the possibility that broad use of Prevnar 13™ could reveal adverse reactions not observed in clinical trials.

Serious Adverse Events in All Infant and Toddler Clinical Studies – Serious adverse events were collected throughout the study period for all 13 clinical trials. This reporting period is longer than the 30-day post-vaccination period used in some vaccine trials. The longer reporting may have resulted in serious adverse events being reported in a higher percentage of subjects than for other vaccines. Serious adverse events reported following vaccination in infants and toddlers occurred in 8.2% among Prevnar 13™ recipients and 7.2% among Prevnar® recipients.

The most commonly reported serious adverse events were in the “Infections and infestations” system organ class, including bronchiolitis (0.9%, 1.1%), gastroenteritis (0.9%, 0.9%), and pneumonia (0.9%, 0.5%) for Prevnar 13™and Prevnar®, respectively.

There were 3 (0.063%) deaths among Prevnar 13™ recipients and 1 (0.036%) death in Prevnar® recipients, all as a result of Sudden Infant Death Syndrome (SIDS). These SIDS rates are consistent with published age-specific background rates of SIDS from the year 2000.

Solicited Adverse Reactions in the 3 US Infant and Toddler Studies – The most commonly reported solicited adverse reactions (≥20%) in US clinical trials with Prevnar 13™ were redness, swelling, and tenderness at the injection site, fever, decreased appetite, irritability, increased sleep, and decreased sleep.

Unsolicited Adverse Reactions in the 3 US Infant and Toddler Safety Studies – The following were determined to be adverse drug reactions based on experience with Prevnar 13™ in clinical trials: Reactions occurring in greater than 1% of infants and toddlers: diarrhea, vomiting, and rash.

Reactions occurring in less than 1% of infants and toddlers: crying, hypersensitivity reaction (including face edema, dyspnea, and bronchospasm), seizures (including febrile seizures), and urticaria or urticaria-like rash.

DRUG INTERACTIONS: Concomitant Immunizations – In clinical trials, Prevnar 13™ was administered concomitantly with the following US licensed vaccines: Pediarix [Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Hepatitis B (Recombinant), and Inactivated Poliovirus Vaccine Combined] (DTaP-HBV-IPV) and ActHIB [Haemophilus b Conjugate Vaccine (Tetanus Toxoid Conjugate)] (PRP-T) for the first 3 doses and with PedvaxHIB [Haemophilus b Conjugate Vaccine (Meningococcal Protein Conjugate)] (PRP-OMP), M-M-R II [Measles, Mumps, Rubella Virus Vaccine Live] (MMR), and Varivax [Varicella Virus Vaccine Live], or ProQuad [Measles, Mumps, Rubella, and Varicella Virus Vaccine Live] (MMRV) and VAQTA [Hepatitis A vaccine, Inactivated] (HepA) for dose 4.

When Prevnar 13™ is administered at the same time as another injectable vaccine(s), the vaccines should always be administered with different syringes and given at different injection sites.

Do not mix Prevnar 13™ with other vaccines/products in the same syringe.

Immunosuppressive Therapies – Children with impaired immune responsiveness due to the use of immunosuppressive therapy (including irradiation, corticosteroids, antimetabolites, alkylating agents, and cytotoxic agents) may not respond optimally to active immunization.

USE IN SPECIFIC POPULATIONS: Pregnancy Pregnancy Category C – Animal reproduction studies have not been conducted with Prevnar 13™.

It is also not known whether Prevnar 13™ can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity.

Pediatric Use – Safety and effectiveness of Prevnar 13™ in children below the age of 6 weeks or on or after the 6th birthday have not been established. Prevnar 13™ is not approved for use in children in these age groups. Immune responses elicited by Prevnar 13™ among infants born prematurely have not been specifically studied.

Geriatric Use – The safety and effectiveness of Prevnar 13™ in geriatric populations have not been established. Prevnar 13™ is not to be used as a substitute for 23-valent pneumococcal polysaccharide vaccine (PPV23) in geriatric populations.

OVERDOSAGE: Overdose with Prevnar 13™ is unlikely due to its presentation as a pre-filled syringe. However, there have been reports of overdose with Prevnar 13™ defined as subsequent doses administered closer than recommended to the previous dose. In general, adverse events reported with overdose are consistent with those which have been reported with doses given in the recommended schedules of Prevnar 13™.

NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, Impairment of Fertility – Prevnar 13™ has not been evaluated for any carcinogenic or mutagenic potential, or impairment of fertility.

HOW SUPPLIED/STORAGE AND HANDLING: Pre-filled syringe, 1 dose (10 per package) – NDC 0005-1971-02.

Store refrigerated at +2ºC to +8ºC (36ºF to 46ºF).

The vial stopper and the tip cap and rubber plunger of the pre-filled syringe do not contain latex.

Do not freeze. Discard if the vaccine has been frozen.

This product’s label may have been updated. For current package insert and further product information, please visit www.wyethhcp.com or call our medical communications department toll-free at 1-800-934-5556.

Wyeth® Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101 U.S. Govt. License No. 3 W10543C001 ET Rev 02/10 CPT Code 90670

262841-01 266704-01

costs $40,000 to $50,000 per life-year saved,” she noted. Dr. Trinh also quoted the quality-adjusted time without symptoms and toxicity (Q-TWIST) analysis conducted by Cole et al (J Clin Oncol 1996;14:2666-2673), which found that patients who received IFN enjoyed a gain of 7.6 quality-adjusted months compared with the observation group. This clinical benefit, she added, is statistically significant when patients value quality of life during time with toxicity more than quality of life after relapse.

Finally, Dr. Trinh said that a “real life” survey of melanoma patients done by Kilbridge et al (J Clin Oncol 2001;19:812823) confirmed that melanoma patients rate quality of life with melanoma recurrence much lower than quality of life without recurrence, despite suffering severe treatment-related toxicity.

Dr. Anderson Not Convinced Subsequent trials of high-dose IFN for resected high-risk melanoma patients have not confirmed the survival results initially seen in E1684, although they have demonstrated the same toxic effects of the drug, Dr. Anderson countered. On further analysis of the long-term data from E1684, the statistical significance of the OS benefit disappeared.

In her argument against high-dose IFN, she reviewed the intergroup E1690 trial by Kirkwood et al (J Clin Oncol 2000;18-2444-2458), which prospectively evaluated high- and lowdose IFN regimens in comparison with observation in 642 high-risk melanoma patients. The high-dose IFN regimen consisted of induction with 20 MIU/m2 intravenous interferon daily five days per week for four weeks, followed by maintenance with 10 MIU/m2 subcutaneously three times per week for 48 weeks. The low-dose regimen consisted of 3 MIU delivered subcutaneously three times per week for two years.

After 52 months of follow-up, the estimated five-year relapse-free survival rate was 44% in the high-dose arm, 40% in the low-dose arm and 35% in the observation arm.

Compared with the E1684 trial, in which the high-dose IFN arm had an estimated relapse-free survival rate of 37%, the hazard ratio in E1690 indicated a 21% improvement in relapse-free survival, Dr. Anderson pointed out.

Unfortunately, this advantage did not persist with regard to OS. The estimated five-year OS rate was 52% in patients randomized to the high-dose IFN arm, compared with 53% in the low-dose IFN arm and 55% for patients randomized to observation alone.

“Ultimately, the results of this study did not confirm [the E1684 trial],” Dr. Anderson said. “Adjuvant high-dose interferon really does not provide any

Hem/Onc Pharmacy 41

Pharmacy Practice News â&#x20AC;˘ May 2010

In Focus benefit for increased survival.â&#x20AC;?

Toxicities, too, were a problem. â&#x20AC;&#x153;In this E1690 trial, there were no treatment-related deaths in the high-dose interferon arm, but the toxicity was still pretty phenomenal and rivaled what was seen in the E1684 study, where 78% of patients had grade 3 or worse toxicities. These levels of toxicity provide a significant amount of distress, decreased quality of life and discomfort to our patients.â&#x20AC;?

The toxic effects also impacted treatment plans and reduced the amount of IFN that patients were able to receive.

Forty-five percent of patients had a delay and 41% had a reduction in dose for any reason during the induction phase, and 49% of patients had a delay and 48% had a reduction in dose for any reason during maintenance. â&#x20AC;&#x153;There were actually more cases of patients in the E1690 trial with a delay or a dose reduction than in ECOG 1684,â&#x20AC;?

Dr. Anderson pointed out. â&#x20AC;&#x153;So, taking everything into consideration here, that interferon-alfa used as adjuvant therapy in high-risk melanoma patients after resection does not prolong survival, that there are significant toxicities and a decrease in quality of life associated with its use, it really makes it difficult to justify the use of interferon-alfa therapy in this particular setting.â&#x20AC;?

Points of Agreement Although the controversy surrounding high-dose IFN for resected high-risk melanoma continues, the debaters said they could agree on a few things. â&#x20AC;&#x153;We both agree that there would be little debate about the use of this regimen if it did not have such tremendous toxicity,â&#x20AC;? Dr. Trinh said. â&#x20AC;&#x153;It sounds like a clichĂŠ, but it is true to say that the debate surrounding high-dose interferon comes down to risk and benefit considerations.â&#x20AC;?

Both added that when patients are faced with making a choice between a watch-and-wait approach or adjuvant high-dose IFN, clinicians should discuss with them in detail their risk for relapse, the controversy regarding highdose IFN, and explore their willingness to accept IFN toxicity in exchange for a chance at increased OS. Treatment decisions should also take into account the patientsâ&#x20AC;&#x2122; life expectancy as well as any potential contraindications to IFN therapy. Additionally, patients should be clearly informed that they can discontinue IFN at any point if toxicity becomes an issue.

Convincing Arguments On Both Sides Commenting on the debate for Pharmacy Practice News, Myke R. Green, PharmD, from University Medical Center, Tucson, Ariz., said that although

these studies date back to the mid-1990s, many controversies with these data confound clinicians to this day. â&#x20AC;&#x153;Both E1684 and E1690 included patients using a staging system that is different than currently used. Both of these studies did not utilize sentinel lymph node biopsies, one of the most important predictors of prognosis. Furthermore, high-dose interferon-alfa was FDAapproved while E1690 was ongoing,

based upon results of E1684. This may have led to a cross-over bias in E1690, which was the study that ignited this controversy,â&#x20AC;? he said.

Dr. Green cited a recently published review and meta-analysis of several trials of adjuvant high-dose IFN-alfa for high-risk melanoma (J Natl Cancer Inst 2010;102:493-501). â&#x20AC;&#x153;The authors conclude that the use of high-dose interferon-alfa leads to improvements in dis-

ease-free survival and overall survival.

However, cost-effectiveness or toxicity of treatment was not taken into consideration in this manuscript.â&#x20AC;?

In light of convincing arguments from both sides of this issue, it is incumbent upon the practitioner to inform patients about the controversy surrounding this therapy, in addition to the toxicity and logistical aspects of use of high-dose IFN-alfa, Dr. Green said. â&#x20AC;&#x153;Only once full disclosure has been made can patients make an informed decision.â&#x20AC;? â&#x20AC;&#x201D;Fran Lowry

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42

Hem/Onc Pharmacy

Pharmacy Practice News • May 2010

In Focus

Oncology Pharmacists Can Help Cancer Survivors Cope New Orleans—Oncology pharmacists have a key role to play in helping cancer survivors cope with the physical and psychological effects of their treatment, Rowena N. Schwartz, PharmD, said during a presentation at the sixth annual meeting of the Hematology/Oncology Pharmacy Association (HOPA).

“There are psychosocial issues that we, as pharmacists, can help identify and hopefully prevent,” she said. “The key thing is that, as patients leave your direct care, make sure there is some plan in place for the type of issues they may come across. Stress the need to always get patients’ symptoms evaluated and

‘Our role as educators shouldn’t simply be to tell them that their chemotherapy can cause nausea and vomiting; rather, I think it should be to tell them that they may experience symptoms such as insomnia, and that these symptoms should be managed.’

—Rowena N. Schwartz, PharmD Speaking at a workshop on the psychosocial issues that can affect adult survivors of cancer, Dr. Schwartz, director of Oncology and Weinberg Pharmacy at The Johns Hopkins Hospital, Baltimore, and incoming HOPA president, said that oncology pharmacists can educate patients about the long-term effects of cancer that may be manageable and that definitely should be evaluated.

managed, either through their cancer team or with the help of their primary care doctor, because this is the thing that will make their quality of life better overall.”

In 2005, according to Surveillance, Epidemiology and End Results (SEER) data, there were close to 11 million cancer survivors in the United States, 60% of whom were older than 65 years. The

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most common cancers were breast, prostate, colorectal and gynecologic (Prin Care Clin Office Pract 2009;36:721-741).

“Eleven million is probably a vast underestimation,” Dr. Schwartz commented. “Also, a majority of those survivors are older than 65, and every one of us knows that patients posttreatment go back to their primary care physicians and are treated for comorbidities that are going to be impacted, not only in terms of physiologic, but also in terms of psychological and social issues resulting from their cancer.”

She added that the most common cancers “are great to list, but the reality is if you are dealing with someone who has, for example, Hodgkin’s lymphoma, it may not be the most common, but it would be the most important for that particular patient.”

There is an overlap between psychological and physical issues post–cancer treatment and pharmacists must consider both aspects, Dr. Schwartz said.

However, the current literature offers very little information, particularly about psychological issues. Dr. Schwartz cited an article by Stein et al (Cancer 2008;112:2577-2592), which found that the reported prevalence of psychological long-term effects varied considerably. For example, incidence of depression ranged from 0% to 50%; anxiety disorder, 5% to 25%; and post-traumatic stress disorder, 0% to 32%.

“It’s very hard to get a good feel for what the problem actually is,” she said.

“One of the reasons you see these ranges is because a patient isn’t a patient isn’t a patient. So an individual needs to be evaluated for his or her individual risk and particular treatment.”

Certain subgroups, such as patients with head and neck cancer, have a very high risk for depression. Anxiety disorders are also fairly prevalent among cancer survivors. However, serious psychiatric disorders are rare, and the risk for depression among cancer survivors as a whole is not as high as one would expect, Dr. Schwartz said.

Sleep disturbances are another sequela of cancer treatment. General sleep disruption is common during chemotherapy, and patients on chemotherapy report rates of insomnia that are three times higher than that in the general population, Dr. Schwartz noted.

Insomnia can begin from the time of diagnosis and can persist for years, she added. “The problem with insomnia during treatment is that it can often be a side effect of the medications, so people think it’s a short-term thing.

But we found that insomnia is actually one of the persistent physical results of cancer and/or cancer treatment.”

A study evaluating insomnia in 982 cancer patients and survivors using a questionnaire found that 30% reported insomia.

Of these, 76% had difficulty with frequent awakenings, 44% had difficulty falling asleep, 35% reported waking up for long periods, and 33% said they woke up too early (Davidson et al.

Soc Sci Med. 2002:54:1309-1321).

In another study (J Clin Oncol 2010: 28:292-298), 37% of patients (median age, 58 years; range, 22-93 years) with a wide variety of cancers reported insomnia symptoms after their first chemotherapy cycle, and 43% met the criteria for insomnia syndrome, as defined by the American Psychiatric Association, including difficulty falling asleep, staying asleep, early awakening and nonrestorative sleep.

In this study, younger patients (<58 years) and women with breast cancer had the greatest risk for insomnia, and the insomnia persisted after the end of chemotherapy. In addition, patients with insomnia had increased complaints of depression and fatigue.

“Insomnia, depression and fatigue are a cluster of symptoms that we need to be aware of. When a patient presents with one complaint, we should consider other factors that may also be involved,” Dr. Schwartz said. “Interventions targeting one symptom may improve the downstream symptoms.”

Sexual dysfunction is another problem cancer survivors face, although its prevalence is not well described, Dr. Schwartz noted. The prevalence of sexual dysfunction may vary depending on patientrelated or disease-related factors.

Cancer survivors’ post-diagnosis motivation and ability for sexual activity may be affected by medical issues, psychosocial reasons caused by changes in body image or sexual response, and also an unwillingness to seek advice regarding sex.

Pharmacists may be able to help by modifying cancer treatment to spare sexual function, managing erectile

Hem/Onc Pharmacy 43

Pharmacy Practice News • May 2010

In Focus dysfunction and managing sexual pain, Dr. Schwartz said.

Finally, employment or the lack thereof is another psychosocial issue with which pharmacists may be able to help cancer survivors cope. “We can minimize side effects of treatment so that people can go to work; we can treat cancer-related symptoms, evaluate prognostic factors, and improve current return-to-work strategies,” Dr. Schwartz suggested. “Knowing that patients want to go back to work, and realizing that it is something that will impact their financial, psychological and social wellbeing, is important for us as pharmacists to at least look at.”

She also said that more education should be directed at cancer survivors so that they know where to go when they have a problem when they are not routinely managed by the cancer care team.

“It may not be their oncology pharmacist, it may be their primary care physician or their community pharmacy, but we must tell them that these symptoms can occur and that they should be addressed. Our role as educators shouldn’t simply be to tell them that their chemotherapy can cause nausea and vomiting; rather, I think it should be to tell them that they may experience symptoms such as insomnia, and that these symptoms should be managed,” she concluded.

‘Symptoms of cognitive impairment include fatigue and disruptions in thinking and memory. All these complications are rarely reported and are only beginning to gain recognition in terms of their significance in affecting a cancer survivor’s quality of life and ability to return to society as an active contributor.’

—Siu-Fun Wong, PharmD

function, to illustrate the significant impact of these adverse effects on can-

cer survivors and their families,” Dr. Wong said.

But many cancer survivors can suffer yet another effect for up to 10 years or even longer, and that is cognitive impairment, she said.

“Symptoms of cognitive impairment include fatigue and disruptions in thinking and memory. All these complications are rarely reported, and are only beginning to gain recognition in terms of their significance in affecting a cancer survivor’s quality of life and ability to return to society as an active contributor.”

—Fran Lowry

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A Timely Topic “The topic is definitely timely as the number of cancer survivors continues to rise,” Siu-Fun Wong, PharmD, professor of pharmacy practice and administration, Western University of Health Sciences, in Pomona, Calif., told Pharmacy Practice News.

As indicated by data from the American Cancer Society, the five-year relative survival rate for all cancers diagnosed during 1996-2004 is 66%, up from 50% during 1975-1977, she noted. “In addition, we have become more aggressive in treating early-stage cancer patients who are likely to be long-term cancer survivors, so the need to address longterm side effects and complications is warranted.”

Dr. Wong added that Dr. Schwartz’s recognition that the care of many survivors takes place in the primary care setting emphasizes the need to involve pharmacists who may work in that setting. “We need to think beyond those pharmacists who practice in the specialty area and approach the pharmacists who practice in many other settings who may or who will encounter cancer survivors. We need to heighten their awareness and education,” she said.

“Dr. Schwartz did a good job addressing the domino effect of some of these complications starting from insomnia to depression and fatigue to sexual dys-

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44

Hem/Onc Pharmacy

Pharmacy Practice News • May 2010

In Focus

TOXICITIES continued from page 1

pretreatment is required, and management protocols in place to manage these toxicities should they occur.”

In all, the FDA approved five new agents in 2009-2010: everolimus (Afinitor, Novartis); pazopanib (Votrient, GlaxoSmithKline); pralatrexate (Folotyn, Allos Therapeutics); romidepsin (Istodax, Gloucester Pharmaceuticals); and ofatumumab (Arzerra, GlaxoSmithKline). The FDA also approved these new formulations: morphine-naltrexone, ferumoxytol, and temozolomide.

Everolimus Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, was approved for the treatment of advanced renal cell carcinoma (RCC) after the failure of sunitinib (Sutent, Pfizer) or sorafenib (Nexavar, Bayer). Dosing is 10 mg once daily with or without food.

There are two tablet strengths—5 and 10 mg—and the CMAX is one to two hours.

High-fat meals decrease its absorption “so patients can’t go to Burger King and grab a hamburger and some French fries and then take their pill,” said Dr. O’Bryant.

Approval was based on results of the RECORD-1 (Renal Cell cancer treatment with Oral RAD001 given Daily) trial (Lancet 2008;372:449-456), which randomized patients with RCC who had failed sunitinib or sorafenib to 10 mg oral everolimus once daily plus best supportive care, or to placebo plus best supportive care.

Treatment with everolimus resulted in a 70% decrease in the risk for progression compared with placebo.

Progression-free survival (PFS) in the everolimus group was 4 months versus 1.9 months in the placebo group.

As a result, the trial was stopped early, and placebo patients were allowed to cross over into the everolimus treatment group. No overall survival (OS) data have been reported with the study because of the potential confounding of the crossover. The benefit with everolimus was seen regardless of age, previous therapies, gender, location of treatment and disease state, Dr. O’Bryant noted.

Everolimus interacts with strong and moderate inhibitors of cytochrome P450 3A4 (CYP 3A4) and P-glycoprotein (PgP), and strong inducers of CYP3A4, “so we need to make sure we are monitoring our patients and assessing their concurrent therapies, including alternative or complementary therapies they might be taking,” said Dr. O’Bryant. Serum concentrations of everolimus can increase twofold in patients with Child-Pugh Class B hepatic impairment. In this popula-

‘It is very important for pharmacists to learn, assess and understand the adverse events that are associated with these [recently approved] agents, and then have a predefined monitoring process, a pretreatment plan when [appropriate] and then have established management protocols to manage those toxicities.’

—Cindy L. O’Bryant, PharmD

tion, the dose should be reduced to 5 mg per day.

“Having been an investigator on hepatic dysfunction studies where we used the Child-Pugh classification, I caution that those patients are very tenuous and can come in and out of moderate dysfunction into severe dysfunction and back. Patients with this classification need to be monitored very closely and cautiously and you need to be making adjustments to meds or discontinuing meds as appropriate,” she said.

AEs with everolimus include stomatitis, infections, asthenia, fatigue, cough, and diarrhea. Laboratory abnormalities include anemia, elevated blood lipids, hyperglycemia, lymphopenia, elevated creatinine, elevated liver function tests (LFTs) and bilirubin.

“We need to pay attention to possible pneumonitis. Most cases will resolve but there have been some fatal cases reported, so any alterations in pulmonary function need to be taken seriously,” Dr. O’Bryant said.

Stomatitis is extremely prevalent with everolimus. Therefore, proper oral hygiene is essential, she added.

Patients who have intolerable or persistent toxicities that interfere with their treatment can have their doses reduced to 5 mg daily.

reduced to 400 mg per day.

As with all vascular endothelial growth factor (VEGF) inhibitors, hypertension is a common AE. “We see this whenever patients take these drugs on a daily basis, and the longer they are on therapy the more likely we are to see it develop and to see it worsen,” noted Dr. O’Bryant. In patients who have persistent hypertension, defined as 150/90 mm Hg despite treatment, the dose should be decreased to 400 mg and then further to 200 mg per day if necessary.

Also, patients should stop pazopanib therapy seven days prior to surgery and after their surgery to allow adequate time for wound healing, which can be an issue with VEGF inhibitors, she said.

Less than 1% of patients will develop grade 4 proteinuria on pazopanib. This should be monitored, despite its rare occurrence. Diarrhea, depigmentation of the hair, nausea, anorexia, vomiting and fatigue are other AEs seen with pazopanib.

Patients should be monitored with LFTs at baseline and then once a month for four months for hepatotoxicity, which can be fatal in some cases. QTc prolongation, stroke, transient ischemic attacks and myocardial infarctions also can occur with pazopanib.

Pralatrexate Pazopanib The second new drug to be approved for the treatment of RCC, pazopanib, is a multi-tyrosine kinase inhibitor. Indicated for advanced RCC with no qualifying criteria of failure to previous therapy, it is dosed at 800 mg orally once daily without food and comes in 200- and 400mg tablets.

Approval was based on results of the VEG105192 trial (J Clin Oncol 2009;27[15s]:A5021). PFS among the 290 patients randomized to pazopanib 800 mg was 9.2 months, versus 4.2 months in 145 patients randomized to placebo (P<0.001). OS data have not yet matured, Dr. O’Bryant said.

As is the case with everolimus, drug interactions can occur with inhibitors and inducers of CYP 3A4 and substrates of CYP 3A4, 2D6 and 2C8 with a narrow therapeutic index.

Patients with moderate hepatic impairment at baseline should be limited to 200 mg per day. Patients on concomitant, strong CYP 3A4 inhibitors should have their dose of pazopanib

Pralatrexate is indicated for relapsed or refractory peripheral T-cell lymphoma (PTCL). Dosing is 30 mg/m2 IV over three to five minutes once a week for six weeks, in seven-week cycles.

Approval was based on results of the PROPEL (Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma) trial (American Society of Hematology Annual Meeting 2008, abstract 261), which was the largest prospective trial in patients with PTCL. In this study, the overall response rate among the 109 patients treated with pralatrexate was 27%, the complete response was 11%, and the median duration of response was 9.4 months.

Drug interactions are what one would expect from a drug in this class, Dr. O’Bryant said, and include the potential for delayed renal clearance when given with nonsteroidal anti-inflammatory drugs, probenecid and trimethoprimsulfamethoxazole.

AEs that occur with pralatrexate include mucositis, nausea, fatigue, constipation, pyrexia, edema and cough. Lab

abnormalities include thrombocytopenia, anemia, neutropenia, hypokalemia, and increased LFTs. Patients should be monitored for myelosuppression, renal dysfunction, elevated LFTs and mucositis.

“There is a very detailed description in the package insert for dealing with these adverse events,” Dr. O’Bryant said.

“If mild to moderate toxicity occurs, the drug is held and then restarted at the same dose. If more severe grade 3 toxicity is present, the drug is held and then restarted at a reduced dose. If the toxicity is very severe, the drug is discontinued. As you use this drug in your practice and you have issues of dose modification, rely on this package insert as a resource.”

Vitamin B12 and folic acid supplementation can help minimize toxicities, she added.

Romidepsin Romidepsin is a histone deacetylase inhibitor indicated for patients with cutaneous T-cell lymphoma (CTCL) who have received at least one prior systemic therapy. FDA approval was based on two Phase II trials in 167 patients with relapsed or refractory CTCL (J Clin Oncol 2009;27:5410-5417). The trials showed an overall response rate of 25% to 34% and duration of response of 13.7 to 15 months.

Romidepsin interacts with strong inhibitors of CYP 3A4 and PgP, potent inducers of CYP 3A4, and coumadin derivatives.

“The details of the interaction with coumadin are not known, but an increase in the PT [prothrombin time] and INR [international normalized ratio] was seen, so it is important to think about when you are treating patients who are also on anticoagulation therapy,” Dr. O’Bryant noted. “Also, make sure you are monitoring CBC [complete blood count] and electrolytes.”

AEs include nausea, fatigue, vomiting, infections, constipation, pruritis and hypotension. Moreover, cardiovascular events, including QTc prolongation, can occur with romidepsin, and patients need to be potassium- and magnesiumreplete prior to their first dose. Also, because romidepsin is an inhibitor of the estrogen receptor, it may decrease the effectiveness of oral contraceptives.

“Make sure you warn your patient if

•

see TOXICITIES, page 46

46

Hem/Onc Pharmacy

Pharmacy Practice News â&#x20AC;˘ May 2010

In Focus

TOXICITIES continued from page 44

there is a possibility she could become pregnant, â&#x20AC;? Dr. Oâ&#x20AC;&#x2122;Bryant said.

Ofatumumab Ofatumumab, a human monoclonal antibody, is indicated for chronic lymphocytic leukemia (CLL) that is refractory to fludarabine and alemtuzumab.

Dosing initially is 300 mg IV followed one week later by 2,000 mg IV weekly for seven doses, and then 2,000 mg IV every four weeks for four doses.

Because it is a monoclonal antibody and there is always the chance for infusion-related reactions, it is suggested that patients be premedicated with acetaminophen, or an oral or IV antihistamine, as well as an IV corticosteroid. â&#x20AC;&#x153;About 44% of patients will have an infusion-related reaction after the first dose. That decreases to about 30% of patients after the second dose, and decreases further with each subsequent dose,â&#x20AC;? Dr. Oâ&#x20AC;&#x2122;Bryant said.

There have been no formal drug interaction studies done with ofatumumab.

Besides premedicating for infusion

reactions, patients should be monitored for neurologic dysfunction, hepatitis B reactivation and small bowel obstruction. â&#x20AC;&#x153;You can actually see a progressive multifocal leukoencephalopathy with this drug, so any patients who have any kind of altered CNS [central nervous system] function or mental status need to be discontinued immediately and then reassessed as to whether or not to continue with ofatumumab,â&#x20AC;? Dr. Oâ&#x20AC;&#x2122;Bryant said. â&#x20AC;&#x153;Many of these [recently approved drugs] are targeted agents. They are not our traditional, cytotoxic chemotherapy

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drugs and their toxicity profiles can be different from the traditional toxicities we see,â&#x20AC;? she added. â&#x20AC;&#x153;Thus, it is very important for pharmacists to learn, assess and understand the adverse events that are associated with these agents, and then have a predefined monitoring process, a pretreatment plan when [appropriate], and then have established management protocols to manage those toxicities.â&#x20AC;?

Myke R. Green, PharmD, oncology clinical coordinator at University Medical Center/Arizona Cancer Center, Tucson, told Pharmacy Practice News that, while oncology pharmacists enhance the care of the oncology patient in a multitude of ways, â&#x20AC;&#x153;clearly one of the most important is supportive care, including monitoring and managing adverse effects of anti-cancer agents.

As Dr. Oâ&#x20AC;&#x2122;Bryant stated, the key to this is creation of protocols for monitoring toxicity and managing adverse effects.

These care plans should be simple and clearly defined based upon severity of toxicity.â&#x20AC;?

Dr. Green said he predicts that oncology pharmacists will play a bigger role in managing toxicities associated with new anti-cancer drugs. â&#x20AC;&#x153;In the future, as more anti-cancer agents come to market, toxicity assessment and treatment will fall increasingly upon the oncology pharmacist.

Patients will depend upon oncology pharmacists utilizing these protocols to mitigate toxicity and maximize the anti-cancer benefits of these drugs and enhance quality of life.â&#x20AC;? â&#x20AC;&#x201D;Fran Lowry

pharmacy practicenews. com Visit our Web site for coverage of the latest developments in clinical medicine, technology, policy, and pharmacy operations & management.

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Pharmacy Practice News â&#x20AC;˘ May 2010

Formulary Management

SWITCH continued from page 34

However, the lack of uniform evaluation and standardized testing for HIT in the literature precludes more definitive and reliable estimates of the relative risks for HIT of UFH and LMWH.6 Essentially, we emphasized that historically, both carried similar risk, particularly when orthopedic patients were carved out from the safety data. Also, because we practice evidence-based medicine, we could not argue with the American College of Chest Physiciansâ&#x20AC;&#x2122; 1A recommendation.

Nevertheless, we assured physicians that orthopedic surgery patients would be excluded from the interchange and that we would closely monitor rates of PE, DVT and HIT. After the Pharmacy & Therapeutics Committee and the Medical Executive Committee approved the initiative, staff received education that continued well after the interchange began in March 2009.

When we launched the interchange, the facility implemented an automatic substitution policy and pharmacists were given full power to substitute orders for enoxaparin with low-dose UFH when appropriate.

of 0.014 and 0.013 per 1,000 patient-days for Cohorts 1 and 2, respectively.

At a time when economic analyses between thromboprophylactic treatments are limited by a paucity of clinical trials comparing treatment regimens with one another rather than with placebo, this study (albeit retrospective) appears to shed some light on the issue.

This therapeutic interchange has demonstrated that optimal thromboprophylaxis, from a costâ&#x20AC;&#x201C;benefit perspective, may be achieved among medical, critically ill and oncology patients. Other Saint Barnabas institutions have also

made the switch, resulting in an annual savings of $500,000 for the entire health care system, and in turn, the preservation of full-time provider positions during a fiscally challenging time.

References 1. Geerts WH, Bergqvist D, Pineo GF, et al.

Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:381S-453S. 2. Heit JA. The potential role of direct thrombin inhibitors in the prevention and treatment of venous thromboembolism. Chest. 2003;124(3 Suppl):40S-48S.

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4. Leizorovicz A, Mismetti P. Preventing venous thromboembolism in medical patients. Circulation. 2004;110 (suppl 1):IV13-IV19.

5. Oâ&#x20AC;&#x2122;Connor PJ, DiBona JR. Balancing costs and outcomes through partnerships with consultants. Am J Health Syst Pharm.

2005;62(2):139-141.

6. Locke CFS, Dooley J, Gerber J. Rates of clinically apparent heparin-induced thrombocytopenia for unfractionated heparin vs. low molecular weight heparin in nonsurgical patients are low and similar. Thromb J. 2005;3(1):4.

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Outcomes Analysis In evaluating the impact of this formulary decision on patient outcomes, we conducted a study measuring DVT, PE and HIT rates six months before and six months after conversion among critically ill, medically ill and oncology patients.

In the retrospective evaluation, patients older than 18 years were stratified into pre-interchange Cohort 1 (63.6% and 36.4% of whom were treated with enoxaparin and UFH, respectively) and postinterchange Cohort 2 (28.6% and 71.4% of whom were treated with enoxaparin and UFH, respectively). DVT rates were similar between Cohorts 1 and 2 (2.31 and 2.42 per 1,000 patient-days, respectively).

Likewise, PE rates were similar between Cohorts 1 and 2 (1.28 and 1.1 per 1,000 patient-days, respectively). Each cohort had one reported case of HIT, with a rate

3. Cohen AT. Discoveries in thrombosis care for medical patients. Semin Thromb Hemost.

2002;28(suppl 3):13-17.

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Applied Therapeutics: The Clinical Use of Drugs Mary Anne Koda-Kimble; Lloyd Yee Young; Brian K. Alldredge; Robin L. Corelli; B. Joseph Guglielmo; Wayne A. Kradjan; Bradley R. Williams

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

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Assuring Continuous Compliance with Joint Commission Standards: A Pharmacy Guide: Seventh Edition Charles P. Coe; John P. Uselton

The new seventh edition of Assuring Continuous Compliance with Joint Commission Standards: A Pharmacy Guide provides expert help in assuring that your pharmacy is compliant.

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Basic Pharmacokinetics

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Cardiovascular Pharmacotherapy: A Point-of-Care Guide

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Concepts in Pharmacogenomics

Sunil S. Jambhekar; Philip J. Breen

This book provides an understanding of the principles of pharmacokinetics and biopharmaceutics and of how these principles can be applied to achieve successful drug therapy. The application of principles and equations are illustrated by relevant data and chapters conclude with related problem sets and problem-solving exercises.

Michael A. Crouch

ASHP’s Cardiovascular Pharmacotherapy: A Point-of-Care Guide is designed with the busy practitioner, resident and student in mind. The 18 chapters are organized by disease state and each one includes visually scannable elements such as tables and flow charts; pathophysiological reasons for selecting specific pharmacotherapies; selected guideline statements from leading organizations; evidence-based treatment algorithms; recent clinical controversies; and frequently asked questions.

Martin M. Zdanowicz

The new science of pharmacogenomics aims to understand how an individual’s genetic composition affects his or her response to a specific drug or class of drugs.

By studying such characteristics as drug metabolizing enzymes, drug transporter activity and receptor sensitivity, a pharmacist is better able to prescribe the right drug the first time.

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Drug Induced Movement Disorders, Second Edition

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Pharmacotherapy: A Pathophysiologic Approach

Stewart A. Factor; Anthony E. Lang; William J. Weiner

This book will continue to be the source text of information on drug-induced movement disorders authored and edited by the pioneers in the field. It will be an invaluable addition to the library of any neurologist. The understanding of drug-induced movement disorders is extremely difficult, and many physicians and clinicians find this a difficult and complex area to treat. The unique way in which the plethora of different drugs react and manifest with the patient’s exact condition is particularly hard to manage and diagnose.

Joseph T. DiPiro; Robert L. Talbert; Gary C. Yee; Gary R. Matzke; Barbara G. Wells; L. Michael Posey

Pharmacotherapy: A Pathophysiological Approach uses evidence-based approaches to the drug treatment of diseases. It is the most widely used and comprehensive pharmacotherapy textbook/reference avaialable for pharmacists and prescribers. Now in a new full-color format.

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Teddy Bear Book: Pediatric Injectable Drugs: Eighth Edition

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Women’s Health Across the Lifespan: A Pharmacotherapeutic Approach

Stephanie J. Phelps; Emily B. Hak; Catherine M. Crill

Teddy Bear Book, Pediatric Injectable Drugs, the only reference that compiles IV and intramuscular administration recommendations specifically for pediatric patients, has been updated for 2007.

Laura Borgelt; Mary Beth O’Connell; Judith A. Smith; Karim Anton Calis

This book is a groundbreaking publication, a unique primary reference developed to help educate pharmacy students, pharmacists and other health care professionals in an area of deservedly growing interest and importance. This new book contains contributions from more than 150 clinical experts in pharmacy, medicine and nursing. It is edited by nationally recognized educators and researchers.

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Workbook for Pharmacology for Pharmacy Technicians Kathy Moscou; Karen Snipe

Specially designed to parallel material in Pharmacology for Pharmacy Technicians, this helpful workbook provides in-depth study and review of the pharmacology concepts you need to master for a successful career in pharmacy technology. Its user-friendly format and engaging learning exercises make it easy to understand both basic and advanced pharmacologic concepts. Practical application activities provide valuable practice in applying what you learn to real-world scenarios.

PPN0510

Up Front 49

Pharmacy Practice News • May 2010

Late Breaker

PRACTICE continued from page 4

participating organizations,” said Sharon Corbitt, APhA’s external communications director. John Norton, a spokesman for the National Community Pharmacists Association, said, “We would prefer the forthcoming multiple pharmacy group response effort to speak for us.”

Pharmacy Leader Sees Strength in Numbers Collaborative practices with health and hospital system pharmacists make physicians more efficient and effective in their practice, said Ernest R. Anderson Jr., RPh, MS, system vice president of pharmacy at Caritas Christi Health Care, which manages six communitybased hospitals in the New England area. “To lump hospital and healthsystem pharmacists in with all other pharmacists is a big mistake,” he told Pharmacy Practice News.

While the pharmacy workforce varies in terms of residency training and degrees, “one fact that should not be in dispute is the level of basic sciences (pharmaceutical and biomedical), pharmacology and therapeutics training that pharmacists receive as compared to physicians,” Dr. Manasse wrote. He noted that most physicians do not receive substantial education about medication use until well into their residencies. “In fact,” he noted, “pharmacists in academic health sci-

ence centers and elsewhere often play a key role in assuring that resident physicians learn to prescribe appropriately and safely.”

Dr. Manasse also called two AMA assertions “patently false.” One states that neither the Accreditation Council for Pharmacy Education nor state licensing requirements mandate direct patient contact for student practice experience, when in fact both do so. The other claims that no evidence exists that the profession has modified the quality or manner in which pharmacy students are trained to provide direct care to patients, when the 2007 accreditation standards for doctor of pharmacy degree programs require that 30% of the curriculum be in the form of pharmacy experience.

“At a minimum, AMA should send a substantial correction to recipients of the pharmacist data series or consider retracting the document altogether,” Dr. Manasse wrote.

AMA Girds for Battle “While some scope of practice expansions may be appropriate, others are not,” wrote Rebecca J. Patchin, MD, AMA board chair in a written statement to Pharmacy Practice News. “The Scope of Practice Data Series is intended to help provide legislators with the necessary background information to help determine if health care professionals are seeking unwarranted practice expansions that are beyond their level of education and training.”

According to Dr. Patchin, “the AMA voluntarily shared the data series modules with various non-physician groups to encourage dialogue and ensure accuracy of the modules. We have received letters from several groups and will review each carefully to determine if changes need to be made to the modules. We continue to welcome constructive feedback from non-physician groups to ensure the modules contain the most current and accurate information,” she wrote.

Lisa Lecas, an AMA spokeswoman, said the document “is just an information module that outlines education and training of different non-physician health care provider groups. It’s a very benign educational document,” she told Pharmacy Practice News.

But many health care practitioners view the AMA’s efforts as far from benign. “It is not appropriate for one health professional group to attempt to discredit the quality of education, credentialing and practice of members of another profession,” wrote the American Academy of Nurse Practitioners and 26 other nursing associations in a Dec. 8, 2009, response to the AMA’s Data Series about nurse practitioners. “No medical society has the legal authority or professional expertise to make such determinations for [nurse practitioners] or any other health care profession,” they wrote.

Proposed Legislation Would Support AMA Position Backed by the AMA and several other

medical associations, Rep. John Sullivan (R-Okla.) and eight co-sponsors in 2007, introduced a bill (HR 2260) that would have required all health care providers other than medical doctors or doctors of osteopathic medicine to issue disclaimers informing patients that they do not have the skills and training of MDs and DOs. Failure to issue these disclaimers would have violated federal unfair and deceptive trade statutes. The bill never made it out of subcommittee, but similar legislation has been introduced in at least three states, according to the American Optometric Association, which was monitoring the situation.

In an effort to defuse AMA’s efforts, 38 health care organizations, including nursing organizations, the American Psychological Association Practice Organization and others representing more than 3 million licensed health care professionals, formed the Coalition for Patients’ Rights.

In a letter to the AMA dated Feb. 9, 2010, the coalition urged the AMA to withdraw the modules. “The modules fail to provide empirical evidence supporting the assumptions within them—that MDs and DOs provide superior care to all other types of health care providers or that the scopes of practice of our members are unsafe, problematic or warrant special scrutiny or study.”

As of press time, the AMA had not withdrawn its modules.

—Ted Agres

Events

ASHP PREVIEW continued from page 6

of attention lately. It’s a change in the marketplace, that’s for sure.”

“This is brand new to hospital pharmacy. It’s brand new to most hospitals,” she added, “and what we’re going to do is identify some practical areas in pharmacy operations and clinical areas that could be designed to meet the [ISO-9001] quality standards required

by DNV.” (ISO-9001 is a quality standard maintained by the International Organization for Standardization.)

The Clinical Quality Standards Series features five different sessions, including an H1N1 update (Monday, 8-9:45 a.m.); a session on gram-negative resistance and antimicrobial stewardship (Monday, 2-5 p.m.); an update on antiplatelet and anticoagulation strategies (Tuesday, 8-10 a.m.); and a session titled “How Low to Go? Implementing the New Hypertension and Cholesterol Guidelines” (Tuesday, 2-4:30 p.m.).

Joseph Saseen, PharmD, BCPS, professor of clinical pharmacy and family medicine at the University of Colorado, Boulder, will lead the session on hyper-

‘[Pharmacists] should probably continue to follow current [hypertension treatment] guidelines but balance them with how individual patients respond.’

—Joseph Saseen, PharmD

tension and cholesterol guidelines, focusing on some of the challenges clinicians face in deciding how low to go when determining optimal blood pressure and lipid levels. Dr. Saseen said his goal was to provide attendees with the knowledge of what is recommended in the guidelines “and to balance that with the evidence to support those goals.”

“With cholesterol, lower clearly is better in high-risk patients,” he said.

However, “with hypertension, it is more challenging now; the data doesn’t support lower goals.”

For example, he said, the guidelines recommend that high-risk patients (such as those with diabetes) maintain a systolic blood pressure of less than 130 mm Hg versus less than 140 mm Hg for

a relatively healthy person. But the INVEST blood pressure study, he noted, showed that there is a danger in being too aggressive. The study evaluated the effects of lowering blood pressure in diabetic patients to a target of below 140 versus below 120. “Surprisingly, they found that less than 120 was no better overall than less than 140,” Dr. Sasseen said. “There were some marginal secondary benefits of less than 120, but there were also more side effects.”

So what should pharmacists do? “They should probably continue to follow current guidelines but balance them with how individual patients respond,” Dr. Saseen said. “It would be premature to say our guidelines are completely wrong.”

Moderating the session on preventing

hospital readmissions will be Richard F. Demers, RPh, MS, FASHP, director of pharmacy services at the University of Pennsylvania Hospital, Philadelphia.

Mr. Demers’ team, including Janelle Ocampo, PharmD, BCPS, clinical pharmacy specialist-internal medicine, Hospital of the University of Pennsylvania, Philadelphia, will discuss the success that the hospital’s pharmacists have had as team members in a project aimed at fostering safer transitions from hospital to community. Project BOOST (Better Outcomes for Older Adults through Safe Transitions) was carried out at six hospitals through a grant from the John A. Hartford Foundation through the Society of Hospital Medicine. The Agency for Healthcare Research and Quality, the Joint Commission and the Centers for Medicare & Medicaid Services were part of the program’s advisory board.

The initial data from the program, which will be presented at the session, “has shown a reduction in length of stay,” noted Mr. Demers, adding that they also “hope to show an impact on readmissions.”

—Bruce Buckley

ß

IMPORTANT SAFETY INFORMATION for SAMSCA™ (tolvaptan) 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.

SAMSCA is contraindicated in the following conditions: – 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 • Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae – During initiation and after titration monitor patients to assess serum sodium concentrations and neurologic status. 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, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction during the first 24 hours with SAMSCA may increase the likelihood of overly-rapid correction of serum sodium, and should generally be avoided • Gastrointestinal Bleeding in Patients with Cirrhosis – Use only when need to treat outweighs this risk • Dehydration and Hypovolemia – In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended. Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted • Co-administration with Hypertonic Saline – Not recommended • Other Drugs Affecting Exposure to SAMSCA – CYP 3A Inhibitors – Do not use with strong inhibitors of CYP 3A; avoid concomitant use with moderate CYP 3A inhibitors – CYP 3A Inducers – Avoid concomitant use with CYP 3A inducers. If co-administered, the dose of SAMSCA may need to be increased – P-gp Inhibitors – The dose of SAMSCA may have to be reduced if co-administered with P-gp inhibitors • Hyperkalemia or Drugs that Increase Serum Potassium – Monitor serum potassium levels in patients with a serum potassium >5 mEq/L and in patients receiving drugs known to increase serum potassium levels Pregnancy and Nursing Mothers – SAMSCA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from SAMSCA, a decision should be made to discontinue nursing or SAMSCA, taking into consideration the importance of SAMSCA to the mother.

Commonly observed adverse reactions – (SAMSCA incidence ≥5% more than placebo, respectively): 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%).

Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the adjacent page.

Available from Otsuka America Pharmaceutical, Inc.

15 mg

30 mg

A choice of 2 dosing strengths To place your order, call your wholesaler or distributor today.

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

First and only oral treatment for clinically significant hypervolemic and euvolemic hyponatremia • Promotes free water clearance • Effective correction of serum sodium • Significant increase in serum sodium concentrations in as early as 8 hours, and the change was maintained for 30 days* • Safety evaluated in >4000 patients in total clinical trials† • The most common adverse reactions in placebo-controlled studies in patients with hyponatremia (SAMSCA incidence ≥5% more than placebo, respectively) included: 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%) • Once-daily oral dosing • Starting dose is 15 mg/day—titrate at intervals of ≥24 hours, up to a maximum of 60 mg/day—without regard to meals • Patients can and should drink in response to thirst *In two identical 30-day, randomized, double-blind, placebo-controlled, multicenter studies, 424 patients with euvolemic and hypervolemic hyponatremia were treated for 30 days with tolvaptan or oral placebo, then followed for an additional 7 days after withdrawal. The primary end points for these studies were the average daily AUC for change in serum sodium from baseline to day 4 (tolvaptan, 4.0 mEq/L vs placebo, 0.4 mEq/L) and baseline to day 30 (tolvaptan, 6.2 mEq/L vs placebo, 1.8 mEq/L). Patients received either tolvaptan or placebo, at a starting dose of 15 mg. † Includes open-label and placebo-controlled trials, in which approximately 650 patients had hyponatremia.

NDC

Dosage

Size

59148-020-50 59148-021-50

15 mg QD 10-count blister pack 30 mg QD 10-count blister pack

INDICATION 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).

Important Limitations 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.

WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM 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.

Please see IMPORTANT SAFETY INFORMATION on adjacent 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 trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

©2009 Otsuka America Pharmaceutical, Inc.

November 2009

0709A-0378A