Pharmacy Practice News - January 2010 - Digital Edition

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Volume 37 • Number 1 • January 2010 ❃

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Trastuzumab, Lapatinib Land One-Two Punch In Resistant Breast Cancer San Antonio—The combination therapy of trastuzumab (Herceptin, Genentech) and lapatinib (Tykerb, GlaxoSmithKline) improves overall survival by 20 weeks compared with lapatinib alone in women with HER2-positive metastatic breast cancer (MBC) who have progressed on therapy with trastuzumab. Survival was roughly 60 weeks in the combination arm and 40 weeks in the lapatinib-only arm, according to study results reported at the recent San Antonio Breast Cancer Symposium.

“This is the first time that someone has shown that continuing Herceptin through progression and adding a second type of anti-HER2 therapy leads to a survival improvement compared to just moving to another drug and eliminating the trastuzumab, so it really validates the concept that trastuzumab is an important

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see ONE-TWO PUNCH, page 26

More Proof Pharmacy Profession Enhances Care, But at a Savings?

P

erhaps you thought it had already been proved: including a clinical pharmacist at an outpatient clinic to assure optimal therapy for blood pressure (BP) management significantly improves patients’ chances for reaching goals. But that finding, previously reached by small, single-site studies of varying designs, has now been confirmed in a large, welldesigned, multisite study published in the Archives of Internal Medicine (2009;169:1996-2002).

The study, involving 402 patients with uncontrolled hypertension at six different clinics across the state of Iowa, showed that adding a pharmacist to a clinical team more than doubled the percentage of patients whose BP was adequately controlled after six months: from 29.9% of patients in the control group to 63.9% of those in the intervention group.

But the study included no cost–benefit analysis, and did not attempt to seek reimbursement for the

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McMahon Publishing

in this issue Up Front Late-Breaker New data link immunosuppressives to skin cancer.

3

Clinical

IVIG FAQ How to dose immunoglobulins in morbidly obese patients.

8

Formulary Management Tirofiban switch triggers debate.

10

Cardiology American Heart Association annual meeting highlights.

12

Hem/Onc Pharmacy Is CHOP-R alternative the new standard of care for indolent lymphomas?

19

Awards Readers get to pick best pharmacist-conducted research study in 2009.

36

Cytotoxic Drug Residues Still Lurking in Health Care Facilities 75% of wipe samples from several hospitals deemed contaminated with at least one chemotherapeutic agent Las Vegas—Despite decades of regulation and policies in health care institutions, workplace contamination from cytotoxic agents is still widespread, even in facilities that have made concerted efforts to foster workplace safety, according to recent studies presented at the ASHP Midyear Clinical Meeting.

Computer keyboards, elevator buttons and flooring were just a few of the areas found to be contaminated with cytotoxic agents—often several hundred feet beyond prep areas that are supposedly designed to prevent the spread of these potentially harmful substances. The findings led one safe-handling expert to warn against continued complacency.

“I want to demythologize the idea that we have taken care of this problem,” stressed presenter Melissa McDiarmid, MD, MPH, DABT, professor

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Operations & Mgmt

see CYTOTOXIC, page 20

Joint Commission Best practices in medication reconciliation.

40

The Team as MVP in Patient Care

Infectious Disease Antibiotic stewardship programs boost outcomes.

45

Leadership in Action Being the “face” of your hospital pharmacy.

48

Educational Review Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations See page

28

Hospitalists–pharmacists among effective collaborations Las Vegas—Years ago, when Larry Wellikson, MD, was in practice and arrived at the hospital to find that an intravenous medication he had ordered had not been delivered, he would “do what every doctor did. I screamed at the person in front of me. I made a big, big ruckus and I got my patient what they needed.”

Today, as the chief executive officer of the Society of Hospital Medicine (SHM), an organization representing 30,000 physician-

hospitalists nationwide, Dr. Wellikson’s viewpoint has changed considerably. He now stresses the need for teamwork and shared responsibility for patient-centered care. He made that point eminently clear as he delivered his “Spotlight on Science” talk titled “Healthcare is a Team Sport: Moving to a Performance-Driven World” to a large audience at the ASHP Midyear Clinical Meeting in December.

see ENHANCING CARE, page 16

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see HOSPITALISTS, page 6

The Book Page Drug-Induced Diseases: Prevention, Detection, and Management, Second Edition James E. Tisdale, PharmD, BCPS, FCCP; Douglas A. Miller, PharmD See page

51

Introducing Teva’s New and Improved Product Labeling NDC#s are prominently placed in top left corner

Lot number is imprinted for easier tracking

TALLman lettering, used when appropriate, helps reduce dispensing errors

Bar Coded with a scannable Standard RSS bar code

Strength is highlighted in color for better visibility.

Products with multiple strengths are distinguished by different colors.

Manufacturing location of product

Expiration Date

For up-to-date information on all of our products, including many latex-free and preservative-free injectables, visit www.tevausa.com

©2009, Teva Pharmaceuticals USA

8430 A

19 Hughes • Irvine, California 92618 800.729.9991 • www.tevausa.com

Up Front 3

Pharmacy Practice News • January 2010

Capsules LATE-BREAKER

surf

Heart Transplant Drugs Linked to Skin Cancer A

JANUARY 2010

watch

lthough immunosuppressive medications offer a lifesaving benefit to heart transplant splant patients—the prevention of organ rejection—that protection comes at a price: an increased risk for skin cancer as early as five years post-transplant, a new Mayo Clinic study has found.

After 15 years, the risk was even more pronounced: nearly half all heart transplant patients developed some form of skin cancer, Jerry Brewer, MD, and colleagues reported (Arch Dermatol 2009;145:1391-1396).

Because immunosuppressive medications are lifetime requirements for transplant patients to prevent organ rejection, “looking at 15-year risk is legitimate,” Dr. Brewer told Pharmacy Practice News. “We need to pay attention to these data and make sure our patients are taught how to protect themselves long-term against sun exposure.”

In their retrospective study, the investigators reviewed the medical records of all heart transplant recipients at Mayo Clinic from 1988 to 2006. Their objective was to measure the cumulative incidence of both new and recurring skin cancers and also to determine what risk factors most contributed to the development of the malignancies.

They found that 312 patients developed 1,395 new skin cancers (either basal or squamous cell carcinomas).

The cumulative incidence for any skin cancer was 20.4%, 37.5% and 46.4% at five, 10 and 15 years post–heart transplant, respectively. The incidence of squamous cell carcinoma in patients who had initially developed a basal cell carcinoma was 98.1% after five years, the investigators reported.

In terms of specific risk factors, several emerged, including post-transplant herpes simplex viral infections, increased age and the use of the immunosuppressant mycophenolate mofetil (CellCept, Roche).

Dr. Brewer, an assistant professor of dermatology at Mayo Clinic, Rochester, Minn., said the increased risk seen with mycophenolate mofetil occurred only in patients with basal cell carcinoma, and was only significant in comparison with azathioprine.

“I’m really not sure why only mycophenolate mofetil was statistically significant in our study,” he said.

“It could be that our clinical practice uses more of the drug, so that the power in the analysis needed for cyclosporine or azathioprine to become significant in terms of skin cancer risk just wasn’t there.” But he stressed that, based on earlier studies, “all three drugs can correlate with higher skin cancer risk.”

Thus, patients on any of the three drugs need to be given thorough counseling on sun protection strategies, Dr. Brewer stressed. “Regular self-skin examinations and dermatologic follow-up exams, the use of sunscreens, limiting sun exposure whenever possible—all are appropriate when educating these patients,” he said.

He also cited additional factors that are associated with an elevated skin cancer risk in transplant recipients: • duration and degree of immunosuppressive therapy • a history of increased ultraviolet radiation exposure • male gender • infection with human papillomavirus • fair complexion with blue eyes and blond hair • pretransplant disease (e.g., polycystic kidney disease and cholestatic liver disease)

The five most-viewed articles last month on pharmacypracticenews.com: 1. FDA Sees Propofol Shortage Easing 2. Guidelines for the Management of Febrile Neutropenia

3. Medication Storage Tops List of Joint Commission Citations

4. Before Investing in IT, Take Time To Observe 5. A Specialty Coming of Age Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

[rare heard but potentially here strainlethal MRSA] ‘This

demonstrates characteristics that

first

are frankly frightening if it were to become more widespread.’

See article, page 46

—Robert Rapp, PharmD

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EDITORIAL BOARD

see TRANSPLANT DRUGS, page 39

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

ADMINISTRATION

James O’Neill, Senior Systems Manager

Robert Adamson, PharmD, Livingston, NJ Ernest R. Anderson Jr., MS, RPh, Boston, MA

Volume 37 • Number 1 • January 2010 • pharmacypracticenews.com

ANESTHESIOLOGY/PAIN Robert Barkin, PharmD, Chicago, IL Julie A. Golembiewski, PharmD, Chicago, IL Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY

NUCLEAR PHARMACY Jeffrey Norenberg, PharmD, Albuquerque, NM

Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Kate O’Rourke, Contributing Editors James Prudden, Group Editorial Director

Indu Lew, PharmD, Livingston, NJ

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

CARDIOLOGY

Robert Ignoffo, PharmD, San Francisco, CA

C. Michael White, PharmD, Storrs, CT

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

CNS/PSYCHIATRY

Cindy O’Bryant, PharmD, Aurora, CO

BIOTECHNOLOGY

Charles F. Caley, PharmD, Storrs, CT Lawrence Cohen, PharmD, BCPP, FASHP, FCCP, Spokane, WA Larry Ereshefsky, PharmD, San Antonio, TX COMPLEMENTARY AND ALTERNATIVE MEDICINE Cathy Rosenbaum, PharmD, Cincinnati, OH CRITICAL CARE John W. Devlin, PharmD, BCPS, FCCM, Boston, MA Judi Jacobi, PharmD, FCCM, Indianapolis, IN

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Dan Radebaugh, Director of Production and Technical Operations

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PEDIATRICS Gretchen Brummel, PharmD, BCPS, Hudson, Ohio

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INFECTIOUS DISEASES

EDITORIAL STAFF

Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH Peggy McKinnon, PharmD, Detroit, MI David P. Nicolau, PharmD, Hartford, CT Robert P. Rapp, PharmD, Lexington, KY

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4 Up Front

Pharmacy Practice News • January 2010

Your Letters

More Shades of Gray in ‘White Bagging’ Model To the Editor: red Pane has written an excellent article on the recent and everexpanding practice of “white bagging” to supply physician practices and hospitals with drugs for patient administration (“White Bagging: A New Challenge for Your Hospital,” December, page 38).

As Mr. Pane stated, the intent of this model, in which the drugs are supplied by a specialty pharmacy company under contract with the insurer, is to reduce the costs associated with these expensive medications. Although there may be some benefits to this drug distribution model, on balance it raises significant operational issues. Thus, in Massachusetts, we are fighting against the “white bagging” requirement with one of the local insurance companies.

If we look at this issue from the patient’s perspective, there may be a lower co-payment if the drug is provided under the pharmacy benefit rather than medical benefit, as Mr. Pane stat-

F

ed. However, there also may be delays in therapy. Typically, there is a prior authorization process for many of these drugs, which can take a few days.

If blood work to ensure the correct dosage is required before the drug can be shipped to the physician practice or hospital, further delays in patient care are possible. The alternative to prevent these delays is to send the drug to the provider prior to the results of the lab work or in some cases to send multiple doses of medication to the provider. Once again, Mr. Pane aptly stated that these patient-specific drugs are housed at the physician office or hospital awaiting the patient visit and the results of laboratory tests to verify the specific dose of medication.

In my experience, however, there are

times when these drugs are not administered to the patient due to changes in dosing, changes in the medical status of the patient or the death of the patient. The patient-specific drugs in these cases have been bought and billed by the specialty pharmacy, but will never be administered.

As I have informally surveyed pharmacists in hospitals, all relate that they have patient-specific drugs on their shelves that will never be administered, due to these factors. I believe there is an underappreciation of the significant costs that have been incurred by the insurance company in these cases.

Fortunately, there is a better way. If hospitals buy and bill for these medications on their own, they can eliminate the losses they’re incurring from undis-

pensed drugs. Hospitals only mix the appropriate dose of the drug after the patient has been assessed during the clinic visit and the laboratory values have been evaluated to determine the appropriate dose of the drug. Hospital pharmacies do not want to manipulate drugs that have been prepared by the specialty pharmacy. If the medications are sent to the hospital pharmacy requiring compounding prior to administration, the pharmacy assumes liability and administrative overhead costs for which there is no reimbursement.

I encourage hospital pharmacists to communicate the undue burden, the inconvenience to patient care and hidden costs of the white bagging model to insurance companies that want to provide drugs to patients in this manner.

Ernest R. Anderson Jr., MS, RPh System Vice President of Caritas Christi Health Care System Brighton, Mass.

Leadership Concepts Not Resonating With Staff To the Editor: have read Ernie Anderson’s “Leadership in Action” column with great interest. I have spent 38 years in the field—20 as a technician and 18 as a pharmacist. My career has been mostly hospital-based, where I worked at facilities ranging in size from 50 to 450 beds in eight locations. I have always had great interest in the ideas Mr. Anderson has expressed. But I have to say that I have had a considerable amount of difficulty implementing them with my staff.

I have been initiating the conversation about these same principles of trust, communication and interaction in every practice setting for my entire career. In all but one environment, I have been met with either “the deer in the headlights” look or open hostility. I suspect that one might think I am a confrontational sort, but I am in fact soft-spoken and easygoing.

I observe that there are many reasons for the resistance I’ve met; two are most prevalent. The first is that communication is a very complex beast. As I suspect you have long observed, most folks who practice pharmacy fall into a personality/intellectual profile that is proficient at remembering enormous amounts of information filed in many small mental boxes. Although this makes them good at tasks relevant to our profession, it gives us a group of people who are, for the most part, not very creative or flexible. I also have observed that as a group, we are very

I

good at expressing ourselves, but very poor at listening. Put another way, we are very good at doing, but very poor at contemplative skills.

The second reason for the pushback I’ve seen has to do with the nature of leadership. I observe that pharmacy administration is overwhelmed. The kinds of issues that you raise rarely get attention when competing with budget, staffing and all the rest. Education also is related to this. Most pharmacy leaders have no formal training in administration.

But I don’t want my negative experiences in this area to detract from what Mr. Anderson has accomplished with his writings. Indeed, in the stacks and stacks of pharmaceutical journals that I have been exposed to over the years, his is the first voice that has expressed these kinds of ideas on leadership and its impact on pharmacy practice. I congratulate Mr. Anderson on finding a publication that supports what he has to say; I wish him well in his journey.

Mike Lahr, BS, Pharm, PharmD Clinical Pharmacist Salem Regional Medical Center Salem, Ore.

Mr. Anderson responds: Thanks for your feedback. Regarding your first point about the “deer in the headlights look” when you ask pharmacy managers about some of these leadership concepts: I would say that if these managers do not even acknowledge the merits of those concepts, they are lacking in emotional intelligence, a quality popularized in Daniel Goleman’s book, “Emotional Intelligence: Why It Can Matter More Than IQ.” What I have found over the years is that a good clinician does not a manager make. In pharmacy we are taught to think scientifically (left brain) and not to see the relational aspects of a given situation. Pharmacists may have high IQs, but that does not necessarily mean they have high EQs—emotional intelligence quotient, if you will. The good news is that emotional intelligence can be learned (as opposed to IQ). So much of EQ has to do with communication and feeling in your gut. I often ask managers the following question: “If you got a sense that something was wrong in a particular situation, could you read the situation between the spoken words?”

You state that pharmacy managers store information in unrelated sections in their brain and lack creativity and flexibility. Both of these attributes tend to be right-brain functions. Again, pharmacists, being scientific-based people, are more left-brain than right-brain.

What needs to be learned is to use both sides of the brain. Again this goes back to the EQ. Over the next several months, I am going to start a new book called the “Leaders Playbook,” which I will mention in some of my upcoming columns. I intend to deal with some of these issues and hopefully I will be able to teach a few practical ways that pharmacists can learn some of these skills.

I agree with you that pharmacists have so much to keep up with in the scientific literature that they may not have time to read some of these books on leadership and life planning. This is part of the reason why I address leadership issues in my writings; I’m trying to give pharmacists “Cliffs Notes” on some of these concepts. What I often find is that pharmacists agree with the concepts but have trouble putting them into practice. We are creatures of habit and habits are hard to break.

Lastly, Pharmacy Practice News has been incredibly supportive in all that I have published. I do get a fair amount of feedback, which I encourage.

To all of my readers, keep the comments coming!

6 Up Front

Pharmacy Practice News • January 2010

Collaborative Care

HOSPITALISTS continued from page 1

“Hospitalists think about teams,” Dr. Wellikson said. “They are used to functioning as a team both within our hospital medicine groups, but also with pharmacists and nurses. They know that if things are not working today, if they don’t get the head of pharmacy in there, the head of the ED [emergency department], the head of nursing and figure out how to change things, the organization is going to be just as dysfunctional the following day.”

The Pharmacist’s Role As Dr. Wellikson described it, teamwork means looking at the work that needs to be done and matching it to team members’ capabilities. For example, he said, if a patient arrives with a pulmonary embolism (PE), “the doctor’s job—the hospitalist’s job—might be to diagnose that it is a PE and define the comorbidities. The pharmacist’s job would be to come in and say, ‘For this patient with PE, these are the medications we use in the hospital, and this is the way we’re going to judge what the therapeutic levels are.’”

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)

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

—Cynthia L. LaCivita, PharmD The pharmacist is also the person, he said, who decides to change the medication if it is not working or there has been a reaction to it and is the one who facilitates the transition to outpatient therapy and provides education to

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)

‘Our [ASHP] members have had a good working relationship with the Society of Hospital Medicine. They seem to be open to collaborating on a lot of different issues.’

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

patients about their medications.

“Everybody has a job,” Dr. Wellikson said, “and we should be measuring performance at the unit of a team, not measuring the doctor’s performance or the nurse’s performance, because at the end of the day the patient doesn’t really care [about particular individuals].” He noted that if you’re rooting for a football team, “you might care a little about how many passes the quarterback completed, but you’re really wondering, did we win or lose [as a team]?”

In opening his talk, Dr. Wellikson delivered a stark picture, with patients “more complex and sicker” than ever, “multiple transitions and handoffs and opportunities for medical error,” and national shortages of pharmacists, nurses and primary care physicians.

“Hospitals are worried about their very survival,” he said. “The number of hospitals that are functioning in this country is shrinking every year. And there is a loss of public trust. People are somewhat suspicious of the kind of care they’re going to get.”

Despite these circumstances, he offered glimmers of hope, with legislation in Washington on the verge of extending health insurance to millions of Americans and some $20 billion about to be spent in the next decade on physical plant changes in hospitals around the country. Over the next few years, Dr. Wellikson said, providers will need to tackle some of health care’s biggest issues: reducing costs, becoming more efficient, delivering quality and value, and rewarding performance.

“And because I like to be—and I think ASHP and the pharmacists like to be—a little ahead of the curve,” he said, “this is the time to start thinking about how we are going to be prepared to deliver health care in that new world.”

Dr. Wellikson also focused on the characteristics of high-performance organizations, noting that they are made up of skilled teams and create “a widespread culture” of motivated individuals who are highly concentrated “on metrics, extremely execution-driven and committed to continual process improvement and rapid adaptation.”

Many of the country’s top medical centers are high-performance organizations, Dr. Wellikson said, but “at the end of the day we’re going to need to figure out how we get a little slice” of whatever is working for the Kaiser Permanentes, Mayo Clinics and the

Up Front 7

Collaborative Care Geisinger Health Systems, “and bring it down to the 50-bed rural hospital.”

Dr. Wellikson also noted that the SHM and ASHP had joined with nursing and other hospital provider organizations to form the Hospital Care Collaborative. In September, the group published a set of common principles to guide future collaborative efforts to enhance patient-centered care. “We’re going to be thinking about what kind of tools we can develop for these high-performance teams.”

Two years ago, the SHM and ASHP published a joint statement on hospitalist–pharmacist collaboration. The document focused on opportunities for hospitalist–pharmacist alliances to enhance patient care, but cited certain “barriers” to collaboration including “real and perceived professional boundaries, poor integration of technology systems, inadequate pharmacist and hospitalist staffing, time constraints, inadequate funding and resources, lack of third-party compensation for clinical pharmacy services, and the competing obligations weighing on both professions.”

‘We should be measuring performance at the unit of a team, not measuring the doctor’s performance or the nurse’s performance …’

—Larry Wellikson, MD One of the joint statement’s co-authors, Cynthia L. LaCivita, PharmD, director of education and special programs at the ASHP Foundation, noted that individual hospitals and health systems “may have different challenges, but the key is really communication. Being open to collaborating and communicating will go a long way toward helping both hospitalists and pharmacists to overcome those barriers.”

“Our members have had a good working relationship with the [SHM],” Dr. LaCivita added. “They seem to be open to collaborating on a lot of different issues. Medication reconciliation is a topic on which we have worked together. They have the same objectives with regard to improving patient care. It’s a win-win situation.”

That team approach resonated with other pharmacists as well. “As a pharmacist who collaborated daily with physicians and nurses in an ICU satellite pharmacy many years ago, it was gratifying to see the value pharmacists bring to the team finally being acknowledged and accepted nationally,” said Tom Westerkamp, MS, RPh, medical information manager at Baxter Healthcare Corporation.

—Bruce Buckley

Less time processing. More time practicing.

The Pyxis® Medication Communication System helps pharmacists spend less time processing orders and managing inventory. The result? More time with patients. Studies show that drug interventions can increase by at least three times1 when pharmacists are clinically involved with the patient. It’s just one more way CareFusion combines technology and intelligence to help improve safety and efficiency. To learn more, visit our website at carefusion.com.

Alaris®

MedMined™

Pyxis®

1 Schumock, G.T., Meek, P.D., Ploetz, P.A., et al. Economic Evaluations of Clinical Pharmacy Services 1988–1995. Pharmacotherapy, 1996: 16(6), 1188-1208. © 2009 CareFusion Corporation or one of its subsidiaries. All rights reserved. Alaris, MedMined and Pyxis is a trademark or registered trademark of CareFusion Corporation or one of its subsidiaries. MC0954

8 Clinical

Pharmacy Practice News • January 2010

IVIG FAQ

Immunoglobulins and Obesity Q: How do you dose intravenous immunoglobulin in morbidly obese patients?

A: For more than 30 years, intravenous immunoglobulin (IVIG) has been used as replacement therapy for patients with primary immunodeficiency.1 More recently, the product has been used for a wide array of autoimmune-mediated diseases and for the treatment of antibody rejection in solid organ transplantation.2,3 IVIG works via several mechanisms of action including the modulation of the Fc receptors of phagocytic cells, complement activation, inhibition of cytokine release and interaction with B- and T-cell receptors.4

for the increased Vd into their extra body fluids, without accounting for the increase in fat. It is recommended that dosing be calculated using an adjusted body weight if a patient has a BMI of 30 kg/m2 or higher, or if the patient’s actual body weight is more than 20% over his or her ideal body weight (IBW).

A practical and cost-efficient formula for dosing IVIG in morbidly obese patients using an adjusted body weight can be calculated considering the equations in Table 1.7 The dosing equation in the Table will provide values that account for the extra Vd in obese patients.

It is not uncommon for calculated doses to fall between vial sizes. Such

Jerry Siegel, PharmD, FASHP

an adjusted body weight. In the first example, IVIG is ordered for a 5-ft 4-in., 120-kg woman with primary immunodeficiency. The ordering physician considers giving the patient a dose of 500 mg/kg. To calculate the dose of drug that the patient will require, her BMI must be calculated first.

Patient’s weight = 120 kg × 2.2 = 264 lb Patient’s height = 64 in.

BMI = 703 × [(264 lb)/(64 in. × 64 in.)] = 45 kg/m2 Because the patient’s BMI is greater than 30 kg/m2, the IVIG should be dosed using an adjusted body weight. To calculate an adjusted body weight, first calculate the patient’s IBW.

Table 1.

IVIG Dosing Calculation = Adjusted Body Weight = IBW + 0.5 (actual body weight – IBW) BMI = 703 x (weight in pounds/ height in inches2) IBW (kg) for males = 50 + [2.3 x (height in inches – 60)] IBW (kg) for females = 45.5 + [2.3 x (height in inches – 60)] IVIG Adjusted Body Weight = IBW + 0.5 (actual body weight – IBW) IBW, ideal body weight; IVIG, intravenous immunoglobulin

IVIG is supplied in lyophilized and liquid dosage forms and is supplied as vials with varying increments. Different manufacturers provide 1-, 2.5-, 3-, 5-, 6-, 10-, 12-, and 20-g vials.5 The concentrations of IVIG are usually 5%, 6%, or 10%, depending on the reconstitution or liquid product selected.

The dose of IVIG prescribed varies depending on the indication, but the appropriate dosing regimen in obese patients has long been unclear; studies have traditionally excluded this population.2,3 Taking into account the pharmacokinetic properties of the drug, as well as the product packaging variability, The Ohio State University Medical Center uses the following approach to dose IVIG in obese patients.

Although IVIG has been shown to have very little distribution into the fat,6 there is an increased volume of distribution (Vd) in patients with obesity due to their increased volume of body fluids. Thus, although in general, IVIG should be dosed using actual body weight in patients weighing up to 100 kg with a body mass index (BMI) less than 30 kg/m2; in obese patients, an adjusted body weight should be used to account

For more than 30 years, intravenous immunoglobulin (IVIG) has been used as replacement therapy for patients with primary immunodeficiency. doses should be rounded to the nearest whole vial size available to prevent unnecessary waste. Generally, the goal is to target the rounded doses to be within 10% of calculated doses. The dosing equation in Table 1 provides values that easily can be rounded to vial sizes provided by the manufacturer.

Table 2 demonstrates the importance of dosing patients with obesity using

IBW = 45.5 × [2.3 × (64 in. – 60 in.)] = 54.7 kg Using that IBW, an adjusted body can then be calculated.

Adjusted Body Weight = IBW (54.7 kg) + 0.5 × (actual body weight [120 kg] – IBW [54.7 kg]) = 87.4 kg To calculate the total dose, the dose that the physician ordered (500 mg/kg) is then multiplied by the adjusted body

Senior Director, Emeritus Department of Pharmacy The Ohio State University Medical Center Columbus, Ohio

Kristin Inman Brower, PharmD Clinical Pharmacist The Ohio State University Medical Center Columbus, Ohio

weight (87.4 kg), yielding 43,700 mg, or 43.7 g.

For a calculated dose of 43.7 g, the dose should be rounded to 42 g. After dose escalation, the maximum tolerated infusion rate was 2 mg/kg per hour. The infusion rate of a 6% preparation in this case would be calculated as follows: Maximum tolerated infusion rate (2 mg/kg per minute) × adjusted body weight (87.4 kg) × (1 g/1,000 mg) × 700 mL/42 g (6 g/100 mL in 6% preparation, ie, 700 mL/42 g) × (60 min/1 h) = 174.8 (175) mL per hour.

The second example also highlights the importance of using an adjusted body weight in the dosing of IVIG in patients who are obese. IVIG is ordered for a 6-ft 2-in., 150-kg male professional football player for the treatment of idiopathic thrombocytopenic purpura. The dosing options vary from 400 mg/kg per day for five days to 500 mg/kg per day for four days or 1,000 mg/kg per day for two days. At the highest doseper-day option (1,000 mg/kg per day), he would receive 150 g of IVIG per day if the actual body weight were used.

If a 5% solution were used, this would be 3,000 mL of IVIG fluid per day (5 g/100 mL in 5% preparation, i.e., 3,000 mL/150 g). The volume and time for infusion may be difficult for the patient to tolerate.

To address this problem, a 10% solution is selected for administration. Additionally, because his BMI is greater than

Table 2. Examples of Dosing of IVIG in Morbidly Obese Patients

Height, Weight, in. kg

Dosing BW, kg

BMI

% Body Weight Above IBW

Dose Using Actual BW, g

Dose Using Adjusted BW, g

No. Vials Needed For Rounded Adjusted BW Dose

Patient

Dose

Female 48 y

500 mg/kg

64

120

87.4

45

37.5

60

43.7

If 6-g, use 7 vials (42 g) 6% solution = 700 mL

Male 24 y

1,000 mg/kg

74

150

116

42

45.2

150

116

If 20-g, use 6 vials (120 g) 10% solution = 1,200 mL

BMI, body mass index; BW, body weight; IBW, ideal body weight

Clinical 9

Pharmacy Practice News • January 2010

IVIG FAQ 30 kg/m2 and the actual body weight is more than 20% above the patients’ IBW, the IVIG should be dosed using an adjusted body weight. To calculate an adjusted body weight, first calculate the patient’s IBW. IBW = 50 + [2.3 × (74 in. – 60 in.)] = 82.2 kg Adjusted Body Weight = 82.2 kg + 0.5 × (150 kg – 82.2 kg) = 116 kg Using the adjusted body weight (116 kg), the calculated dose of IVIG is 116 g, and this dose should be rounded to 120 g, allowing for the use of six 20-g vials. At a maximum infusion rate of

2 mg/kg per minute, the rate would be 140 mL per hour, not the 180 mL per hour that would be calculated using actual body weight. Maximum tolerated infusion rate (2 mg/kg per minute) × adjusted body weight (116 kg) × (1 g/1,000 mg) × 1,200 mL/120 g (10 g/100 mL in 10% preparation, i.e., 1,200 mL/120 g) × (60 min/1 h) = 140 mL per hour.

In conclusion, IVIG should be dosed using adjusted body weight in obese patients to account for distribution into extra body fluids. Adjusted body weight should be used if a patient has a BMI of 30 kg/m2 or greater or if the patient’s

actual body weight is more than 20% over IBW. At our institution, we recommend calculating the adjusted body weight using the equation, Adjusted Body Weight = IBW + 0.5 × (actual body weight – IBW) for ease of calculation.

Intravenous (Human) [package insert]. Kankakee, IL: CSL Behring LLC; October 2008.

4.

Crow A, Lazarus A. The mechanisms of action of intravenous immunoglobulin and polyclonal anti-D immunoglobulin in the amelioration of immune thrombocytopenic purpura: what do we really know? Transfus Med Rev. 2008;22(2):103-116.

5.

Siegel J. Intravenous immune globulins: therapeutic, pharmaceutical, administration, and cost considerations. Pharmacy Practice News Special Edition. 2009:20-27.

6.

Koleba T, Ensom MH. Pharmacokinetics of intravenous immunoglobulin: a systematic review.

Pharmacotherapy. 2006;26(6);813-827.

7.

Provan D, Nokes T, Agrawal S, Winer J, Wood P. National Health Service. Clinical guidelines for the use of immunoglobulin use: second edition. http:// www.dh.gov.uk/en/Publicationsandstatistics/ Publications/PublicationsPolicyAndGuidance/ DH_085235. Accessed November 23, 2009.

References 1.

Boros P, Gondolesi G, Bromberg JS. High dose intravenous immunoglobulin treatment: mechanisms of action. Liver Transpl.

2005;11(12):1469-1480.

2.

Privigen Immune Globulin Intravenous (Human) 10% Liquid [package insert]. Kankakee, IL: CSL Behring LLC; June 2009.

3.

Carimune NF, Nanofiltered Immune Globulin

CSL Behring BRIEF SUMMARY OF PRESCRIBING INFORMATION

Privigen®, Immune Globulin Intravenous (Human), 10% Liquid Before prescribing, please consult full prescribing information, a brief summary of which follows. Some text and references refer to full prescribing information.

WARNING: ACUTE RENAL DYSFUNCTION/FAILURE Use of Immune Globulin Intravenous (IGIV) products, particularly those containing sucrose, have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephropathy, and death.1 Patients at risk of acute renal failure include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs (see Warnings and Precautions [5.2]). Privigen does not contain sucrose.

For patients at risk of renal dysfunction or failure, administer Privigen at the minimum infusion rate practicable (see Dosage and Administration [2.3], Warnings and Precautions [5.2]).

1 INDICATIONS AND USAGE Privigen is an Immune Globulin Intravenous (Human), 10% Liquid indicated for the treatment of the following conditions.

1.1 Primary Humoral Immunodeficiency Privigen is indicated as replacement therapy for primary humoral immunodeficiency (PI).

This includes, but is not limited to, the humoral immunodeficiency in common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

1.2 Chronic Immune Thrombocytopenic Purpura Privigen is indicated for the treatment of patients with chronic immune thrombocytopenic purpura (ITP) to raise platelet counts.

3 DOSAGE FORMS AND STRENGTHS Privigen is a liquid solution containing 10% IgG (0.1 g/mL) for intravenous infusion.

4 CONTRAINDICATIONS Privigen is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.

Because it contains the stabilizer L-proline, Privigen is contraindicated in patients with hyperprolinemia.

Privigen is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity.

5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Severe hypersensitivity reactions may occur (see Contraindications [4]). In case of hypersensitivity, discontinue the Privigen infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions.

Privigen contains trace amounts of IgA ( 25 mcg/mL) (see Description [11]). Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Privigen is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction (see Contraindications [4]).

5.2 Renal Failure Ensure that patients are not volume depleted before administering Privigen. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Privigen. For patients judged to be at risk of developing renal dysfunction, administer Privigen at the minimum infusion rate practicable (see Boxed Warning, Dosage and Administration [2.3]).

5.3 Hyperproteinemia Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving Privigen and other IGIV product treatments. It is critical to clinically distinguish true hyponatremia from a pseudohyponatremia that is associated with or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap, because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thrombotic events.2 5.4 Thrombotic Events Thrombotic events may occur following treatment with Privigen and other IGIV products.3-5 Patients at risk include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known/suspected hyperviscosity.

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients judged to be at risk of developing thrombotic events, administer Privigen at the minimum rate of infusion practicable (see Dosage and Administration [2.3]). Weigh the potential risks and benefits of IGIV against those of alternative therapies in all patients for whom Privigen therapy is being considered.

5.5 Aseptic Meningitis Syndrome (AMS) AMS may occur infrequently with Privigen (see Adverse Reactions [6, 6.1]) and other IGIV product treatments. Discontinuation of IGIV treatment has resulted in remission of AMS

within several days without sequelae.6 AMS usually begins within several hours to 2 days following IGIV treatment.

AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting (see Patient Counseling Information [17]). Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis.

AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. 5.6 Hemolysis Privigen may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.7-9 Hemolytic anemia can develop subsequent to Privigen therapy due to enhanced RBC sequestration and/or intravascular RBC destruction.10 Hemolysis, possibly intravascular, occurred in two subjects treated with Privigen in the ITP study (see Adverse Reactions [6, 6.1]). These cases resolved uneventfully. Six other subjects experienced hemolysis in the ITP study as documented from clinical laboratory data.

Monitor patients for clinical signs and symptoms of hemolysis (see Patient Counseling Information [17]). If these are present after Privigen infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis.

5.7 Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients following IGIV treatment.11 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following treatment.

Monitor patients for pulmonary adverse reactions (see Patient Counseling Information [17]). If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and the patient’s serum.

TRALI may be managed using oxygen therapy with adequate ventilatory support.

5.8 Volume Overload The high-dose regimen (1 g/kg/day for 2 days) used to treat patients with chronic ITP is not recommended for individuals with expanded fluid volumes or where fluid volume may be of concern (see Dosage and Administration [2.2]).

5.9 Transmissible Infectious Agents Privigen is made from human plasma. Based on effective donor screening and product manufacturing processes (see Description [11]), Privigen carries an extremely remote risk of transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) is also considered to be extremely remote. No cases of transmission of viral diseases or CJD have been associated with the use of Privigen. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare professional to CSL Behring Pharmacovigilance at 1-866-9156958. Before prescribing Privigen, the physician should discuss the risks and benefits of its use with the patient (see Patient Counseling Information [17]).

5.10 Monitoring: Laboratory Tests Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter.

Because of the potentially increased risk of thrombosis, consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies.

If signs and/or symptoms of hemolysis are present after an infusion of Privigen, perform appropriate laboratory testing for confirmation.

If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum.

5.11 Interference With Laboratory Tests After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test.

6 ADVERSE REACTIONS The most serious adverse reaction observed in clinical study subjects receiving Privigen for PI was hypersensitivity in one subject. The most common adverse reactions observed in >10% of clinical study subjects with PI were headache, pain, nausea, fatigue, and chills.

The most serious adverse reactions observed in clinical study subjects receiving Privigen for chronic ITP were aseptic meningitis syndrome in one subject and hemolysis in two subjects.

Six other subjects in the ITP study experienced hemolysis as documented from clinical laboratory data (see Warnings and Precautions [5.5, 5.6]). The most common adverse reactions observed in >10% of clinical study subjects with chronic ITP were headache, pyrexia/hyperthermia, and anemia.

6.1 Clinical Trials Experience Because different clinical studies are conducted under widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical studies and may not reflect the rates observed in practice.

Treatment of Primary Humoral Immunodeficiency In a prospective, open-label, single-arm, multicenter clinical study, 80 subjects with PI (with a diagnosis of XLA or CVID) received Privigen intravenously every 3 or 4 weeks for up to 12 months (see Clinical Studies [14.1]). All subjects had been on regular IGIV replacement therapy for at least 6 months prior to participating in the study. Subjects ranged in age from 3 to 69; 57.5% were male and 42.5% were female.

The safety analysis included all 80 subjects, 16 on the 3-week schedule and 64 on the 4-week schedule. The median doses of Privigen administered intravenously ranged from 200 to 888 mg/kg every 3 weeks (median dose 428.3 mg/kg) or 4 weeks (median dose 440.6 mg/kg). A

10 Clinical

Pharmacy Practice News • January 2010

Formulary Management

Antiplatelet Switch Study Stirs Debate Anaheim, Calif.—Switching from the antiplatelet drug eptifibatide to tirofiban has the potential to save hundreds of thousands of dollars with no detriment to patients, according to an analysis at a Utah medical center. But some pharmacists have expressed concern that the two medications may not be truly interchangeable.

For the study, pharmacists at Intermountain Medical Center in Murray, Utah, performed an analysis comparing

the total cost of the glycoprotein IIb/ IIIa inhibitors (GPIs) tirofiban (Aggrastat, Iroko) and eptifibatide (Integrilin, Schering-Plough) among patients with acute coronary syndrome (ACS) undergoing percutaneous coronary interventions (PCI), such as angioplasty or stent placement.

The study, led by Regan Healy, PharmD, a pharmacy practice resident, and Katy Mathews, PharmD, a cardiology clinical pharmacist, factored in variables includ-

total of 1038 infusions of Privigen were administered, 272 in the 3-week schedule and 766 in the 4-week schedule. Of the 1038 infusions, 435 were administered to females and 603 to males.

Routine premedication was not allowed. However, subjects who experienced two consecutive infusion-related adverse events (AEs) that were likely to be prevented by premedication were permitted to receive antipyretics, antihistamines, NSAIDs, or antiemetic agents. During the study, 8 (10%) subjects received premedication prior to 51 (4.9%) of the 1038 infusions administered.

Temporally associated AEs are those occurring during or within 72 hours after the end of an infusion, irrespective of causality. In this study, the upper bound of the 1-sided 97.5% confidence interval for the proportion of Privigen infusions temporally associated with one or more AEs was 23.8% (actual proportion: 20.8%). This is below the target of 40% for this safety endpoint. The total number of temporally associated AEs was 397 (a rate of 0.38 AEs per infusion), reflecting that some subjects experienced more than one AE during the observation period.

Table 2 lists the temporally associated AEs that occurred in more than 5% of subjects during a Privigen infusion or within 72 hours after the end of an infusion, irrespective of causality.

Table 2: Adverse Events Occurring in >5% of Subjects With PI During a Privigen Infusion or Within 72 Hours After the End of an infusion, Irrespective of Causality Adverse Event Subjects (%) [n=80] Infusions (%) [n=1038] Headache 35 (43.8) 82 (7.9) Pain 20 (25.0) 44 (4.2) Fatigue 13 (16.3) 27 (2.6) Nausea 10 (12.5) 19 (1.8) Chills 9 (11.3) 15 (1.4) Vomiting 7 (8.8) 13 (1.3) Pyrexia 6 (7.5) 10 (1.0) Cough 5 (6.3) 5 (0.5) Diarrhea 5 (6.3) 5 (0.5) Stomach discomfort 5 (6.3) 5 (0.5) *Excluding infections.

Of the 397 temporally associated AEs reported for the 80 subjects with PI, the investigators judged 192 to be related to the infusion of Privigen (including 5 serious, severe AEs described below). Of the 187 non-serious AEs related to the infusion of Privigen, 91 were mild, 81 were moderate, 14 were severe, and 1 was of unknown severity. The most common temporally associated AEs judged by the investigators to be “at least possibly” related to the infusion were headache (29% of subjects), pain (14% of subjects), nausea (11% of subjects), fatigue (11% of subjects), and chills (11% of subjects).

Sixteen subjects (20%) experienced 41 serious AEs. Five of these were related severe AEs (hypersensitivity, chills, fatigue, dizziness, and increased body temperature) that occurred in one subject and resulted in the subject’s withdrawal from the study. Two other subjects withdrew from the study due to AEs related to Privigen treatment (chills and headache in one subject; vomiting in the other).

Seventy-seven of the 80 subjects enrolled in this study had a negative direct antiglobulin test (DAT) at baseline. Of these 77 subjects, 36 (46.8%) developed a positive DAT at some time during the study. However, no subjects showed evidence of hemolytic anemia.

During this study, no subjects tested positive for infection due to human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or B19 virus (B19V).

Treatment of Chronic Immune Thrombocytopenic Purpura In a prospective, open-label, single-arm, multicenter clinical study, 57 subjects with chronic ITP and a platelet count of 20 x 109/L or less received a total of 2 g/kg dose of Privigen administered as 1 g/kg intravenous infusions daily for 2 consecutive days (see Clinical Studies [14.2]). Subjects ranged in age from 15 to 69; 59.6% were female and 40.4% were male.

Concomitant medications affecting platelets or other treatments for chronic ITP were not allowed. Thirty-two (56.1%) subjects received premedication with acetaminophen and/or an antihistamine.

Table 3 lists the temporally associated AEs that occurred in more than 5% of subjects with chronic ITP during a Privigen infusion or within 72 hours after the end of a treatment cycle (two consecutive infusions) with Privigen, irrespective of causality.

Table 3: Adverse Events Occurring in >5% Subjects With Chronic ITP During a Privigen Infusion or Within 72 hours After the End of a Treatment Cycle*, Irrespective of Causality Adverse Event Headache Pyrexia/hyperthermia Nausea Epistaxis Vomiting Blood unconjugated bilirubin increased Blood conjugated bilirubin increased Blood total bilirubin increased Hematocrit decreased

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

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

6 (10.5)

6 (5.3)

5 (8.8)

5 (4.4)

4 (7.0) 3 (5.3)

4 (3.5) 3 (2.6)

ing high-bolus dosing, weight-based dosing, various infusion durations and nursing administration fees, in addition to manufacturer discounts. The hospital treats approximately 3,000 patients with ACS each year.

The results, presented at the American College of Clinical Pharmacy’s annual meeting, estimated an expense decrease of 52%, with approximate annual savings of $812,000, at the center. The medical center, which is in the midst of a

Three subjects experienced three serious AEs, one of which (aseptic meningitis) was related to the infusion of Privigen.

One subject withdrew from the study due to gingival bleeding, which was not related to Privigen.

Eight subjects, all of whom had a positive DAT, experienced transient drug-related hemolytic reactions, which were associated with elevated bilirubin, elevated lactate dehydrogenase, and a decrease in hemoglobin level within two days after the infusion of Privigen. Two of the eight subjects were clinically anemic but did not require clinical intervention.

Four other subjects with active bleeding were reported to have developed anemia without evidence of hemolysis.

In this study, there was a decrease in hemoglobin after the first Privigen infusion (median decrease of 1.2 g/dL by Day 8) followed by a return to near baseline by Day 29.

Fifty-six of the 57 subjects in this study had a negative DAT at baseline. Of these 56 subjects, 12 (21.4%) developed a positive DAT during the 29-day study period.

6.2 Postmarketing Experience Because postmarketing reporting of adverse events is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. Evaluation and interpretation of these postmarketing reactions is confounded by underlying diagnosis, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance.

Privigen Postmarketing Experience Adverse reactions reported during worldwide postmarketing use of Privigen do not differ from what has been observed in clinical studies with Privigen and from what is known for IGIV products.

General The following mild to moderate reactions may occur with the administration of IGIV products: headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, skin reactions, wheezing or chest tightness, nausea, vomiting, rigors, back pain, chest pain, myalgia, arthralgia, and changes in blood pressure. Immediate hypersensitivity and anaphylactic reactions are also a possibility.

The following adverse reactions have been identified and reported during the post-approval use of IGIV products.12 Renal: Acute renal dysfunction/failure, osmotic nephropathy Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test Musculoskeletal: Back pain Gastrointestinal: Hepatic dysfunction, abdominal pain General/Body as a Whole: Pyrexia, rigors 7 DRUG INTERACTIONS Passive transfer of antibodies may transiently interfere with the immune response to live virus vaccines such as measles, mumps, and rubella.13 The immunizing physician should be informed of recent therapy with Privigen so that appropriate measures may be taken (see Patient Counseling Information [17]).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Privigen.

It is not known whether Privigen can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Privigen should be given to pregnant women only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation.14,15 8.3 Nursing Mothers Use of Privigen in nursing mothers has not been evaluated.

8.4 Pediatric Use Treatment of Primary Humoral Immunodeficiency Privigen was evaluated in 31 pediatric subjects (19 children and 12 adolescents) with PI. There were no apparent differences in the safety and efficacy profiles as compared to those in adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. The safety and effectiveness of Privigen have not been established in pediatric patients with PI who are under the age of 3.

Treatment of Chronic Immune Thrombocytopenic Purpura Safety and effectiveness of Privigen have not been established in pediatric patients with chronic ITP who are under the age of 15.

8.5 Geriatric Use Clinical studies of Privigen did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects.

Use caution when administering Privigen to patients age 65 and over who are judged to be at increased risk of developing renal insufficiency (see Boxed Warning, Warnings and Precautions [5.2]). Do not exceed recommended doses, and administer Privigen at the minimum infusion rate practicable.

Manufactured by: CSL Behring AG Bern, Switzerland

* Two consecutive daily infusions.

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

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

Based on June 2009 revision.

formulary conversion proposal, had tirofiban on the formulary but eptifibatide on the list for procedures being performed in the cardiac catheterization laboratory, Dr. Healy said. Part of the evidence supporting the switch, he noted, was a report suggesting that tirofiban is similar to eptifibatide for platelet activity (EuroIntervention 2007;3:371-380; JAMA 2008;299:1788-1799. Epub 2008 Mar 30).

Caution Urged But Paul Dobesh, PharmD, associate professor of pharmacy practice at the University of Nebraska Medical Center’s College of Pharmacy in Omaha, said that pharmacists should use caution when making these kinds of substitutions. “The clinical data on tirofiban is probably the weakest of any of the GPI drugs out there,” he said. “So they’re extensively cutting the price.”

‘It has been established that, when dosed appropriately, tirofiban can be compared with other agents within the glycoprotein IIb/IIIa inhibitor class.”

—Katy Mathews, PharmD Pharmacists and other clinicians also need to look at patient outcomes both 30 days and six months after discharge from the hospital to assess the drug’s efficacy, Dr. Dobesh said. A study he directed while at the St. Louis College of Pharmacy in the late 1990s looked at outcomes among PCI patients receiving tirofiban, which had largely replaced abciximab at the medical center. The results, published in The Annals of Pharmacotherapy (2003;37:1375-1380), found that incidence of death and heart attack tended to be worse with tirofiban than with abciximab at 30 days (12% vs. 4.8%; P=0.163) and six months following discharge (18.1% vs.

6%; P=0.032).

“The perceived economically driven change in medication selection from abciximab to tirofiban may not have been appropriate based on the negative trends seen in this review,” Dr. Dobesh and his colleagues wrote. “To maintain optimal patient outcomes, this change should be re-evaluated.”

Amy Seybert, PharmD, associate professor of pharmacy and therapeutics at the University of Pittsburgh School of Pharmacy, agrees with Dr. Dobesh, noting that neither of the clinical trials cited by the Intermountain pharmacists were

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Pharmacy Practice News • January 2010

Formulary Management direct comparisons of tirofiban to eptifibatide. “I would not feel comfortable stating that they are interchangeable,” Dr. Seybert said. “There is much more data that is needed before we could do that.”

Dr. Mathews countered that she still is “confident that tirofiban can support evidence-based practice at this time despite history with previous clinical trials” showing that other GPI drugs are superior to tirofiban. For example, the TARGET (Do Tirofiban and ReoPro Give Similar Efficacy Trial [N Engl J Med 2001;344:1888-1894]) trial demonstrated that tirofiban offered less protection from major ischemic events than did abciximab.

“It has been established that, when dosed appropriately, tirofiban can be compared to other agents within the glycoprotein IIb/IIIa inhibitor class,” Dr. Mathews said. “This has been shown in platelet studies as well as randomized clinical outcome trials.”

One study (JAMA 2008;299:1788-1799.

Epub 2008 Mar 30), for example, compared tirofiban at adjusted dose with abciximab “and found it noninferior,” Dr. Mathews said. “There also have been head-to-head studies evaluating platelet function with abciximab, tirofiban and eptifibatide [Am J Cardiol 2006;97:489493], showing that all three agents were comparable with respect to inhibition of platelet aggregation.”

Although tirofiban does not have FDA approval for certain indications, such as bolus dosing immediately before PCI, she added, new ST segment elevation myocardial infarction (MI) guidelines from the American College of Cardiology/ American Heart Association (Circulation 2009;1202271-2306) “recommend this new high bolus dose of tirofiban. Many facilities across the country have successfully made this transition.”

Dr. Dobesh cautioned that “the higherdose studies have only been powered to evaluate the ability of tirofiban to inhibit platelet aggregation compared with abciximab … there have been no larger studies evaluating clinical outcomes as the primary end point with the use of tirofiban at this new dose.”

However, Gary Mount, PharmD, director of pharmacy at Baptist Medical Center South (BMCS), in Montgomery, Ala., who organized a recent switch from eptifibatide to tirofiban at his institution, told Pharmacy Practice News that several European studies support the higher dosing strategy. He cited, as an example, the Advance trial (J Am Coll Cardiol 2004;44:14–19), the 3T/2R (Tailoring Treatment with Tirofiban in Patients Showing Resistance to Aspirin or Resistance to Clopidogrel) trial (Circulation 2009;119:3215-3222) and the On-TIME (Ongoing Tirofiban in Myocardial Infarction Evaluation) 2 trial (Lancet 2008;372:537–546).

C. Michael White, PharmD, professor of pharmacy at the University of Connecticut in Storrs and Director of UCONN/ Hartford Hospital Evidence-Based Practice Center, said that several of the studies being pointed to in support of the switch “are shaky and based on platelet inhibition studies,” he noted. As for the On-TIME 2 trial, “it’s placebo-controlled and based on prehospital administration of tirofiban. As such, it has nothing to do with the comparative effectiveness of tirofiban and eptifibatide.”

The Utah team, as well as Dr. Mount and his colleague, Mary McKnight,

PharmD, clinical pharmacy manager at BMCS, maintain that the tirofiban switch makes sense. “If we had all the money in the world, ReoPro [abciximab] would be the way to go,” said Dr. McKnight. But under the current economic pressures most hospitals are facing, “that agent really has to be reserved for very high-risk patients,” she said.

With respect to the other two GPI agents, Dr. McKnight said it made sense to switch from the more expensive medication, eptifibatide, to the less expensive option, tirofiban, because both drugs have a class IIa recommendation in the

new ST segment MI guidelines published in Circulation. “I really don’t see a true benefit of Integrilin over Aggrastat,” she added.

In Dr. White’s view, it all depends on how far you want to push the data when considering such a switch. “It is not unreasonable to institute a strategy of substitution from eptifibatide to tirofiban,” he said, “as long as it is understood that the decision is based on a low strength of evidence and that the choice may ultimately be found to be a poor one.”

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12 Clinical

Pharmacy Practice News • January 2010

Cardiology For C. Michael White, PharmD commentary on the

American Heart Association 2009 Roundup Orlando, Fla.—The American Heart Association’s (AHA) Scientific Sessions 2009 were structured around seven core areas of cardiology practice and included basic, clinical, population and translational studies. The following are just a few of the highlights from the meeting.

The Star of the Show?

One of the studies that generated a lot of buzz was the ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies) trial.

The study found that the addition of extended-release niacin to statin monotherapy produced a greater regression of atherosclerosis as measured by carotid intima media thickness (IMT) than did the addition of ezetimibe (Zetia, Merck/ Schering Plough) in patients at high cardiovascular risk already at their lowdensity lipoprotein cholesterol (LDL-C) goal. The results were presented in a late-breaking plenary session by Allen J. Taylor, MD, from Walter Reed Army Medical Center and Medstar Research Institute, Washington Hospital Center, Washington, D.C., and published simultaneously Nov. 16 online in The New England Journal of Medicine (N Engl J Med 2009; DOI:10.1056/NEJMoa907569; http://www.nejm.org).

The open-label study enrolled 363 patients with coronary heart disease (CHD) or a CHD risk equivalent already on long-term statin therapy and who had achieved an LDL-C level below 100 mg/dL and a high-density lipoprotein cholesterol (HDL-C) level below 50 mg/dL if they were men, or below 55 mg/dL if they were women.

The patients were randomized to receive extended-release niacin 2,000 mg per day to raise their HDL-C levels, or to ezetimibe 10 mg per day to lower their LDL-C levels further. Over the 14-month study period, the mean HDLC level in the niacin group increased by 18.4%, to 50 mg/dL (P<0.001), and the mean LDL-C level in the ezetimibe group decreased by 19.2%, to 66 mg/dL (P<0.001). Additionally, niacin therapy significantly reduced LDL-C and triglyceride levels, whereas ezetimibe reduced HDL-C and triglyceride levels.

Compared with ezetimibe, niacin was more efficient in reducing mean carotid IMT, which was measured by carotid ultrasonography (P=0.003), leading to a significant reduction of both mean and maximal carotid IMT (P<0.001 for both comparisons).

Patients in the niacin group also had a lower incidence of major cardiovascular events than patients in the ezetimibe group (1% vs. 5%; P=0.04).

‘Giving these patients a trial of drug treatment first, and then referring them either for surgery or angioplasty if it turns out they need an intervention, is a rational strategy. It’s costeffective, and we know it is safe.’

—Mark Hlatky, MD A paradoxical finding was that use of ezetimibe led to an increase in plaque buildup in association with greater reduction in LDL-C levels.

“We hypothesize that this may stem from unintended biologic effects of this agent,” Dr. Taylor said. “This finding was from an ad hoc analysis that was done after the trial was completed and it is hypothesis-generating. It surprised us, but the finding needs to be confirmed in other studies.”

The results of ARBITER 6-HALTS answer a common clinical question, Dr. Taylor said. “We didn’t know which was better,” he told reporters at a packed news briefing. “But in this study of comparative effectiveness of two common strategies— using niacin to raise HDL cholesterol, or using ezetimibe to lower LDL cholesterol—the results are clear. When niacin was added to a statin, niacin was superior to ezetimibe in reversing artery wall plaque buildups,” he said.

The ARBITER 6-HALTS trial was supported by Abbott, which markets Simcor, a combination therapy that includes extended-release niacin and simvastatin.

HEALL Shows Benefit of HighDose Losartan for Heart Failure Another trial at AHA Scientific Sessions 2009 that attracted widespread attention explored the relation between dose and clinical outcomes of angiotensin receptor blockers for treating patients with heart failure. Sponsored

by Merck, the HEALL (Heart Failure End Point Evaluation of Angiotensin II Antagonist Losartan) study found that pushing the dose of losartan up to 150 mg per day reduced the rate of death or admission for heart failure in patients with New York Heart Association

(NYHA) class II-IV heart failure, a left ventricular ejection fraction less than 40% and intolerance to angiotensinconverting enzyme inhibitors (ACEIs).

The HEALL study was presented by lead author Marvin A. Konstam, MD, of Tufts University School of Medicine, Boston, and published online in The Lancet (Lancet 2009; DOI:10.1016/ S0140-6736[09]61913-9; http://www. thelancet.com).

HEALL enrolled 3,846 patients from 255 sites in 30 countries between November 2001 and March 2005, and continued to track outcomes until the end of March 2009. Most of the patients (60%) had NYHA class II heart failure.

They also had to have documented intolerance to ACEIs “in order to justify being randomized to one of two doses of the angiotensin receptor blocker,” Dr. Konstam explained.

The patients were randomly assigned to losartan 150 mg (n=1,927) or losartan 50 mg (n=1,919), given once daily. The primary end point was a composite of death or admission for heart failure, and analysis was by intention to treat.

With a median follow-up time of 4.7 years, 828 (43%) patients in the 150-mg group died or were admitted to hospital for heart failure compared with 889 (46%) in the 50-mg group (hazard ratio [HR], 0.90; 95% confidence interval [CI], 0.820.99; P=0.027). Looking at the outcomes separately, 635 patients in the high-dose group died compared with 665 patients in the low-dose group, but the difference was not statistically significant.

Hospital admissions were 13% lower in the high-dose patients compared with the low-dose patients (450 vs.

503, respectively; P=0.025), Dr. Konstam reported.

Study drug discontinuation occurred

AHA meeting, see page 13.

in 7.7% of the high-dose group and 7% of the low-dose group, who stopped losartan because of adverse events, mainly renal impairment, hyperkalemia and hypotension.

Renal impairment was the reason for drug discontinuation in 454 patients in the high-dose, and in 317 patients in the low-dose group.

“These adverse events can be very important to a small group of patients and it is very crucial that we monitor very closely all patients for their renal function, blood pressure and serum potassium,” Dr. Konstam said.

Say Yes to Drugs First Giving type 2 diabetes patients with stable CHD immediate coronary revascularization is just as effective as treating them with drugs, but much more costly, according to two different but related studies presented in a clinical trial update.

In the BARI 2D (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetics) study, which included 2,368 individuals with type 2 diabetes and angiographically documented heart disease, five-year cardiac death rates were similar in patients receiving intensive medical management or prompt revascularization (5.7% vs. 5.9%), Bernard R. Chaitman, MD, of St. Louis University School of Medicine, Missouri, reported. However, when patients had more severe heart disease, they did better with prompt revascularization than with medical management, he told delegates.

In these patients, heart attacks, and death or heart attack were significantly less frequent among subjects who received prompt revascularization than medical management (10% vs. 17.6% for heart attacks and 21.1% vs. 29.2% for the composite of death or heart attack), but only if they also got insulin sensitization, the investigators reported.

In the cost-effectiveness analysis of the BARI 2D data, Mark Hlatky, MD, from Stanford University, Stanford, Calif., reported that managing patients with type 2 diabetes who had mild or moderate heart disease with drugs would be much less costly to the health care system than sending them immediately for revascularization. This analysis showed that the cost for patients who were treated right away with coronary artery bypass graft surgery was $55,966, whereas the cost for those who were treated with medical therapy was $34,096 (P<0.0001). For patients treated immediately with angioplasty, the cost was $46,890 compared with $35,354 for those who were medically managed (P<0.0001).

These costs were determined at

Clinical 13

Pharmacy Practice News • January 2010

Cardiology two years, but remained essentially unchanged at four years of follow-up, Dr. Hlatky said.

“Giving these patients a trial of drug treatment first, and then referring them either for surgery or angioplasty if it turns out they need an intervention, is a rational strategy. It’s cost effective, and we know it is safe,” he said.

Both trials were published online at the time of their presentations in Circulation (Chaitman B, et al. Circulation 2009; DOI:10.1161/circulationaha.109.91311; http://circ.ahajournals. org; Hlatky M, et al. Circulation 2009; DOI:10.1161/circulationaha.109.912709; http://circ.ahajournals.org).

Viagra for Kids Sildenafil, a drug used to treat erectile dysfunction and pulmonary arterial hypertension, significantly improves ventricular performance in children and young adults after they have undergone the Fontan operation for single-ventricular defects, David J. Goldberg, MD, from the Children’s Hospital of Philadelphia, told AHA delegates (abstract 2161).

“Sildenafil inhibits phosphodiesterase type 5, resulting in pulmonary vasodilation and enhanced ventricular performance in adults with structurally normal hearts,” Dr. Goldberg said. “We reasoned that these actions may improve the physiologic and clinical status of patients with single-ventricle physiology after the Fontan operation.”

The Fontan procedure is an operation that directs systemic venous blood directly to the pulmonary arteries, bypassing the heart. It is the third surgery in staged reconstruction for singleventricle defects.

As part of a larger study, called SAFO (Sildenafil after the Fontan Operation), Dr. Goldberg and his colleagues sought to examine the impact of sildenafil on ventricular function.

T h e re s e a rc h e r s randomized 27 children and young adults (mean age, 14.9±5.1 years) who had undergone the Fontan operation (mean time from surgery, 11.3±3.8 years) to receive sildenafil 20 mg three times daily or placebo for six weeks. After a six-week washout period, the children were crossed over to the opposite arm for an additional six weeks. Echocardiograms were performed before and after each phase and measured ventricular function.

In all subjects, there was a significant improvement in mean myocardial performance index (MPI) during the sildenafil phase compared with the placebo phase (P<0.01). There was an indication of improved diastolic performance and increased cardiac output with sildenafil, but these differences did not reach statistical significance.

Finally, there was no difference in the average MPI improvement between the

Pharmacist’s Perspective

C

. Michael White, PharmD, FCP, FCCP, professor of pharmacy, University of Connecticut, Storrs, offered the following commentary on some of the AHA studies highlighted.

PPI interactions. The Sweeney et al retrospective cohort study documenting clopidogrel/PPI interactions is noteworthy. C. Michael White, The next day, the FDA notified health care professionals of the PharmD drug interaction, so this is something that clinicians need to be aware of. Clearly, patients who are receiving clopidogrel with omeprazole or pantoprazole should be alerted to the potential for this drug interaction and alternatives should be discussed. Alternatives can include switching the PPI to esomeprazole or lansoprazole or switching to newer thienopyridines such as prasugrel (Effient, Daiichi Sankyo/Lilly).

Coming up ACEs. The HEALL study suggests that in patients unable to take dual ACEI–ARB (angiotensin receptor blocker) therapy, that higher-dose ARB is indicated but judicious monitoring for blood pressure, serum potassium and creatinine is indicated. Whether losartan 150 mg daily would have been superior to losartan 100 mg daily is not known. In blacks, the use of maximum FDA-approved ARB therapy with a hydralazine-nitrate combination is still the evidence-based way to go.

Drugs versus surgery. In the BARI2D study, the benefits of aggressive interventional therapy (PCI or bypass surgery) versus optimal medical management were evaluated in patients with stable ischemic heart disease and type 2 diabetes mellitus. For most patients, aggressive interventional therapy and optimal medical therapy were similarly effective in reducing cardiac death and heart attacks. Patients assigned to aggressive interventional therapy had higher two-year costs ($55,966) compared with patients treated with optimal medical management ($34,096).

In the subpopulation with extensive coronary artery disease (CAD), however, bypass surgery was superior to medical management. The take-home message for pharmacists is that optimal medical therapy is a viable and cost-effective option for most patients if aggressive therapy and patient compliance are achieved. However, this is not commonplace in clinical practice where drugs with proven morbidity and mortality benefit are not used in many patients and dosing is usually suboptimal. Only one-third of U.S. patients are achieving blood pressure and lipid goals. The pharmacist is in the best position to check the lists of medications the patient is receiving and to contact the physician if gaps are found. The pharmacist also is in the best position to reinforce the need for compliance and the expected benefits.

Up the Statins. In the ARBITER 6-HALTS trial, researchers looked at the effects of high-intensity statin therapy used to achieve an LDL below 100 mg/dL, using adjuvant agents such as ezetimibe (Zetia, Merck/Schering Plough) or niacin. Although ezetimibe reduced LDL more than niacin, it was inferior at lowering triglycerides and raising high-density lipoprotein (HDL). This resulted in greater reductions in carotid intima media thickness (IMT; a surrogate for the rate of atherosclerosis) in the niacin-treated patients compared with ezetimibetreated patients. The incidence of major cardiovascular events was lower in the niacin group than in the ezetimibe group (1% vs. 5%; P=0.04).

There are limitations in using carotid IMT to predict what is occurring in the coronary arteries and limitations associated with focusing too much on cardiovascular events because it was not a primary aim of the trial. Even so, this trial confirms that niacin reduces the growth of atherosclerosis and that ezetimibe does not seem to possess the same ability.

Pharmacists first need to ensure that the maximum dose of a statin or maximum tolerated dose is being used before deciding on adjunctive therapy. If patients are still not at their aggressive LDL goal of 60 to 70 mg/dL, pharmacists may wish to talk to their patients with CAD and mixed lipidemias (higher triglycerides and lower HDL) receiving ezetimibe about the potential benefits of extended-release niacin over ezetimibe.

right ventricular (RV)-dominant subgroup and the non–RV-dominant subgroup, indicating a benefit regardless of ventricular morphology.

“We speculate that enhanced ventricular performance may result in improved exercise performance and quality of life,” the researchers concluded.

Dabigatran Safety Data In RE-DEEM In the RE-DEEM study, which explored the safety of four different doses of dabigatran in acute coronary syndrome (ACS) patients on dualplatelet inhibition with aspirin and

clopidogrel (Plavix, Bristol MyersSquibb), investigators reported that use of dabigatran was associated with a low overall bleeding rate.

The oral anticoagulant first came to prominence in early 2009 in Barcelona, Spain, at the European Society of Cardiology, where the RE-LY (Randomized Evaluation of Long-term anticoagulant therapy) trial results showed dabigatran to be more effective than warfarin in preventing stroke in patients with atrial fibrillation (AF), with a risk for bleeding that was equal to that of warfarin.

Here, the RE-DEEM investigators,

led by Jonas Oldgren, MD, PhD, from Uppsala University Hospital, Uppsala, Sweden, randomized patients to four different dabigatran doses or placebo, and followed them for six months for major bleeding as defined by the criteria of the International Society of Thrombosis and Haemostasis. The secondary outcome measure was a composite of cardiovascular death, nonfatal myocardial infarction (MI) or stroke.

Dr. Oldgren reported that major bleeding occurred in two of 371 (0.5%) patients on placebo; three of 369 (0.8%) patients on dabigatran 50 mg twice daily; one of 368 (0.3%) patients on dabigatran 75 mg; eight of 406 (2.0%) patients on dabigatran 110 mg; and four of 347 (1.2%) patients on dabigatran 150 mg.

The rates of the composite of cardiovascular death, nonfatal MI or stroke were as follows: placebo, 3.8% (n=16); dabigatran 50 mg, 4.6% (n=17); dabigatran 75 mg, 4.8% (n=18); dabigatran 110 mg, 3% (n=12); and dabigatran 150 mg, 3.4% (n=12).

Additionally, dabigatran produced a significant 45% reduction in coagulation activity at all doses as indicated by D-dimer levels, Dr. Oldgren reported.

He concluded that using dabigatran in doses up to 150 mg twice a day can be used “with modestly increased bleeding risk” in ACS patients on dualantiplatelet therapy, which is of relevance for AF patients after ACS and stenting. Dr. Oldgren added that the RE-DEEM study supports the rationale for evaluation of the 110- and 150-mg doses on clinical outcomes in a larger, adequately powered study.

RE-DEEM’s official discussant, Elaine Hylek, MD, MPH, from Boston University Medical Center, said that caution was needed in extrapolating these data to an AF population. She also questioned whether clopidogrel was the correct comparator to use in this setting.

“The pivotal question for this and other ACS trials of factor IIa and Xa inhibitors is whether clopidogrel is the right comparator, given the changing landscape with drugs like ticagrelor or prasugrel?”

Dabigatran is being developed by Boehringer Ingelheim, which sponsored the study. Several authors of the study are employees at the company.

PCI-PPI Mortality Link?

In another study, Joseph Sweeny, MD, from Mount Sinai Medical Center in New York City, and colleagues reported that death rates were higher among angioplasty patients who took proton pump inhibitors (PPIs).

“Proton pump inhibitors are frequently co-administered with aspirin and clopidogrel as gastrointestinal prophylaxis

•

see AHA HIGHLIGHTS, page 14

14 Clinical

Pharmacy Practice News • January 2010

Cardiology

AHA HIGHLIGHTS continued from page 13

following percutaneous coronary interventions [PCIs],” Dr. Sweeny said in his presentation. “However, PPIs have been reported to variably inhibit cytochromes P45O [CYP] 3A4 and CYP 2C19, and data suggest they reduce the efficacy of clopidogrel.”

The investigators performed a retrospective cohort study of 8,311 consecutive patients who underwent PCI with drug-eluting stents between April 2003 and June 2007, and who were followed

until June 30, 2008.

Overall, 17% (n=1,385) of the patients were taking PPIs. Rabeprazole (Aciphex,, Esai) was not included in this his analysis due to the low number er of patients (37) on the drug. Over a mean of two years of follow-up, 602 patients died. The mortality rate was higher among patients taking PPIs than those not taking them (53.5 and 33 deaths per 1,000 person-years, respectively).

After multivariable adjustment, the risk for death was 30% higher with PPIs (HR, 1.30; 95% CI, 1.06-1.60). Com-

pared with patients not taking PPIs, the multivariable-adjusted risk among patients taking omeprazole p was wa 72% higher (HR, 1.72; 95% CI, 1.11-2.68) and with pantoprazole, t l it was 54% higher (HR, 1.54; 95% CI, 1.13-2.10). Two other PPIs, esomeprazole and lansoprazole, were not associated with risk.

Use of PPIs was also associated with a nonsignificant increased risk for 30-day stent thrombosis and target lesion revascularization following PCI, Dr. Sweeny reported.

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The day after this presentation, the FDA notified health care professionals of safety concerns about a drug interaction between clopidogrel and omeprazole (see related article, page 15). A statement jointly issued by the American College of Cardiology and the AHA said that the FDA’s statement was not based on any new published, peerreviewed clinical trials showing changes in cardiovascular outcomes, and invited its members to visit http://www. fda.gov/Drugs/DrugSafety/Public HealthAdvisories/ucm110594.htm for the full FDA announcement.

Eat Your (Genetically Modified) Soybeans With fish stocks declining and fears about mercury contamination growing, oil from soybeans modified through biotechnology might be a good source of omega-3 fatty acids, according to a study presented by William Harris, PhD, from Sanford School of Medicine, University of South Dakota, in Sioux Falls.

“We need an alternative plant-based source of omega-3 fatty acids, preferably one that is more effectively converted to eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA] than α-linolenic acid [ALA],” Dr. Harris explained. “Stearidonic acid [SDA] is the product of the rate-limiting enzyme in the conversion of ALA to EPA and, through biotechnology, can be produced at levels of 20% to 30% in soybean oil.” However, it was necessary to determine the extent to which the SDA in this novel soybean oil would raise blood levels of the omega-3 index (red blood cell EPA plus DHA levels) in humans, he said.

Healthy volunteers (N=252) were randomized to one of three groups: treatment with SDA soybean oil, plus 1 g per day soybean oil in gel caps (the SDA treatment group); or to regular soybean oil with either EPA (the EPA group) or 1 g per day soybean oil in gel caps (the control group).

An analysis in 157 subjects showed that about 4 g of SDA soybean oil raised the omega-3 index as much as 1 g of EPA (17.7% with SDA and 19.7% with EPA; P<0.001 for both) versus controls. Red blood cell DHA levels did not change in any group. The relative efficiency of SDA was about 18% that of EPA. SDA soybean oil has the potential to raise omega-3 levels like fish oil omega-3s can, and this should reduce risk for cardiovascular disease, Dr. Harris noted. “I don’t know how much more it will cost than regular soybean oils, but processing is the same,” he said. “No new production facilities or methods are needed. To my understanding, this will be a very practical way of fortifying foods with omega-3.”

—Fran Lowry

Clinical 15

Pharmacy Practice News • January 2010

Drug Interactions

Questions on PPI–Clopidogrel Interaction Keep Coming A

recent warning issued to patients by the FDA has led to an outcry from the medical community. The Nov. 17 statement told patients to avoid taking the combination of omeprazole (Prilosec/ Prilosec OTC, Procter & Gamble) and clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership), even if they separate ingestion of the two medications by up to 12 hours.

Additionally, the FDA noted that esomeprazole (Nexium, AstraZeneca) may have similar interactions with clopidogrel, and that the evidence does not rule out an interaction between other proton pump inhibitors (PPIs) and the anticoagulant.

But several clinicians are questioning whether the interactions have enough clinical relevance to warrant the FDA warning.

Evidence Debatable Some high-quality trials show that omeprazole interferes with clopidogrel’s ability to inhibit platelet aggregation, but others do not. Despite this, an FDA news release accompanying the pronouncement states that omeprazole blocks the CYP2C19 enzyme—which converts the ingested form of clopidogrel into its biologically active form—“thereby reducing the effectiveness of Plavix.”

Many clinicians feel that the federal agency erred in the wording of its pronouncement and should have waited for firmer evidence before determining whether the combination of a PPI and clopidogrel is safe for patients at risk for heart attacks or strokes who use clopidogrel to prevent blood clots.

In an editorial published online a week before the FDA pronouncement, one of the leading authorities on PPIs, Loren Laine, MD, professor of medicine at the Keck School of Medicine of the University of Southern California, Los Angeles, comes to a drastically different conclusion than did FDA officials (Am J Gastroenterol 2009 Nov 10 [Epub ahead of print]): “As the presence of PPIs and clopidogrel in plasma is short-lived, separation by 12 to 20 hours should in theory prevent competitive inhibition of CYP metabolism and minimize any potential, though unproven, clinical interaction,” Dr. Laine and co-author Charles Hennekens, MD, concluded. “The PPI may be [taken] before breakfast and clopidogrel at bedtime, or the PPI may be taken before dinner and clopidogrel at lunchtime.”

Pharmacist’s Perspective Sarah Spinler, PharmD, professor of clinical pharmacy and program coordinator of residency and fellowship at Philadelphia College of Pharmacy,

University of the Sciences, also suggested that the FDA may have overreached with its warning about PPI and clopidogrel interactions.

Dr. Spinler said she does not dispute that omeprazole and esomeprazole reduce the efficiency of the conversion of clopidogrel into its active metabolite.

She also conceded that the available evidence shows that separating ingestion of omeprazole and clopidogrel by 12 hours does not appear to mitigate

this effect. She does, however, question whether this is clinically significant.

Dr. Spinler pointed out that it is difficult to quantify the active metabolite of clopidogrel—this means that it is difficult to assess how much of an impact other medications have on the amount of active clopidogrel.

“There is no gold standard measurement for platelet aggregation inhibition,” Dr. Spinler noted in an e-mail to Pharmacy Practice News. “Some studies measured

the absolute differences between ex vivo platelet aggregation inhibition with the IPA [inhibition of platelet aggregation] assay, which uses an adenosine diphosphate stimulus; these showed differences that were not large—10% or less.”

Moreover, “other studies used the VASP [vasodilator-stimulated phosphoprotein], and these showed differences of about 20% to 30%.” Dr. Spinler also noted that other enzymes also affect the production see CLOPIDOGREL, page 18

16 Clinical

Pharmacy Practice News • January 2010

Cardiology

ENHANCING CARE continued from page 1

pharmacists’ services.

What’s more, another study published in the same issue of Archives (2009;169:20032010) looked at whether a pharmacist-facilitated hospital discharge program could successfully resolve all medication discrepancies, yet failed to reduce the rate of readmissions or subsequent emergency department visits.

Still, an accompanying editorial concluded that the studies, “in the context of available literature, make the case that team-based interventions enhance quality of care and improve clinical outcomes, with mixed effects on medical service use and costs.”

experienced pharmacist review each patient’s records for BP control and treatment and to make drug therapy recommendations faceto-face to physicians based on national guidelines.

At three control offices, pharmacists were available for consultation only if requested by a physician and avoided management of the patients in the control group. The study was designed as an effectiveness trial or a more “real-world” implementation of the intervention.

They found that the mean BP decreased 6.8/4.5 mm Hg in the control group and 20.7/9.7 mm Hg in the intervention group (P<0.05 for betweengroup systolic BP comparison) during the six-month study.

‘Despite the mandate to reconcile medications at discharge, the effects of using a pharmacist may be much smaller than anticipated in real-world settings.’

—Paul C. Walker, PharmD Barry L. Carter, PharmD, the lead author of the BP study, acknowledged that previous papers had shown that the addition of a clinical pharmacist or nurse can improve outcomes in hypertensive patients; indeed, Dr. Carter recently published a meta-analysis of 37 prior controlled trials showing just that (Arch Intern Med 2009;169:1748-1755).

“But many of those studies involved small numbers of patients in one clinic with one pharmacist. Many of the other studies [excluded from] our meta-analysis did not include a control group,” said Dr. Carter, a professor in the Division of Clinical and Administrative Pharmacy at the University of Iowa’s College of Pharmacy in Iowa City. “What we demonstrated in this study, branching it into six clinics with three as control groups, using very structured blood pressure measures by research assistants or nurses and a strong study design, is that the findings are real. They can be translated into community-based clinics.”

The study defined adequate BP control as being less than 130/80 mm Hg for patients with diabetes or kidney disease, and 140/90 mm Hg for others.

Long-Term Commitment Dr. Carter and colleagues evaluated six family medicine residency-training offices that all had employed a clinical pharmacy faculty member for many years. These pharmacists were all residency-trained and experienced ambulatory care practitioners. The study randomized three clinics to have an

Although a smaller randomized trial published last year by Dr. Carter showed a stronger effect of a pharmacist intervention (J Clin Hypertens 2008;10:260271), the study lasted longer (nine months) and was more rigid in how the intervention was implemented. That study was designed as an efficacy trial of the implementation of the intervention under ideal circumstances.

The current study, Dr. Carter said, was “more like what would happen in the real world—we left it up to the clinics to implement the model. We’re doing another study now in 27 clinics around the country called the CAPTION [Collaboration Among Pharmacists and Physicians to Improve Outcomes Now] trial.

This study was funded by the National Institutes for Health for $8.5 million and the design will be to propose the intervention model that we have shown works, but to step back and measure how well each clinic implements the intervention. We will also be studying what happens when the intervention is shut off after nine months in one arm, continued for 24 months in another arm, compared with a control arm.

This study will also evaluate how well the intervention works in high numbers of racial minorities.”

Direct Patient Care Deemed Crucial Michael S. Maddux, PharmD, FCCP, executive director of the American College of Clinical Pharmacy, pointed out that clinical pharmacists in the interventional arm of the Iowa Clinics study

Clinical 17

Pharmacy Practice News • January 2010

Cardiology published in November were actually required to review each patient’s charts and make recommendations when their BP was not being adequately controlled.

“That tells me that it’s not just about having clinical pharmacists available,” Dr. Maddux said. “It’s about having them involved in direct patient management.”

Deborah S. Minor, PharmD, FAHA, a clinical pharmacist who specializes in hypertension control, expressed optimism that the model developed by Dr. Carter could work in other environments.

“We have observed similar control rates using a collaborative model in our hypertension referral clinic population, in a different geographic area with greater racial/ethnic diversity and higher initial blood pressures,” said Dr. Minor, executive vice chair and associate professor in the Department of Medicine, Division of General Internal Medicine/Hypertension, at the University of Mississippi Medical Center in Jackson. (For details on the practice model, see Pharmacy Practice News, July 2009, page 1.)

to discharge, readmission rates did not differ significantly between it and the control group at 14 days (12.6% vs. 11.5%; P=0.65) or 30 days (22.1% vs. 18%; P=0.17), nor did emergency department visits (2.8% vs. 2.2%, respectively; P=0.60).

“Our results have important implications for health care systems struggling to implement strategies to address mandates regarding medication issues at hospital discharge,” concluded the researchers, led by Paul C. Walker, PharmD, clinical associate professor and assistant director of the University of Michigan College of Pharmacy, Ann Arbor.

“In spite of dedicating one full-time pharmacist to this effort, we were unable to have an impact on large numbers of patients,” the paper concluded.

“Despite the mandate to reconcile medications at discharge, the effects of using a pharmacist may be much smaller than anticipated in real-world settings. The lack of effect on health care resource utilization suggests that this may not be a cost-effective use of the pharmacist.”

The accompanying editorial, by Helene Levens Lipton, PhD, professor of health policy and pharmacy in the Department of Clinical Pharmacy at the

University of California, San Francisco’s School of Pharmacy, conceded that clinical pharmacy services might not be widely implemented until their cost effectiveness is demonstrated.

But, she wrote, “Given the mounting evidence of pharmacists’ contributions in improving patient quality of care in team-based practices, a comprehensive effort should be undertaken … to ensure that pharmacists and other appropriate clinicians are included on the team and receive reasonable reimbursement.”

—Dan Hurley

In the treatment of VWD, Humate-P® stands alone

Benefits Elusive Heartening as Dr. Carter’s results were, the other study accompanying it in the Archives failed to find the hoped-for benefits accruing from a medication-reconciliation intervention conducted by pharmacists for patients being discharged from a hospital (2009;169:2003-2010).

The study used a prospective, alternating-month design to compare outcomes of 358 patients receiving the intervention with 366 controls. All patients were being discharged to home and were considered at high risk for medication-related problems due to the number or types of medications prescribed, multiple medication changes during hospitalization or problems managing medications. The intervention consisted of having a clinical pharmacist assess the medication therapy, reconcile discrepancies, screen for adherence concerns, provide patient counseling and education and conduct postdischarge telephone follow-up.

Although all discrepancies were resolved in the intervention group prior

What’s Your View?

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Have pharmacists done an adequate job documenting the value of their clinical services, whether in hypertension clinics or other care settings?

Send replies to

ppneditor@mcmahonmed.com

Humate-P® is the only von Willebrand factor (VWF) concentrate that: In over 20 years and more than one-half billion units infused, there is no documented evidence of viral transmission with Humate-P ®.1

Visit us at www.Humate-P.com

• Is approved for the treatment of von Willebrand disease (VWD) and d the prevention of excessive bleeding during and after surgery • Can be used for prevention of bleeding during and after surgery in all VWD types • Contains high molecular weight multimers of VWF—important for correcting the coagulation defect in patients with VWD1

Close as it gets to normal VWF

Important Safety Information Humate-P® is contraindicated in individuals with a history of anaphylactic or severe systemic response to antihemophilic factor or von Willebrand factor preparations, or to any of its components.

Thromboembolic events have been reported in VWD patients receiving coagulation factor replacement, especially in the setting of known risk factors for thrombosis. Caution should be exercised and antithrombotic measures considered.

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

The most common adverse reactions reported in patients receiving Humate-P® are allergic-anaphylactic reactions, including urticaria, chest tightness, rash, pruritus, edema, shock, chills and fever, and hypervolemia. For patients undergoing surgery, the most common adverse reactions are postoperative wound or injection-site bleeding.

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

Please see brief summary of prescribing information on next page.

Reference: 1. Data on file, CSL Behring LLC. ©2009 CSL Behring LLC, 1020 First Avenue, PO Box 61501, King of Prussia, PA 19406-0901, USA | www.CSLBehring-US.com

IO#09-HUM-009

11/2009

18 Clinical

Pharmacy Practice News • January 2010

Drug Interactions

CLOPIDOGREL continued from page 15

of the active metabolite. However, her most serious objection was to the FDA’s interpretation of the evidence as showing a clear, clinically deleterious interaction between omeprazole and clopidogrel.

Timing of Meals Underscored Maurice Cerulli, MD, program director for gastroenterology and hepatology at Long Island Jewish Medical Center in New Hyde Park, N.Y., and a past president of the New York Society for Gastro-

intestinal Endoscopy, believes that the standard practice of taking omeprazole or other PPIs at breakfast and clopidogrel at night likely obviates any clinically significant interactions.

“I have a number of other concerns [about the FDA warning],” Dr. Cerulli noted in an e-mail response to a query about the FDA statement from Pharmacy Practice News. “My primary worry is that this may cause patients who are currently taking aspirin, Plavix and a PPI for prophylaxis against NSAID [nonsteroidal anti-inflammatory drug]-induced ulcers to stop taking the PPI. This would lead

BRIEF SUMMARY OF PRESCRIBING INFORMATION

CSL Behring

Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized Humate-P Manufactured by: CSL Behring GmbH 35041 Marburg, Germany US License No. 1765

Distributed by: CSL Behring LLC Kankakee, IL 60901 USA

Before prescribing, please consult full prescribing information, a brief summary of which follows.

Some text and references refer to full prescribing information.

INDICATIONS AND USAGE Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P , is indicated in adult patients for treatment and prevention of bleeding in hemophilia A (classical hemophilia). Humate-P is also indicated in adult and pediatric patients with von Willebrand disease for (1) treatment of spontaneous and trauma-induced bleeding episodes and (2) prevention of excessive bleeding during and after surgery. This applies to patients with severe VWD as well as patients with mild to moderate VWD where use of desmopressin is known or suspected to be inadequate.

Controlled clinical trials to evaluate the safety and efficacy of prophylactic dosing with Humate-P to prevent spontaneous bleeding have not been conducted in VWD subjects. Adequate data are not presently available on which to evaluate or to base dosing recommendations in this setting.

CONTRAINDICATIONS Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P , is contraindicated in individuals with a history of anaphylactic or severe systemic response to antihemophilic factor or von Willebrand factor preparations. It is also contraindicated in individuals with a known hypersensitivity to any of its components.

WARNINGS Thromboembolic events have been reported in VWD patients receiving Antihemophilic Factor/von Willebrand Factor Complex replacement therapy, especially in the setting of known risk factors for thrombosis.16,17,18 Early reports might indicate a higher incidence in females. In addition, endogenous high levels of FVIII have also been associated with thrombosis but no causal relationship has been established. In all VWD patients in situations of high thrombotic risk receiving coagulation factor replacement therapy, caution should be exercised and antithrombotic measures should be considered. See also DOSAGE AND ADMINISTRATION. Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P , is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease.

Because Humate-P is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current viral infections and by inactivating and/or removing certain viruses during manufacture. Stringent procedures, utilized at plasma collection centers, plasma testing laboratories, and fractionation facilities are designed to reduce the risk of virus transmission. The primary virus reduction step of the Humate-P manufacturing process is the heat treatment of the purified, stabilized aqueous solution at 60 C for 10 hours (i.e., pasteurization). In addition, the purification procedure, which includes several precipitation steps and an adsorption step, used in the manufacture of Humate-P also provides virus reduction capacity (see DESCRIPTION section for virus reduction factors). Despite these measures, such products may still potentially contain human pathogenic agents, including those not yet known or identified. Thus the risk of transmission of infectious agents cannot be totally eliminated. Any infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to CSL Behring at 1-800-504-5434 (in the U.S. and Canada). The physician should discuss the risks and benefits of this product with the patient.

PRECAUTIONS It is important to determine that the coagulation disorder is caused by factor VIII or VWF deficiency, since no benefit in treating other deficiencies can be expected.

Thromboembolic events have been reported in VWD patients receiving coagulation factor replacement therapy, especially in the setting of known risk factors for thrombosis. In these patients, caution should be exercised and antithrombotic measures should be considered.

As a precaution, the administration equipment and any unused Humate-P should be discarded after use.

Information for Patients Some viruses, such as parvovirus B19 or hepatitis A, are particularly difficult to remove or inactivate at this time.

Parvovirus B19 may most seriously affect pregnant women, or immune-compromised individuals.

Although the overwhelming number of hepatitis A and parvovirus B19 cases are community acquired, there have been reports of these infections associated with the use of some plasma-derived products. Therefore, physicians should be alert to the potential symptoms of parvovirus B19 and hepatitis A infections and inform patients under their supervision receiving plasma-derived products to report potential symptoms promptly.

Symptoms of parvovirus B19 may include low-grade fever, rash, arthralgias and transient symmetric, nondestructive arthritis. Diagnosis is often established by measuring B19 specific IgM and IgG antibodies. Symptoms of hepatitis A include low grade fever, anorexia, nausea, vomiting, fatigue and jaundice. A diagnosis may be established by determination of specific IgM antibodies.

Laboratory Tests Antihemophilic Factor/von Willebrand Factor (Human), Dried, Pasteurized, Humate-P , contains blood group isoagglutinins (anti-A and anti-B). When very large or frequently repeated doses are needed, as when inhibitors are present or when pre- and post-surgical care is involved, patients of blood groups A, B and AB should be monitored for signs of intravascular hemolysis and decreasing hematocrit values and be treated appropriately, as required.

The Factor VIII levels of VWD patients receiving Humate-P should be monitored using standard coagulation tests, especially in cases of surgery. Strong consideration should also be given to monitoring VWF:RCo levels in VWD patients receiving Humate-P for the prevention of excessive bleeding during and after surgery. It is advisable to monitor trough VWF:RCo and FVIII:C levels at least once daily in order to adjust the dosage of Humate-P as needed to avoid excessive accumulation of coagulation factors (see DOSAGE AND ADMINISTRATION).

Pregnancy Category C Animal reproduction studies have not been conducted with Antihemophilic Factor/von Willebrand Factor (Human).

It is also not known whether Humate-P can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Humate-P should be given to a pregnant woman only if clearly needed.

Pediatric Use Hemophilia A Adequate and well-controlled studies with long-term evaluation of joint damage have not been done in pediatric subjects. Joint damage may result from suboptimal treatment of hemarthroses. For immediate control of bleeding for Hemophilia A, the general recommendations for dosing and administration for adults, found in the DOSAGE AND ADMINISTRATION section, may be referenced.

Von Willebrand Disease The safety and effectiveness of Humate-P for the treatment of von Willebrand disease was demonstrated in 26 pediatric subjects, including infants, children and adolescents but has not been evaluated in neonates. The safety of Humate-P for the prevention of excessive bleeding during and after surgery was demonstrated in 8 pediatric subjects (ages 3 through 15) with VWD. Of the 34 pediatric subjects studied for both treatment of VWD and prevention of excessive bleeding during and after surgery, four were infants (1 month to under 2 years of age), 23 were children (2 through 12 years), and 7 were adolescents (13 through 15 years).

As in adults, pediatric patients should be dosed based upon weight (kg) in accordance with information in the DOSAGE AND ADMINISTRATION section.

Geriatric Use Clinical studies of Humate-P® did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. As for all patients, dosing for geriatric patients should be appropriate to their overall situation.

ADVERSE REACTIONS The most serious adverse reaction observed in patients receiving Antihemophilic Factor/von Willebrand Factor Complex (Human), Dried, Pasteurized, Humate-P®, is anaphylaxis. Thromboembolic events have also been observed in patients receiving Humate-P® for the treatment of VWD (see WARNINGS). Reports of thromboembolic events in VWD patients with other thrombotic risk factors receiving coagulation factor replacement therapy have been obtained from spontaneous reports, published literature, and a European clinical study. Early reports might indicate a higher incidence in females. In some cases, inhibitors to coagulation factors may occur. However, no inhibitor formation was observed in any of the clinical trials.

Although few adverse reactions have been reported in clinical studies and in the postmarketing setting in patients receiving Humate-P® for treatment of hemophilia A and VWD, the most commonly reported are allergic-anaphylactic reactions (including urticaria, chest tightness, rash, pruritus, edema, and shock). For patients undergoing surgery, the most common adverse reactions are postoperative wound or injection-site bleeding.

‘I would want to see a large enough clinical trial with a PPI less dependent on metabolism by CYP2C19 [than omeprazole] before I can come to any conclusion.’

—Sarah A. Spinler, PharmD to an increased risk for ulcer hemorrhage, which in turn can cause hypotension, reduced blood flow to the heart, a heart attack and death or hospitalization.

The scenario of ulcer hemorrhage due to aspirin and Plavix is common in hospitals across the country.”

There has been only one prospective study of the omeprazole–clopi-

Adverse Reactions in Clinical Trials Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. von Willebrand Disease Treatment of VWD Allergic symptoms, including allergic reaction, urticaria, chest tightness, rash, pruritus, and edema, were reported in 6 of 97 (6%) subjects in a Canadian retrospective study. Four of 97 (4%) subjects experienced seven adverse events that were considered to have a possible or probable relationship to the product. These included chills, phlebitis, vasodilation, paresthesia, pruritus, rash, and urticaria. All were mild in intensity with the exception of a moderate case of pruritus.

In a prospective, open-label safety and efficacy study of Humate-P® in VWD subjects with serious life- or limbthreatening bleeding or undergoing emergency surgery, seven of 71 (10%) subjects experienced nine adverse reactions. These were mild vasodilation (1/9), allergic reactions (2/9), pruritus (1/9), and paresthesia (2/9); moderate peripheral edema (1/9) and extremity pain (1/9); and severe pseudothrombocytopenia (platelet clumping with a false low reading) (1/9). Humate-P® was discontinued in the subject who experienced the peripheral edema and extremity pain.

VWD Subjects Undergoing Surgery Among the 63 VWD subjects who received Humate-P for prevention of excessive bleeding during and after surgery, including 1 subject who underwent colonoscopy without the planned polypectomy, the most common adverse events were postoperative hemorrhage (35 events in 19 subjects with five subjects experiencing bleeding at up to three different sites), postoperative nausea (15 subjects), and postoperative pain (11 subjects). Postoperative hemorrhagic adverse events are shown in Table 7.

Table 7: Hemorrhagic Adverse Events in 63 Surgical Subjects Adverse Event

Surgical Procedure Category

Number of Subjects/ Events

Onset* (Number of Events) Post

Mild

Mod

Major

8/11

7

4

9

–

2

Minor Oral Major Minor

2/2 2/6 4/4 1/1

2 – 2 1

– 6 2 –

1 3 3 1

1 3 1 –

– – –

Cerebral hemorrhage/ subdural hematoma Gastrointestinal bleeding Menorrhagia Groin bleed Ear bleed Hemoptysis Hematuria

Major

1/2

2#

–

–

2

–

Major

1/3

§

3

–

–

2

1

Major Oral Major Major Major

1/1 1/1 1/1 1/1 1/1

1+ – 1 1 1

– 1 – – –

– 1 1 1 1

1 – – – –

– – – – –

Shoulder bleed

Major

1/1

1

–

1

–

–

On Wound/injection site bleeding

Epistaxis

* # § +

Severity (Number of Events)

Severe

On = on-therapy; onset while receiving Humate-P or within 1 day of completing Humate-P administration.

Post = post-therapy; onset at least one day after completing Humate-P administration Reported as serious adverse events after intracranial surgery Two of these events reported as serious adverse events occurring after gastrojejunal bypass Reported as serious adverse event requiring hysterectomy after hysteroscopy and dilation and curettage

Table 8 lists the non-hemorrhagic adverse events reported in at least two subjects, regardless of causality, and the adverse events that were possibly related to Humate-P . Pulmonary embolus that was considered possibly related to Humate-P occurred in one elderly subject who underwent bilateral knee replacement.

Table 8: Non-Hemorrhagic and Possibly Related Adverse Events (AE) in 63 Surgical Subjects Body System

Body as a Whole

Cardiovascular

Digestive

Hemic and Lymphatic System Metabolic/Nutritional Nervous

Skin and Appendages Urogenital

Adverse Event

Pain Fever Abdominal Pain Infection Surgery Back Pain Facial Edema Chest Pain Pulmonary Embolus# Thrombophlebitis# Nausea Constipation Vomiting Sore Throat Anemia / Decreased Hemoglobin Increased SGPT Dizziness Headache Increased Sweating Insomnia Pruritus Rash Urinary Retention Urinary Tract Infection

Number of Subjects with an AE Possibly Related to Humate-P® – – – – – – – – 1 1 1 – 1 –

Number of Subjects with an AE Regardless of Causality* 11 4 3 3 3 2 2 3 1 1 15 7 3 2

–

2

1 1 1 – – – 1 – –

1 5 4 3 2 3 1 4 2

* Occurring in two or more subjects # These events occurred in separate subjects

Eight subjects experienced 10 postoperative serious adverse events: one with subdural hematoma and intracerebral bleeding following intracranial surgery related to an underlying cerebrovascular abnormality; one with two occurrences of gastrointestinal bleeding following gastrojejunal bypass; and one each with sepsis, facial edema, infection, menorrhagia requiring hysterectomy following hysteroscopy and dilation and curettage, pyelonephritis, and pulmonary embolus.

Postmarketing Experience The following adverse reactions have been identified during postapproval use of Humate-P®.

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 Humate-P® exposure.

Adverse reactions reported in patients receiving Humate-P® for treatment of VWD or hemophilia A are allergicanaphylactic reactions (including urticaria, chest tightness, rash, pruritus, edema, and shock), development of inhibitors to Factor VIII, and hemolysis. Additional adverse reactions reported for VWD are thromboembolic complications, chills and fever, and hypervolemia.

Evaluation and interpretation of these postmarketing events is confounded by underlying diagnoses, concomitant medications, pre-existing conditions, and inherent limitations of passive surveillance.

Healthcare professionals should report serious adverse events possibly associated with the use of Humate-P® to CSL Behring at 1-800-504-5434 or FDA’s MedWatch reporting system at 1-800-FDA-1088.

Adapted from October 2007 revision.

dogrel interaction: the COGENT trial.

Partial results of the trial were presented by Deepak Bhatt, MD, MPH, at the Transcatheter Cardiovascular Therapeutics conference in September 2009. This Phase III trial—which was halted prematurely when the sponsor, Cogentus Pharmaceuticals (Palo Alto, Calif.) declared bankruptcy—was designed to assess the effects of oncedaily administration of the investigational combination of clopidogrel 75 mg and omeprazole 20 mg or placebo in patients requiring treatment with clopidogrel for at least 12 months.

There were no significant differences between the two groups regarding rates of all cardiovascular events (69, clopidogrel–omeprazole group; 67, placebo group), heart attack alone or revascularization alone. There was a higher rate of gastrointestinal events in the placebo group.

“In my opinion, the trial was too short to be able to draw any conclusions from it,” commented Dr. Spinler. “In addition, the study was not powered to detect differences in cardiovascular event rates but, rather, gastrointestinal events, and the CV [cardiovascular] events reported in the trial were few in number.”

What About Other PPIs? Concerning possible interactions of clopidogrel with other PPIs, Dr. Spinler noted that there is no conclusive evidence of this to date. “I would want to see a large enough clinical trial with a PPI less dependent on metabolism by CYP2C19 [than omeprazole] before I can come to any conclusion,” she said.

Dr. Cerulli agreed that the jury is still out on other PPIs. He added that “not all PPIs are metabolized the same way. For example, pantoprazole is metabolized by a different pathway and hence should not interact with Plavix.”

M. Brian Fennerty, MD, president-elect of the American Society for Gastrointestinal Endoscopy, suggested that physicians continue to use their own judgment in deciding whether to prescribe a PPI to patients taking clopidogrel.

“Gastroenterologists need to be aware of this FDA warning but should take into account patient-specific risk factors—including why the PPI is being prescribed and risks to the patient if they do not use a PPI—as well as the totality of the available clinical data in reaching a recommendation on use of PPIs in patients also taking clopidogrel.”

—Rosemary Frei, MSc

Hem/Onc Pharmacy 19

Pharmacy Practice News â&#x20AC;˘ January 2010

In Focus For indolent lymphomas:

Bendamustine-R Is Potential New Standard New Orleansâ&#x20AC;&#x201D;The combination of bendamustine (Treanda, Cephalon) and rituximab (Rituxan, Biogen Idec/ Genentech) is better tolerated and more effective than the current standard of CHOP-R (cyclophosphamide, hydroxydaunorubicin, Oncovin and prednisolone plus rituximab) for the treatment of indolent lymphomas, according to the results of a large, Phase III multicenter study.

The greater efficacy was somewhat unexpected; the researchers had anticipated similar efficacy with greater tolerability. â&#x20AC;&#x153;These promising results suggest that the combination of bendamustine and rituximab [bendamustine-R] has the potential to become the new standard, first-line treatment option for patients with these non-Hodgkinâ&#x20AC;&#x2122;s lymphoma entities,â&#x20AC;? said Mathias J. Rummel, MD, PhD, head of the Department of Hematology, University Hospital, Giessen, Germany. Presenting these results on behalf of Studiengruppe Indolente Lymphoma at the annual meeting of the American Society of Hematology (ASH; abstract 405), Dr. Rummel said the study did not just suggest comparable efficacy, but â&#x20AC;&#x153;clear, statistically significant superiority for a better-tolerated regimen.â&#x20AC;?

The study found that the overall response rates were similar in the two arms, but in patients who received bendamustine-R, there were a greater number of complete responses (CRs) and progression-free survival (PFS) was extended.

Although the data are impressive, both Dr. Rummel and the co-chairman of the Scientific Program Committee for this yearâ&#x20AC;&#x2122;s ASH meeting, Richard A. Van Etten, MD, PhD, were careful to describe the data not as practice changing but as â&#x20AC;&#x153;potentiallyâ&#x20AC;? practice changing. This caution, despite a Phase III study that clearly showed both an efficacy and a safety advantage, was explained by Dr. Van Etten, chief of the Division of Hematology and Oncology at Tufts Medical Center, Boston. He clarified that both experts and regulating agencies are reluctant to declare any therapy as first-line on the basis of PFS alone. â&#x20AC;&#x153;In oncology, what we ideally want to see is [an overall] survival advantage for a therapy that is identified as a new standard,â&#x20AC;? Dr. Van Etten commented. Although he agreed that the results were compelling, he indicated that there are a number of additional steps in the process, including longer follow-up and publication of the data, which would be necessary for changing the characterization of bendamustine-R from a potential to an established firstline therapy.

â&#x20AC;&#x153;I think these data are very exciting; if we can improve response and minimize toxicity, then our patients may benefit in both ways.â&#x20AC;?

â&#x20AC;&#x201D;LeAnne Kennedy, PharmD

Study Detailed In the study, conducted at 82 centers in Germany, patients with a relapsed or refractory indolent lymphoma (follicular, marginal zone, WaldenstrĂśms or small lymphocytic) or mantle cell cancer were randomized to the conventional CHOP-R regimen given on a 21-day schedule or to a regimen on a 28-day schedule that combined 90 mg/m2 bendamustine on days 1 and 2 with 375 mg/m2 rituximab on day 1. The median age of the study population was 65 years. Relevant characteristics, including age, stage, bone marrow infiltration and extranodal involvement, were comparable between the groups. The primary outcome was PFS, but safety and tolerability also were monitored closely.

Overall response rates over a median observation time of 32 months and a median of six treatment cycles in both groups were almost identicalâ&#x20AC;&#x201D;92.7% for bendamustine-R and 91.3% for CHOP-R. However, the quality of the response was better with bendamustine-R, including a greater number of CR (39.6% vs. 30%; P=0.03). More importantly, the PFS was two years longer in patients on bendamustine-R relative to CHOP-R (54.9 vs. 30 months; P=0.0002). The efficacy advantage was reinforced by other data showing that the bendamustine-R arm was superior including longer time to next treatment (not yet reached on bendamustine-R vs. 46 months on CHOP-R; P=0.0002) and event-free survival (54 vs.

31 months; P=0.0002). In the follow-up so far, there has been a similar number of deaths in each arm, so overall survival has not differed.

When efficacy was assessed separately in those with follicular lymphoma, which represented 54% of the study population, the relative advantage of bendamustine-R over CHOP-R was consistent with that observed for the whole population. For example, the median time to PFS has not yet been reached in those randomized to bendamustine-R versus 46 months in those who received CHOP-R.

effects. Most grade 3 and 4 hematologic side effects, including neutropenia (10.7% vs. 46.5%; P<0.0001) and leukocytopenia (12.1% vs. 38.2%; P<0.0001) were far less common with bendamustine-R. Those on bendamustine-R were also less likely to receive granulocyte colony-stimulating factor than those on CHOP-R. The lower rate of cytopenias is likely to explain the lower rate of infectious complications in the bendamustine-R arm (P=0.04).

Whereas almost all patients on the CHOP-R regimen had hair loss, there was no hair loss in patients on bendamustine-R more severe than grade 1.

Peripheral neuropathy (P<0.0001) and stomatitis (P<0.0001) also were significantly less common with bendamustine-R. The only side effects more

common with bendamustine-R were erythematous skin reactions (P=0.01).

Although CHOP-R remains the standard of care for aggressive lymphomas in which there is potential for cancer remission, a better-tolerated therapy for indolent lymphomas, which are considered incurable, has major clinical advantages. The authors emphasized that it is particularly important for noncurative treatments to extend survival with an acceptable quality of life.

Pharmacistâ&#x20AC;&#x2122;s Perspective Asked for her comment, LeAnne Kennedy, PharmD, pharmaceutical care coordinator, hematology and oncology, Baptist Medical Center, Wake Forest University, in Winston-Salem, N.C., said that she was encouraged. â&#x20AC;&#x153;I think these data are very exciting; if we can improve response and minimize toxicity, then our patients may benefit in both ways,â&#x20AC;? Dr. Kennedy said. However, â&#x20AC;&#x153;it will be interesting to see if the insurance companies respond with appropriate payment.â&#x20AC;? â&#x20AC;&#x201D;Ted Bosworth

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20

Hem/Onc Pharmacy

Pharmacy Practice News • January 2010

In Focus Contaminated vial

CYTOTOXIC continued from page 1

of medicine and director of the University of Maryland School of Medicine’s Occupational Health Program, in Baltimore. Some of these drugs, she noted, “came out of chemical/biological warfare from World War I. If that doesn’t get our respect, I don’t know what does.”

The studies—one a National Institute for Occupational Safety and Health (NIOSH) investigation conducted at three facilities, another done at Massachusetts General Hospital (MGH) in Boston and the third, a subanalysis of the main NIOSH study—underscore the need for stepped-up efforts to address the contamination and better protect workers. The studies provide an extensive amount of new data about problem areas, particularly surface contamination, that are leading to biologically important exposures for health care workers.

Comprehensive Study The main NIOSH study was designed to provide “a comprehensive evaluation of the workplace and the potential sources of exposure,” said lead investigator Thomas H. Connor, PhD, a research biologist at NIOSH. Dr. Connor noted that other studies have been done on cytotoxic contamination, but none has looked at the issue in such a comprehensive manner. Dr. McDiarmid, who was a co-investigator on the trial, added, “We had about 10,000 handling events, which really helps our power.”

The NIOSH-led team evaluated three sites—University of Maryland Medical Center, in Baltimore; University of North Carolina Memorial Hospitals, in Chapel Hill; and the University of Texas M.D. Anderson Cancer Center, in Houston—and looked for contamination from five commonly used chemotherapeutic agents—cyclophosphamide, cytarabine, 5-fluorouracil (5-FU), ifosfamide and paclitaxel.

To determine exposure, the investigators had exposed workers at the sites (pharmacists, pharmacy technicians, nurses and nursing aides) complete a sixweek drug-handling diary listing all the drugs handled and the specific tasks performed. They performed wipe samples of surfaces, took air samples and collected urine samples from the workers, comparing them with a matched control population. The samples were taken from biological safety cabinets, counter tops, waste containers, drug trays, passthrough windows, floors, patient rooms, nursing stations, IV bags and other areas.

In addition to taking air samples from pharmacy areas, the investigators outfitted health care workers with air-collection devices to obtain personal air samples that would assess the air the

Contaminated final product Passive transfer Active transfer

Contamination of the environment

RN contamination

Figure. Sources of cytotoxic contamination.

worker was inhaling for a given period.

They also performed single-cell gel electrophoresis tests (also known as comet assays) to measure DNA damage.

For each worker, they evaluated variables including exposure, the number of handling events for all five agents combined and separately, the mutagenicity of the drugs handled, the use of personal protective equipment (PPE), and the use of closed-system transfer devices (CSTDs).

They used liquid chromatographytandem mass spectroscopy (LC/MS/ MS) techniques to analyze the samples, which Dr. Connor noted have been validated in studies to be highly specific and sensitive for detecting the five drugs being evaluated.

Substantial Contamination Found The NIOSH results show that “surface contamination is still an issue in pharmacy and nursing areas,” with pharmacy areas generally having “more positive samples and higher values than nursing [areas].” Defining the limit of detection (LOD) as 1 ng/cm2 for cyclophosphamide, cytarabine and ifosfamide, and 0.7 for 5-FU and paclitaxel, they found that of the 80 wipe samples taken from pharmacy areas, 75% had values above the LOD for at least one of the five drugs. Of the 65 nursing samples, 42% had values above the LOD for at least one drug.

In addition to a high number of contaminated samples, the degree of contamination from some of the wipe samples was significant (Table). “There were excursions of some values that were really quite substantial,” said Dr. Connor.

He noted that at one of the sites, there was “some contamination uncovered in an adjoining office area.” Additionally, two pharmacists at that site were found to have “measurable levels of cyclophosphamide in their urine.” Dr. Connor said

that this site did have some flaws in its design, in that the drug preparation area was open to an office area and it had no clean-room design with an anteroom or pass-through windows. The design of the site has since been rectified and a clean room has been added.

At another of the sites, the highest contamination found—910 ng/cm2 of 5-FU—came from a waste container lid in a nursing station. Noting that they also detected a high level of ifosfamide on that waste container (19.8 ng/cm2), Dr. Connor speculated that there was “probably some breakdown of work practice at this nursing station.”

Their findings indicated that some of these agents could linger for prolonged periods of time. In one spot, they detected cyclophosphamide in floor tiles six months after a spill. “These drugs, especially cyclophosphamide and ifosfamide, can get into the flooring material and just stay there,” Dr. Connor said. “They probably penetrate the material.”

The results indicate that such spills might be prevented with CSTDs. At sites 1 and 2 (Maryland and North Carolina), where CSTDs were not used, 108 spills were reported during the 4,422 handling events that occurred. In contrast, at site 3 (Texas), where CSTDs were used, no spills were reported during the 5,223 handling events.

Dr. Connor acknowledged that the investigators only sampled five drugs, so they don’t know for sure what’s going on with the other 100 or so other antineoplastic agents “that are out there,” but he said he assumes the study findings hold for the drugs that were not sampled.

Massachusetts Study The MGH study was prompted by a need for information on the relative value of CSTDs in reducing environmental contamination and employee risk of exposure. An MGH task force was

formed in mid 2007 to explore the merits of the closed-system devices. Speaking on behalf of the task force, Sami Ahmed, PharmD, clinical lead oncology pharmacist at MGH, said his colleagues looked at the problem of contamination “from loading dock to loading dock” to assess the “global exposure and the risk to all employees.” They wanted to determine how the contamination moves from place to place within the institution. The investigators looked at residues from 10 hazardus drugs and found widespread, low-level contamination from all 10 agents.

Using a validated standardized procedure for sampling, they took hundreds of environmental samples, evaluating for the presence of cyclophosphamide, docetaxel, doxorubicin, etoposide, 5-FU, gemcitabine, ifosfamide, irinotecan, methotrexate and paclitaxel. They used LC/MS and flame-atomic absorption spectrometry methods to analyze the various samples.

The MGH team found “low levels of contamination across the entire chain of custody,” said Dr. Ahmed. As in the NIOSH study, contaminated residues migrated from preparation and administration areas. Dr. Ahmed noted that keyboards 50 feet away from hazardous drug preparation and administration areas, elevator buttons 200 to 300 feet away from such areas and pumps sent home with patients were found to be contaminated. “This was truly a global problem within our institution,” he said.

At their first sampling, in June 2007, the investigators took 148 samples of final IV products and found 104 (70%) to be positive for contamination. They also found significant cross contamination; 47 of the 104 contaminated samples (45%) were positive for drugs not inside the container. In a later test of 45 samples done in June 2009, contamination was found on 80% of final product containers and 14% of transport containers.

The findings suggested two possible methods of contamination—active transfer “related to a breach in technique or protocol,” and passive transfer “related to proper handling of assumed clean but contaminated products.”

There are numerous points where contamination occurs throughout the chain of custody (Figure), said Dr. Ahmed. “The major source of contamination,” he added, “was employee’s hands.” Pointing to workers’ overreliance on gloves, he said that gloves “do not have magical powers.”

If not used properly, gloves may help to transmit contamination.

Contaminated Containers MGH investigators also sampled the outside of manufacturers’ vials of all 10 agents to assess contamination. Of the 79 samples, 77% were contaminated on the exterior of the vial; for all 10 agents, at least some and in some cases all of

Hem/Onc Pharmacy 21

Pharmacy Practice News • January 2010

In Focus the vials sampled tested positive. “If the vial is contaminated, then whatever the technician touches becomes contaminated,” cautioned Dr. Ahmed, noting that the FDA does not require that the outside of the vials be clean.

Audience members expressed concern about the issue of contamination on the outside of containers from manufacturers during the question-and-answer session. One attendee asked the presenters whether there were any initiatives to pressure the FDA to tighten regulations and require that manufacturers clean the outside of containers.

In response, Dr. Connor noted that he had presented the results of three studies assessing surface contamination of drug vials in 2005 (Pharmacy Practice News, March 2005, page 1; Am J Health Syst Pharm 62:475-484). At that time, Dr. Connor and his colleagues reported that the results of the studies “clearly show that surface contamination exists on commercially available vials of cyclophosphamide, ifosfamide, fluorouracil and cisplatin available in the United States and Europe.” They suggested, “contamination can be reduced by using decontamination equipment and protective sleeves during the manufacturing process.”

Thus, the data are there, Dr. Connor said. “We’ve shown it, Mass General has shown it, other studies have shown it.

It’s a problem that’s not going away.”

Dr. Connor said a study conducted by Rudolf Schierl, PhD, of the University of Munich, which is expected to be published in American Journal of HealthSystem Pharmacy in early 2010, is “going to document it even more.”

Luci Power, MS, RPh, senior pharmacy consultant at Power Enterprises, who moderated the ASHP session, wrote an editorial on vial contamination that accompanied Dr. Connor’s earlier study (Am J Health Syst Pharm 2005;62:471), urging pharmacists to pressure manufacturers to clean up the outside of containers. “As pharmacy generally sees to the purchasing of drugs, it is pharmacy’s responsibility to demand clean vials,” she wrote. “We must tell distributors, manufacturers, purchasing groups, professional societies and all other pertinent parties that we are aware of this contamination and that it is unacceptable. We must use our collective influence to pressure manufacturers to address and correct this problem. Changes in drug manufacturing processes are not inexpensive, and manufacturers are unlikely to undertake the needed changes without this pressure.”

Commenting on the issue of contamination on the outside of cytotoxic drug vials to Pharmacy Practice News, Burkhard Wichert, MD, vice president of manufacturing oncology at Baxter Healthcare Corp., noted that “several decades ago, Baxter was the first company to initiate outside cleaning of vials to reduce

contamination prior to delivery to health care facilities. Since then, our extremely thorough cleansing processes have become known to be among the best in the industry. But we continually evaluate our processes, identifying new techniques and technologies to further reduce residue. For example, we are investigating the addition of a protective cover that may be applied to the vials once they have been cleaned to further reduce outside residue.”

Dr. Connor told Pharmacy Practice News that such protective sleeves are “probably a good approach to help reduce contamination,” but he added that the contamination “should not be there in the first place.”

Dr. Wichert maintained that it is difficult to ensure that there is no contamination on the vials. “While we work hard to minimize contamination in our manufacturing process and continually implement new cleaning strategies, we cannot guarantee that cytotoxic drug vials will be completely clear of residue. …

There are myriad points of contact with these vials before they reach the hospitals and pharmacies, and once they leave our facilities, we are unable to control all potential contaminating factors.”

Site 2

Site 3

Cyclophosphamide 7.95/0.70

143/16

9.52/0.47

Cytarabine

20.6/1.33

9.18/0.53

0

mosomal abnormalities, they found that for each handling event, there was a statistically significant increased frequency of damage to chromosome 5 or 7 (P=0.01) and an increased frequency of damage to chromosome 5 alone (P=0.01).

When they looked specifically at handling events with alkylating agents (cyclophosphamide and ifosfamide), they also found a statistically significant increased frequency of damage to chromosome 5 or 7 (P=0.001) and to chromosome 5 alone (P=0.01). In fact, said Dr. McDiarmid, they observed a “fivefold increase in the absolute value of the effect estimate” (the estimate of the insult to chromosomes 5 or 7) for each handling event with alkylating agents compared with all agents.

She concluded, “We are seeing specific types of lesions that … are the signature lesions seen in therapy-related myelodysplastic syndrome and therapyrelated AML, and we’re clearly seeing a dose response, [with] this additional spike in the effect estimate when we look at alkylating agent handling alone.”

The data from these studies, which have been submitted for publication, show that “biologically important exposure to genotoxic drugs is occurring in oncology work settings despite hospital endorsement of safe handling,” concluded Dr. McDiarmid. The bottom line, she said, is that “there is exposure taking place and [these drugs] are getting into people’s bodies. We have this biological progression of evidence here, and we really do need to pay attention.”

Dr. Connor also commented that he recently reviewed the studies conducted worldwide between 1990 and 2009 looking at genetic damage in pharmacists and nurses. He said, “About two-thirds of those show a significant increase in whatever marker they were using for genetic damage in those workers.”

Noting that many of the studies were done in countries in which worker safety standards are not as high as in the United States, he said, “it’s a good indication that there is a risk if you are not following proper procedures in the handling of these drugs.”

5-fluorouracil

2.05/0.19

1.95/0.13

3.47/0.53

Steps To Address the Problem

Ifosfamide

1.41/0.09

6.03/0.65

2.41/0.08

Paclitaxel

0

1.28/0.15

0.43/0.08

Although they acknowledged that improvements have been made since problems with cytotoxic drugs were revealed in the 1970s, the presenters said that in light of the recent findings, it is clear that more needs to be done. In Dr. Connor’s view, “we need good training, retraining, administrative controls, better work practices, in addition to better engineering controls, PPE and the like.”

One recommendation he made related to the importance of proper design. “You really need some type of clean-room technology with an anteroom, with the

Biological Effects of Exposure Although the NIOSH and MGH studies highlight how extensive contamination from hazardous drugs is, they leave open the question of what it means to the exposed workers. Dr. McDiarmid

and her colleagues went a step further and conducted a subanalysis of the NIOSH study at the Maryland site on the chromosomal effects of the five agents they studied.

They largely used the six-week drughandling diary to measure exposures.

Unlike other studies, Dr. McDiarmid looked at signature fingerprint lesions, “the end points that are searched for in therapy-related malignancies [such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML)] and new leukemia patients … to scout out the potential end points that we should be looking at in exposed oncology workers who are underprotected.”

Dr. McDiarmid and her colleagues used fluorescent in situ hybridization (FISH) to evaluate the DNA from the exposed workers, looking for abnormalities in chromosomes 5, 7 and 11, the most common abnormalities found in patients with therapy-mediated MDS or AML. The exposed workers had between one and 918 handling events (mean, 153 events). Comparing those with low levels of exposure (1 to 153 handling events) to those with high levels of exposure (>153 handling events), they found that some differences in DNA damage “are starting to show up,” said Dr. McDiarmid. Although the results were not significant, “it looks like there’s a potential dose response,” she said.

When the Maryland investigators went a step further and assessed the contribution of drug-handling frequency to chro-

Table. Results of Surface Wipe Samples Pharmacy Concentration Maximum/Mean, ng/cm2 Drug

Site 1

Nursing Drug

Concentration Maximum/Mean, ng/cm2 Site 1

Site 2

Site 3

Cyclophosphamide

0.11/0.01

1.42/0.12

0.45/0.07

Cytarabine

0

0

0

5-fluorouracil

1.90/0.08

0

910/35.4

Ifosfamide

1.36/0.05

0.19/0.01

19.8/0.85

Paclitaxel

0

0

0.23/0.01

•

see CYTOTOXIC, page 22

Hem/Onc Pharmacy

Pharmacy Practice News • January 2010

In Focus

Second-line Bevacizumab Plus Chemo Works in MBC San Antonio—The first study to evaluate the addition of bevacizumab (Avastin, Genentech) to chemotherapy as second-line therapy for patients with metastatic breast cancer (MBC) has revealed that the combination improves progression-free survival (PFS).

But the lack of improvement in overall survival, coupled with significant toxicities, has at least one hematology/oncology pharmacist urging caution when interpreting the results or making any changes to clinical practice.

The Phase III RIBBON-2 study included 684 women with MBC who progressed on first-line chemotherapy. The women were randomized 2:1 to receive either chemotherapy plus bevacizumab or chemotherapy alone and were treated until disease progression. They received chemotherapy of the investigators’ choice—44% received a taxane, 23% received gemcitabine (Gemzar, Eli Lilly), 21% received capecitabine (Xeloda, Roche) and 12% received vinorelbine.

Treatment arms were well balanced for demographic and disease characteristics. Median age was 55 years. A slight imbalance was observed for patients with triple-negative breast cancer (estrogen receptor-negative, progesterone receptor–negative, and HER2-negative): 20% in the chemotherapy arm

and 24% in the bevacizumab-containing arm.

For the primary end point of PFS, the addition of bevacizumab resulted in a highly statistically significant 22% improvement from a median of 5.1 months with chemotherapy alone to 7.2 months with the addition of bevacizumab (P=0.0072). An exploratory analysis that looked at PFS results according to type of chemotherapy received suggested that the choice of chemotherapy matters.

“As a class, there was a benefit with taxanes and with capecitabine,” said Adam Brufsky, MD, co-director of the Comprehensive Breast Cancer Center and medical director at the Magee-Women’s Hospital, University of Pittsburgh Cancer Institute. He discussed the results at the recent San Antonio Breast Cancer Symposium (SABCS; abstract 42). Currently, subsequent chemotherapy or hormone therapy is the only FDA-approved option for second-line treatment of advanced human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

Response rates were also much higher with the addition of bevacizumab.

Overall response rates were 39.5% with the combination therapy versus 29.6% with chemotherapy alone. No difference in overall survival was seen in this

CYTOTOXIC

the chain of custody to ensure that their new approaches are working.

Dr. Ahmed said there has to be a cultural change in that PPE is viewed as community protective equipment. “We need to care about all people in the environment and what is good for me should be good for all. All persons handling hazardous drugs have a responsibility to understand the guiding principles of safe handling.” He stressed that transparency and staff participation are critical and that the sponsorship of senior leadership also is important.

When asked by a session attendee about specific recommendations for cleaning biological safety cabinets and other work surfaces, Dr. Connor replied, “After all these years, we don’t have any really good recommendations. There are more than 100 different antineoplastic agents, all with different chemical structures … there’s really no universal method.” He suggested that a good approach is to use a detergent followed by a water rinse, then another detergent and water rinse, followed by alcohol. He referenced the 2006 ASHP guidelines for further recommendations on cleaning (Am J Health Syst Pharm;63:1172-1191).

Ms. Power also stressed the need to get with the program. “I don’t think

continued from page 21

correct amount of air exchanges, the right level of air quality, pass-through windows and so forth because, in general, those help reduce the contamination.” Additionally, although Dr. Ahmed found that “at best, CSTDs could only attenuate the active transfer process, but not passive transfer, which may be more important,” Dr. Connor referred back to the NIOSH study findings as indicating the value of CSTDs. Reiterating that no spills occurred at the site that used CSTDs, he said that some of these devices “have shown they reduce contamination. I think they do contribute to reducing contamination.”

Based on their findings, the team at MGH recommended against the purchase of CSTDs and is working on major revisions to their policies and procedures to prevent contamination due to active transfer. They are also tackling the problem of passive transfer. They are planning to change their storage procedures so that chemotherapy drugs are stored in isolation from other agents, and they are exploring the use of protective sleeves and other options. They also plan to conduct biologic sampling of workers across

interim analysis; 57% of the patients have died.

“A difference in overall survival may emerge with longer follow-up,” Dr. Brufsky said. “We now know that bevacizumab is clearly beneficial as firstline and as second-line therapy. We are interested in a study of continuous bevacizumab in metastatic breast cancer, the so-called RIBBON-3 trial.”

Toxicity with bevacizumab was consistent with previous experience in MBC and other tumor types. No new toxicity signals emerged.

The need for longer-term follow-up notwithstanding, Dr. Brufsky said he was encouraged by the results of the RIBBON-2 trial.

“This is the first Phase III study to show that bevacizumab plus chemotherapy is effective as second-line therapy for metastatic breast cancer,” he said.

“These results are clinically meaningful.

We have few options for second-line chemotherapy in metastatic disease.”

Dissecting the Data Edith Perez, MD, director of the Breast Cancer Program at Mayo Clinic in Jacksonville, Fla., who was not involved with the study, said “it is an important finding that bevacizumab plus several options of chemotherapy improved PFS in patients

exposure is linear. I think you need to put money where you can identify your highest exposure.” Start with the basics, and add on from there, said Ms. Power.

She said health care workers are “in jeopardy” if they handle hazardous drug vials and other packaging without gloves and other PPE and if they do not decontaminate vials and surface areas in

‘I don’t think exposure is linear. I think you need to put money where you can identify your highest exposure.’

—Luci Power, MS, RPh the primary engineering control.

She stressed the importance of double gloving, and she suggested that two shoe covers could be beneficial in areas where hazardous drugs are compounded. She acknowledged that it would require a little planning and that someone at the institution needs to “think it through” and figure out how it would work in that setting.

Another suggestion Ms. Power made was to use two technicians, “one prepar-

Chemotherapy Chemotherapy plus bevacizumab

8 6

Months

22

P=0.0072

7.2

5.1

4 2 0

Figure. Comparison of progression-free survival. who did not get it as first-line.”

Dr. Perez added that bevacizumab plus chemotherapy should be considered for patients with MBC who did not get the drug first-line.

When asked whether the cost of bevacizumab was worth an extra 2.1 months of PFS, Dr. Brufsky acknowledged that cost is an issue. “When we compare trial results, 2.1 months is a mean. There are patients who do much better at one end of the curve. We want to identify characteristics that predict better response,” he commented.

Maura Dickler, MD, attending

•

see BEVACIZUMAB, page 31

ing and one serving. It doesn’t necessarily change what’s happening in the hood, but it changes what’s happening after.” She noted that this work practice is done in Denmark and was brought to her attention by Vagn Handlos, PhD, of the Capital Region Pharmacy in Herlev.

For her part, Dr. McDiarmid said that the extent of the problem could not be denied. “As a minimum, everybody has to get on point here on what we’re supposed to be doing because we can tell you from the walk-throughs we did, that’s not even happening, so it’s probably not happening at your place either.” Beyond that, she suggested a revisiting of the current safe handling guidelines “to identify certain workplace encounters where they are high-hazard, where there is a possibility for breakdown, etc.”

She concluded, “There needs to be a smart way for us to figure out how to deliver competent, compassionate care without putting people at increased risk.

Where we start is by getting everybody on the page with the minimum, and the minimum is the current guidance that’s out there. Right now, I don’t think we can fully assess efficacy, because we don’t know what people are doing.”

—Sarah Tilyou

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Hem/Onc Pharmacy

Pharmacy Practice News • January 2010

In Focus

Sorafenib Combo Holds Promise in Metastatic Breast Cancer San Antonio—Adding sorafenib to chemotherapy extends progression-free survival (PFS) in patients with locally advanced or metastatic breast cancer (MBC), according to two companion Phase IIb studies.

Presented at the recent San Antonio Breast Cancer Symposium (SABCS), the two studies are part of a series of four worldwide Phase IIb clinical trials testing the use of sorafenib (Nexavar, Bayer Healthcare Pharmaceuticals) in

advanced HER2-negative breast cancer in a program called TIES (Trials to Investigate the Effects of Sorafenib in Breast Cancer). Sorafenib is an oral multikinase inhibitor approved for advanced renal cell carcinoma and hepatocellular carcinoma; it is investigational in breast cancer.

Sorafenib Plus Paclitaxel Combo The first study (abstract 44) was a double-blind, randomized placebo-

controlled Phase IIb trial that included 237 patients from the United States, India and Brazil with HER2-negative, advanced breast cancer or MBC. The study randomized 119 patients to paclitaxel (90 mg/m2 weekly) plus sorafenib 400 mg twice daily and 118 patients to the same dose and schedule of paclitaxel plus placebo.

“The study showed activity for sorafenib. Sorafenib may provide added benefit when combined with paclitaxel

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compared with single-agent paclitaxel in the first-line treatment of advanced breast cancer,” said lead investigator William S. Gradishar, MD, a professor of medicine at Northwestern University Feinberg School of Medicine, in Chicago.

Median PFS was 6.9 months in patients in the sorafenib-containing arm compared with 5.6 months in patients receiving paclitaxel alone, representing a 21% reduced relative risk for death or progression, although this was not statistically significant (P=0.0857).

According to Dr. Gradishar, the failure of PFS to reach statistical significance may have been the result of excess deaths in the sorafenib arm (17 of 20) that were not drug-related. These deaths occurred mainly among 17 patients enrolled in India who died of causes not usually seen in the United States, including malaria and tuberculosis.

“These deaths [in India] appeared to skew the PFS,” Dr. Gradishar said. “Time to progression, which does not include deaths, showed a greater advantage for sorafenib plus paclitaxel spread that looks more impressive.”

The addition of sorafenib increased time to progression by 33%. Median duration of response was 5.6 months in patients receiving sorafenib compared with 3.7 months in the paclitaxel-alone arm (P=0.0079), and objective response rates were 67% versus 54%, respectively (P=0.0234).

No unexpected toxicities were reported with the combination of sorafenib and paclitaxel. Hand–foot syndrome was the major toxicity seen in patients receiving sorafenib. Grade 3 hand– foot syndrome occurred in 30% of the sorafenib arm compared with 3% of the paclitaxel-alone arm.

“We are not suggesting that the incidence of hand–foot syndrome is acceptable. As we go forward [with sorafenib], we will have to modify the dose,” Dr. Gradishar said.

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In a separate Phase IIb study presented at SABCS (abstract 45), investigators tested the combination of sorafenib plus capecitabine (Xeloda, Roche). According to the lead author Jose Baselga, MD, a professor at Vall d’Hebron University Hospital, Barcelona, Spain, the combination of sorafenib plus capecitabine was tolerable, with no unexpected major toxicities, and the toxicities that did occur were clinically manageable. A significant benefit was found for PFS with the addition of sorafenib, and subgroup analyses confirmed the robust benefit in both first- and second-line therapy for MBC. The SOLTI-0701 trial had a similar

Hem/Onc Pharmacy 25

Pharmacy Practice News • January 2010

In Focus Patients receiving capecitabine plus sorafenib Patients receiving capecitabine only

50

% of Patients

design to the trial led by Dr. Gradishar; 220 patients with HER2-negative MBC from Spain, France and Brazil were randomized in a 1:1 fashion to receive capecitabine 1,000 mg/m2 for 14 of every 21 days and sorafenib 400 mg twice daily continuously or the same dose and schedule of capecitabine plus placebo.

The dose of capecitabine in this trial is lower than the approved dose of 1,250 mg/m2, Dr. Baselga said. Treatment was continued until progression or unacceptable toxicity.

Patients were over age 18 years and had confirmed HER2-positive, locally advanced unresectable breast cancer or MBC. Seventy percent were hormone receptor–positive; 80% had one prior adjuvant or neoadjuvant chemotherapy. Prior bevacizumab was an exclusion criterion.

The investigators found that the regimen was well tolerated. Most adverse events were grade 1 or 2, with the exception of grade 3/4 hand–foot syndrome, which occurred in 45% of the experimental arm compared with 13% of patients receiving only capecitabine (Figure).

Management of hand–foot syndrome was prespecified in the protocol. For grade 2, 3 and higher, sorafenib was withheld until the condition resolved; a reduced dose was initiated for grade 3 and higher. In the patients who received sorafenib, 65% discontinued treatment due to adverse events compared with 29% of patients in the capecitabine arm. The number of patients who discontinued treatment due to progressive disease also was higher in the group that received sorafenib—15% compared with 7%.

Sorafenib significantly increased median PFS: 6.4 compared with 4.1 months (P=0.006), representing an absolute extension of 2.3 months and a 42% relative risk reduction in progressive disease or death. Response rates were 38% and 30.7%, respectively. In a prespecified subgroup analysis, median PFS in the first-line setting was 7.6 versus 4.1 months, representing a 50% relative risk reduction with the addition of sorafenib.

In the second-line setting, median PFS was 5.7 versus 4.1 months, for a 35% relative risk reduction.

45

40 30 20 13 10 0

Figure. Comparison of grade 3/4 hand–foot syndrome in SOLTI trial.

involved with the studies, the trials show sorafenib has promise in MBC. “Although promise is demonstrated for sorafenib-based chemotherapy combinations based on these studies, additional study is needed to maximize efficacy and reduce toxicity,” said Maura Dickler, MD, attending physician in the Breast Cancer Medicine Service at Memorial SloanKettering Cancer Center, New York City.

Joanna Schwartz, PharmD, BCOP, assistant professor in the Department of Pharmacy Practice at Albany College of Pharmacy and Health Sciences, Vermont Campus, Colchester, had similar senti-

ments. “These trials are intriguing and do show a signal of efficacy for sorafenib in combination with chemotherapy or aromatase inhibitors in advanced breast cancer.” She cautioned that the use of sorafenib in breast cancer “is clearly not ready for prime time” and agreed with other clinicians that optimal dosing should be studied. “The rates of hand– foot syndrome, rash and fatigue were quite high in these studies,” she added, “and larger studies are needed to confirm this preliminary suggestion of benefit.”

—Alice Goodman

More Study Needed “These are impressive results but the toxicity is worrying,” said Stephen R.D. Johnston, MA, PhD, of Royal Marsden NHS Foundation and Trust and Institute of Cancer in London, who was not involved with the study. At the SABCS, he asked Dr. Baselga what percentage of the prescribed dose of sorafenib patients were able to receive. Dr. Baselga said the majority had dose reductions of capecitabine and sorafenib for grade 3 toxicity and only 10% of the sample kept to the initial dose.

According to other clinicians not

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Hem/Onc Pharmacy

Pharmacy Practice News • January 2010

In Focus

ONE-TWO PUNCH continued from page 1

drug to maintain through progression in this setting,” said Edith Perez, MD, director of the Breast Cancer Program at Mayo Clinic in Jacksonville, Fla., who was not involved with the study.

Practice-Changing News Early results from this trial, which were reported at the 2008 annual meeting of the American Society of Clinical Oncology, showed that the combination improved progression-free survival by roughly one month. The updated and planned event-driven survival analysis reported at SABCS, after 75% of the women had died, revealed that patients who received the combination therapy had a 26% reduction in the risk for dying compared with patients who received lapatinib alone, according to lead investigator Kimberly Blackwell, MD. “The survival benefit was seen in spite of the fact that over half of the patients crossed over to go on to receive dual HER2 blockade,” said Dr. Blackwell, associate professor of medicine and director of the Clinical Trials Program in Breast Cancer at Duke University Medical Center, Durham, N.C. “As a practicing clinician, I think it is really amazing that there was not a significant safety signal considering the heavily pretreated nature of these patients.”

According to Andrew Seidman, MD, an attending physician at the Breast Cancer Medicine Service at Memorial SloanKettering Cancer Center, New York City, there are three common approaches to treating patients with trastuzumabrefractory MBC: discontinue trastuzumab and switch to capecitabine (Xeloda, Roche) plus lapatinib, continue trastuzumab and add capecitabine or continue trastuzumab and add lapatinib. The new data, he said, support the use of the trastuzumab-lapatinib option because it is the only approach that has been demonstrated to improve overall survival.

The study that spurred FDA approval of lapatinib in combination with capecitabine in this patient population was based on data that showed improved response rate and time to progression (N Engl J Med 2006;355:27332744). Results from the study testing the combination of capecitabine with or without trastuzumab, published in 2009 (J Clin Oncol 2009;27:1999-2006), also only showed an improvement in response rate and time to progression.

“The survival data from the new study will set this approach apart from the other studies. This is noteworthy and likely will impact clinical practice,” Dr. Seidman said. “It will also drive interest in beginning lapatinib plus trastuzumab alone or in combination with cytotoxic agents even earlier in the treatment of

metastatic breast cancer. Indeed, the combination is already being studied in the postoperative adjuvant setting in the ALTTO [Adjuvant Lapa-

tinib and/or Trastuzumab Treatment Optimization] trial.”

Study Details The study reported at SABCS randomized 296 women with HER2positive MBC who had progressed on trastuzumab-containing regimens to receive either lapatinib 1,500 mg once daily or lapatinib 1,000 mg once daily in combination with trastuzumab 2 mg/kg (after a 4-mg/kg loading dose). If patients had objective disease progression at or after four weeks of lapatinib alone, they were allowed to cross over to the combination arm— 52% ended up crossing over. “Half of these patients [crossed over] before or at week 8, and 46% [did so] after week 8,” Dr. Blackwell said.

Median overall survival following treatment with lapatinib plus trastuzumab was 60.7 weeks compared with 41.4 weeks in patients who received lapatinib alone (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57-0.97; P=0.026). The survival benefit was maintained after adjusting for baseline prognostic factors (HR, 0.71; 95% CI, 0.54-0.93; P=0.012).

Both regimens were well tolerated.

One cardiac-related death occurred in the combination arm and was attributable to a fatal pulmonary embolism. Dr. Blackwell said that diarrhea “was the only significant grade 3/4 adverse event seen in greater than or equal to 5% of the patients enrolled in this heavily pretreated population.” She added that it was “almost certainly attributable

to the lapatinib” and occurred in 8% of those in the combination arm and 7% in the lapatinib arm.

Lapatinib is the only small molecule inhibitor approved in the treatment of HER2-positive breast cancer; it is a dualtargeting agent aimed at HER1 and HER2.

Trastuzumab is a monoclonal antibody that targets HER2.

“Because of the different mechanisms of attack on the HER2 receptor, it was very appealing to combine the two agents within the clinical arena without using a chemotherapy backbone,” Dr. Blackwell said. “In addition, this study was really based on preclinical data that there was synergy between trastuzumab and lapatinib which included enhancement of apoptosis through the downregulation of survivin.” She added that lapatinib has a potential benefit of working against tumors that have become resistant to trastuzumab through a potential resistance mechanism of cleavage of the extracelluar domain, the known binding site for trastuzumab.

Dr. Seidman said the study was important in showing that there was benefit to continuing trastuzumab in patients who appeared to be resistant to the drug. “These are patients who had Herceptin in combination with a number

‘... Clinicians [who prescribe] both trastuzumab and lapatinib ... should be ready for some significant roadblocks, not the least of which is the high cost of these medications.’

—Cindy O’Bryant, PharmD

Patients receiving lapatinib plus trastuzumab

80

Patients receiving lapatinib

70

Survival, wk

26

60.7

60 50

41.4

40 30 20 10 0

Figure 1. Comparison of overall survival.

Patients had HER2-positive metastatic breast cancer and had progressed on trastuzumab-containing regimens.

of different agents and had progressed, and now fairly far along in the course of their disease, lapatinib is being added and they had a 60-week survival at that juncture,” he said. “It’s pretty compelling.”

Dr. Blackwell disclosed that she has received honoraria from Genentech and GlaxoSmithKline and served as a consultant to Genentech.

Barriers to Implementation Cindy O’Bryant, PharmD, past-president of the Hematology/Oncology Pharmacy Association, was more measured in her assessment of Dr. Blackwell’s follow-up study. Although the survival data “are intriguing,” she said, and the results “may be practice-changing, in the sense that they support a relatively new concept—hitting resistant breast cancer with two different drugs, but targeted at the same pathway”—several practical issues remain, she stressed.

“If clinicians want to apply this concept in real-world clinical conditions and start prescribing both trastuzumab and lapatinib to these patients, they should be ready for some significant roadblocks, not the least of which is the high cost of these medications.”

Lapatinib, Dr. O’Bryant noted, is fairly new to the market and won’t be available as a lower-cost generic anytime soon. And while trastuzumab may be closer to going off-patent, “the FDA has yet to delineate any clear-cut policy for determining the bioequivalence of biosimilars,” she said.

Thus, several cost and reimbursement hurdles exist for the dual use of the targeted agents.

In fact, “I just don’t see Medicare paying for this regimen right off the bat,” noted Dr. O’Bryant, a member of the editorial advisory board of Pharmacy Practice News. “And given the current push for health care reform, such financial pressures will only intensify.”

Dr. O’Bryant acknowledged that studies such as Dr. Blackwell’s are not designed to yield cost–benefit data.

“They’re proof-of-concept studies, and from that standpoint, the results are very significant,” she stressed. “They confirm that the HER2 pathway is an important one in terms of blocking tumor growth, and one that we should be hitting hard with our drug regimens as we move forward.”

—Kate O’Rourke, David Bronstein

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• Vivaglobin Sub-Q treatment is injected into the thigh, upper arm, stomach or hips on a weekly basis • Injection-site reactions are typically mild to moderate and decrease substantially over time Important Safety Information Immune Globulin Subcutaneous (Human), Vivaglobin, is indicated for the treatment of patients with primary immunodeficiency (PI).

As with all immune globulin products, Vivaglobin is contraindicated in individuals with a history of anaphylactic or severe systemic response to immune globulin preparations and in persons with selective immunoglobulin A deficiency who have known antibody against IgA. If anaphylactic or anaphylactoid reactions are suspected, discontinue administration immediately and treat as medically appropriate.

Vivaglobin is derived 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.

In clinical trials, the most frequent adverse event was injection-site reaction, consisting of mild or moderate swelling, redness, and itching. No serious local site reactions were observed, and reactions tended to decrease substantially after repeated use. Other adverse events irrespective of causality included headache, gastrointestinal disorder, fever, nausea, sore throat, and rash.

As with all immune globulin (Ig) products, patients receiving Ig therapy for

the first time, receiving a new product, or not having received Ig therapy within the preceding eight weeks may be at risk for developing reactions including fever, chills, nausea, and vomiting. On rare occasions, these reactions may lead to shock. Such patients should be monitored in a clinical setting during the initial administration.

Ig administration can transiently impair the efficacy of live attenuated virus vaccines, such as measles, mumps and rubella.

In clinical studies, administration of Vivaglobin has been shown to be safe and well tolerated in both adult and pediatric subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. Safety and efficacy were not studied in pediatric subjects under two years of age.

Please see brief summary of Prescribing Information on adjacent page.

Manufacturing and Distribution: Vivaglobin is manufactured by CSL Behring AG and distributed by CSL Behring LLC. Vivaglobin is a registered trademark of CSL Behring AG. ©2009 CSL Behring LLC 1020 First Avenue • PO Box 61501 King of Prussia, PA 19406-0901 • USA IO#9B046 12/2008

www.vivaglobin.com

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Hem/Onc In Focus

Table 7 summarizes the most frequent related adverse events by subject reported in the clinical study, and Table 8 summarizes the most frequent related adverse events by infusion.

Vivaglobin® Immune Globulin Subcutaneous (Human) CSL Behring

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

Distributed by: CSL Behring LLC Kankakee, IL 60901 USA

only Before prescribing, please consult full prescribing information, a brief summary of which follows: INDICATIONS AND USAGE Vivaglobin® Immune Globulin Subcutaneous (Human), is indicated for the treatment of patients with primary immune deficiency (PID).

CONTRAINDICATIONS As with all immune globulin products, Vivaglobin® Immune Globulin Subcutaneous (Human) is contraindicated in individuals with a history of anaphylactic or severe systemic response to immune globulin preparations and in persons with selective immunoglobulin A (IgA) deficiency (serum IgA < 0.05 g/L) who have known antibody against IgA. WARNINGS Patients who receive immune globulin therapy for the first time, who are switched from another brand of immune globulin, or who have not received immune globulin therapy within the preceding eight weeks may be at risk for developing reactions including fever, chills, nausea, and vomiting. On rare occasions, these reactions may lead to shock. Such patients should be monitored for these reactions in a clinical setting during the initial administration of Vivaglobin® Immune Globulin Subcutaneous (Human).

If anaphylactic or anaphylactoid reactions are suspected, discontinue administration immediately. Treat any acute anaphylactoid reactions as medically appropriate.

Vivaglobin® is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. Because Vivaglobin® is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the CJD agent. The risk that such plasma-derived products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses during manufacture (see DESCRIPTION section for virus reduction measures). Stringent procedures utilized at plasma collection centers, plasma-testing laboratories and fractionation facilities are designed to reduce the risk of virus transmission. The primary virus reduction steps of the Vivaglobin® manufacturing process are pasteurization (heat treatment of the aqueous solution at 60 C for 10 hours) and ethanol - fatty alcohol / pH precipitation. Additional purification procedures used in the manufacture of Vivaglobin® also potentially provide virus reduction. Despite these measures, such products may still potentially contain human pathogenic agents, including those not yet known or identified. Thus, the risk of transmission of infectious agents cannot be totally eliminated. Any infections thought by a physician to have been possibly transmitted by this product should be reported by the physician or other healthcare provider to CSL Behring at 1-800-504-5434 (in the US and Canada). The physician should discuss the risks and benefits of this product with the patient.

During clinical trials, no cases of infection due to hepatitis A, B, or C virus, parvovirus B19, or HIV were reported with the use of Vivaglobin®.

PRECAUTIONS General-Administer Vivaglobin® Immune Globulin Subcutaneous (Human), subcutaneously. Do not administer this product intravenously. The recommended infusion rate and amount per injection site stated under DOSAGE AND ADMINISTRATION should be followed. When initiating therapy with Vivaglobin®, patients should be monitored for any adverse events during and after the infusion.

Laboratory Tests - After injection of immunoglobulins, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens, e.g., A, B, D may cause a positive direct or indirect antiglobulin (Coombs’) test.

Drug Interactions - Immunoglobulin administration can transiently impair the efficacy of live attenuated virus vaccines such as measles, mumps and rubella. The immunizing physician should be informed of recent therapy with Vivaglobin® Immune Globulin Subcutaneous (Human), so that appropriate precautions can be taken.

Vivaglobin® should not be mixed with other medicinal products.

Pregnancy Category C - Animal reproduction studies have not been conducted with Vivaglobin® Immune Globulin Subcutaneous (Human). It is also not known whether Vivaglobin® can cause fetal harm when administered to a pregnant woman, or can affect reproduction capacity. Vivaglobin® should be given to a pregnant woman only if clearly needed.

Pediatric Use - Vivaglobin® was evaluated in 6 children and 4 adolescents in the US and Canada study and in 16 children and 6 adolescents in the non-IND study. There were no apparent differences in the safety and efficacy profiles as compared to adult subjects.

No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. The safety and efficacy of Vivaglobin® was not studied in pediatric subjects under two years of age.

Geriatric Use - The clinical study of Vivaglobin® Immune Globulin Subcutaneous (Human), did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

ADVERSE REACTIONS In clinical studies, administration of Vivaglobin® Immune Globulin Subcutaneous (Human), has been shown to be safe and well tolerated in both adult and pediatric subjects. Reactions similar to those reported with administration of other immune globulin products may also occur with Vivaglobin®. Rarely, immediate anaphylactoid and hypersensitivity reactions may occur. In exceptional cases, sensitization to IgA may result in an anaphylactic reaction (see CONTRAINDICATIONS).

Should evidence of an acute hypersensitivity reaction be observed, the infusion should be stopped promptly, and appropriate treatment and supportive therapy should be administered.

In the US and Canada clinical study, the safety of Vivaglobin® was evaluated for 15 months (3-month wash-in/wash-out period followed by 12-month efficacy period) in 65 subjects with PID. The most frequent adverse reaction was local reaction at the injection site. Table 5 summarizes the most frequent adverse events by subject reported in the clinical study, and Table 6 summarizes the most frequent adverse events by infusion.

Table 5: Most Frequent Adverse Events by Subject Irrespective of Causality* in the US and Canada Study Adverse Events ( 10% of subjects) Adverse Events at the Injection Site Non-Injection Site Reactions Headache Gastrointestinal disorder Fever Nausea Sore throat Rash Allergic reaction Pain Diarrhea Cough increased

No. of Subjects (% of total) 60 (92%) 31 (48%) 24 (37%) 16 (25%) 12 (18%) 11 (17%) 11 (17%) 7 (11%) 6.7 (10%)† 6.7 (10%)† 6.7 (10%)†

Table 7: Most Frequent Related Adverse Events by Subject* in the US and Canada Study Related Adverse Event ( 2 subjects) Adverse Events at the Injection Site

No. of Subjects (% of total) 60 (92%)

Non-Injection Site Reactions Headache Nausea Rash Asthenia Gastrointestinal disorder Fever Skin disorder Tachycardia Urine abnormality

21 (32%) 7 (11%) 4 (6%) 3 (5%) 3 (5%) 2 (3%) 2 (3%) 2 (3%) 2 (3%)

*Excluding infections Table 8: Most Frequent Related Adverse Events by Infusion* in the US and Canada Study Related Adverse Event ( 2 AEs) (Number of Infusions: 3656)

No. of AEs (Rate**)

Adverse Events at the Injection Site Non-Injection Site Reactions Headache Rash Nausea Nervousness Asthenia Gastrointestinal disorder Skin disorder Urine abnormality Fever Dyspnea Gastrointestinal pain Tachycardia

1787 (49%) 59 (1.6%) 9 (0.2%) 9 (0.2%) 4 (0.1%) 3 (0.1%) 3 (0.1%) 3 (0.1%) 3 (0.1%) 2 (0.1%) 2 (0.1%) 2 (0.1%) 2 (0.1%)

*Excluding infections **Rate = number of reactions/infusion In the non-IND Europe and Brazil clinical study, the safety of Immune Globulin Subcutaneous (Human), Vivaglobin® was evaluated for 10 months in 60 subjects with PID. The adverse events and their rates reported in this study were similar to those reported in the US and Canada study, with two notable exceptions for the related adverse events. These events were 59 episodes of headache (1.6%) and 2 episodes of fever (0.1%) in the US and Canada study and no episodes of headache and 18 episodes of fever (0.8%) in the Europe and Brazil study.

Local (Injection Site) Reactions - Local injection site reactions consisting of mostly mild or moderate swelling, redness and itching, have been observed with the use of Vivaglobin®. No serious local site reactions were observed. The majority of injection site reactions resolved within four days. Additionally, the number of subjects reporting local injection site reactions decreased substantially after repeated use (see Figure 1). Only three subjects in the US and Canada study and one subject in the Europe and Brazil study discontinued due to local site reactions.

Figure 1: Subjects Reporting Local Site Reactions By Infusion US and Canada Europe - Brazil

100

Subjects with AEs at the injection site (%)

BRIEF SUMMARY OF PRESCRIBING INFORMATION

90 80 70 60 50 40 30 20 10 0 0

10

20

Note: Analysis is confined to 70 infusions.

30

40

50

60

70

Infusion

After administration, discard any unused solution and administration equipment in accordance with biohazard procedures.

HOW SUPPLIED Vivaglobin® Immune Globulin Subcutaneous (Human), is supplied in single-use vials containing 160 mg IgG per mL. The following dosage forms are available: NDC 0053-7596-03 NDC 0053-7596-10 NDC 0053-7596-15 NDC 0053-7596-20 NDC 0053-7596-25

Box of ten 3 mL vials 10 mL vial Box of ten 10 mL vials 20 mL vial Box of ten 20 mL vials

Based on April 2007 revision

Table 6: Most Frequent Adverse Events by Infusion Irrespective of Causality* in the US and Canada Study No. of Adverse Events (Rate**)

Adverse Events at the Injection Site Mild Moderate Severe Unknown Severity

1789 (49%) 1112 (30%) 601 (16%) 65 (2%) 11 (< 1%)

Non-Injection Site Reactions Headache Gastrointestinal disorder

159 (4%) 40.3 (1%)†

*Excluding infections **Rate = number of reactions/infusion †Due to missing subject diary information, values listed are estimates.

42853_cslviv_ppn_pi_fa1.indd 1

New Orleans—In a large, multinational Phase III study, nilotinib (Tasigna, Novartis) demonstrated compelling superiority to imatinib (Gleevec, Novartis) as firstline therapy for chronic myeloid leukemia (CML). More patients achieved the primary end point of a major molecular response and fewer patients had disease progression. Nilotinib was at least as well tolerated as imatinib, and the advantage of nilotinib over imatinib was consistent across Sokal risk stratifications, a common scoring system for predicting survival in CML patients.

“Based on these results, we strongly believe that nilotinib may become the new standard of care in newly diagnosed CML,” said Giuseppe Saglio, MD, a researcher at the University of Turin’s San Luigi Gonzaga Hospital in Orbassano, Italy. Dr. Saglio, lead investigator of the study, presented these results at the annual meeting of the American Society of Hematology (abstract LBA1). He indicated that the greater efficacy of nilotinib compared with imatinib is consistent with its greater inhibition of BCR-ABL, a defining molecular defect in CML. In the trial, at 12 months, roughly 20% more patients achieved a major molecular response (MMR) with nilotinib compared with imatinib. Less than 1% of patients in each of the two arms that received nilotinib entered accelerated phase (AP) or blast crisis (BC) in the 12-month period compared with 3.9% of patients in the imatinib arm.

Study Details

STORAGE Store in the refrigerator at 2 - 8 C (36 - 46 F). Vivaglobin® Immune Globulin Subcutaneous (Human), is stable for the period indicated by the expiration date on its label. Do not freeze. Keep vials in storage box until use.

*Excluding infections † Due to missing subject diary information, values listed are estimates.

Adverse Events ( 1% of infusions) (Number of Infusions: 3656)

Nilotinib May Best Imatinib in 1st-line Treatment of CML

12/21/09 2:29:08 PM

In the study, which included 217 participating centers in 35 countries, 846 previously untreated patients with CML were randomized to the standard oncedaily (qd) 400-mg dose of imatinib, 300 mg twice daily (bid) of nilotinib or 400 mg bid of nilotinib. Although the study protocol allowed imatinib patients to increase the dose to 400 mg bid (16% did so), dose escalation was not permitted in either of the nilotinib arms. The primary end point was MMR at 12 months. Complete cytogenetic response (CCyR) at 12 months was a secondary end point.

Other end points included duration of MMR and CCyR, progression-free survival (PFS) and overall survival (OS).

The MMR rates were achieved more quickly at every time point by the nilotinib group starting at three months. At 12 months, the rates of MMR were 44% in the 300 mg bid and 43% in the 400 mg bid nilotinib arms compared with 22% in the imatinib arm (P<0.0001 for

•

see NILOTINIB, page 31

PRINTER-FRIENDLY VERSION AT PHARMACYPRACTICENEWS.COM

Immune Globulins: Therapeutic, Pharmaceutical, Cost, and Administration Considerations JERRY SIEGEL, PHARMD, FASHP Senior Director Emeritus Department of Pharmacy The Ohio State University Medical Center Columbus, Ohio

T

he most common question regarding immune globulin (Ig) products relates to whether they are all the same. Even though clinicians have considered all Ig products to be

clinically equivalent, they are not pharmaceutically equivalent.

It is imperative that Ig products not be interchanged without full consideration of the pharmaceutical differences.

Although all of the products contain primarily IgG, there are trace amounts of other Igs—IgA, IgM—as well as widely different stabilizing agents that may affect tolerability. Product access issues as well as formulary choices and contracting have made it difficult for all products to be available for all patients. Physicians and pharmacists are often faced with choosing a product that may be different from the one the patient was originally prescribed.

Whereas Tables 1 to 4 may help facilitate these decisions, it is important to understand the clinical impact of changing products. The differences in salt, sugar, and overall osmolarity of these products are particularly important when patients have various comorbidities, such as renal dysfunction, diabetes mellitus, vascular disease, or heart failure. Differences between lyophilized and liquid products may result in changes in product concentration and infusion rate as well as tolerability.

One subcutaneous Ig product (Vivaglobin, CSL Behring) is available in the United States for patients with primary immune deficiencies. It should be noted that the subcutaneous preparation is not to be given intravenously, and its bioavailability is not the same as with

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

preparations intended for intravenous use; thus, dosing adjustments are required.

Research is being conducted on the use of IgG in various indications. One product (Gamunex, Talecris) has received approval for use in patients with chronic inflammatory demyelinating polyneuropathy.

The most common reasons for switching products may be clinical in nature and related to tolerability, they may be fiscal and based on contracting issues, or they may be due to product availability. It is best to consider product changes as if the patient is naïve to IVIG use, with increased monitoring and conservative infusion times.

The tables may be helpful in providing optimal care for patients receiving IgG. They should be used as a general guide to help you determine the product that is best for your particular patient population. Because there is considerable variation from batch to batch, the exact numbers represent averages of selected batches; any one batch of any IgG product may have ranges outside these average numbers. Pay attention to products that are distributed under different names but made by the same manufacturer.

For information on adverse reactions, please see the prescribing information for each immune globulin product.

P H A R M AC Y P R AC T I C E N E WS • JA N UA RY 2 0 1 0

1

Table 1. Therapeutic Considerations Producta

Manufacturer

FDA-Approved Indications

IgA Content

pH (After Reconstitution)

Prophylaxis of CMV disease associated with transplantation of kidney, lung, liver, pancreas, and heart

30-200 mcg/mL

5.5

Cytomegalovirus Intravenous Immune Globulin CytoGam

CSL Behring Customer support: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com

Intravenous Immune Globulin Carimune NF

CSL Behring Customer support: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com

ITP, PID

720 mcg/mL (~2%)

6.4-6.8

Flebogamma 5% DIF

Instituto Grifols SA Barcelona, Spain Customer service: (888) GRIFOLS www.grifols.com

PID

2.8±1.6 mcg/mLb (specification value: <50 mcg/mL)

5.6±0.1b

Gammagard Liquid 10%

Baxter Healthcare Corp Direct inquiries: (800) 423-2090 www.baxter.com

PID

37 mcg/mL

4.6-5.1

Gammagard S/D

Baxter Healthcare Corp Direct inquiries: (800) 423-2090 www.baxter.com

CLL, ITP, KS, PID

<2.2 mcg/mL, <1 mcg/mLc

6.4-7.2

Gamunex

Talecris Biotherapeutics Medical info: (800) 520-2807 www.gamunex.com

CIDP, ITP, PID

46 mcg/mL

4.0-4.5

Octagam 5%

Octapharma Pharmazeutika Octapharma USA Customer service: (866) 766-4860 www.octapharma.com

PID

≤200 mcg/mL

5.1-6.0

Privigen 10%

CSL Behring Customer support: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com

ITP, PID

≤25 mcg/mL (specification value) 1.6-3.7 mcg/mL (typical value)

4.6-5.0

PID

≤1.7 mg/mL

6.4-7.2

Subcutaneous Immune Globulin Vivaglobin 16%

CSL Behring Customer support: (800) 683-1288 Medical info: (800) 504-5434 www.cslbehring.com

KEY

D5W

dextrose 5% in water

HCV

hepatitis C virus

BEV

EIA

enzyme immunoassay (formerly ELISA)

HH

inhibition of hemolysis

bovine enterovirus (RNA model)

BVDV bovine viral diarrhea virus

EMCV encephalomyocarditis virus (RNA model)

HIV

human immunodeficiency virus

CF

complement fixation

FDA

Food and Drug Administration

IFA

immunofluorescence assay

CIDP

chronic inflammatory demyelinating polyneuropathy

GPA

guinea pig assay

IgA

immune globulin A

HA

headache

IgG

immune globulin G

CLL

chronic lymphocytic leukemia

HAI

hemagglutination inhibition assay

IgM

immune globulin M

CMV

cytomegalovirus

HAV

hepatitis A virus

CPV

canine parvovirus (model for parvovirus B19)

HBV

hepatitis B virus

IHA ITP

idiopathic thrombocytopenic purpura

2

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

indirect hemagglutination

Table 1. Therapeutic Considerations IgG Subclass,e %

Producta

Plasma Source

Bacteria/Toxin

Viral Inactivation/ Removal

IgG1

IgG2

IgG3

IgG4

Diphtheria Toxin

Escherichia coli

8-24f

SD

65

28

5.2

1.7

>1 IU/mL (GPA)

NA

Halflife, dd

Cytomegalovirus Intravenous Immune Globulin CytoGam

2,000-5,000 donors; top 5% CMV titers selected

Intravenous Immune Globulin Carimune NF

>16,000 donors

23

pH 4.0/pepsin, nanofiltration, TSE removal

60.5

30.2

6.6

2.8

3.6 IU/mL (NT)

1:32 (IHA)

Flebogamma 5% DIF

US donors Plasmapheresis

30±9 (3-week dosing interval) 32±5 (4-week dosing interval)

Specific steps: pasteurization (60°C, 10 h), SD, nanofiltration (35+20 nm).

Unspecific steps: fraction I precipitation, fraction II+III incubation, 4% PEG precipitation, pH 4.0 treatment

66.6

28.5

2.7

2.2

5.7±0.9 IU/mL

NA

Gammagard Liquid 10%

Plasma from FDA-registered donor sites

35

SD, low pH, nanofiltration

60.9

32.1

5

2.1

4.0 units/mL (NT)

NA

Gammagard S/D

Plasmapheresis 10,000 donors

37.7±15

SD

67

25

5

3

2-5 IU/mL (NT); J5 lipid A 1:273

J5 LPS 1:46; 0111B4 LPS 1:12

Gamunex

Plasmapheresis

33

pH 4.2, caprylate chromatography purified, TSE removal

65±4

26±2

5.6± 0.6

2.6± 0.2

≥2 AU/mL

NA

Octagam 5%

US source and recovered plasma

41

SD, pH 4.0

65

30

3

2

5-30 IU/mL

NA

Privigen 10%

>16,000 donors

36.6

pH 4.0 incubation; 20 nm virus filtration; depth filtration; TSE removal

67.8

28.7

2.3

1.2

6.0 (3.8-8.2) IU/mL

NA

Relatively stableg

Ethanol-fatty alcohol/low pH precipitation; pasteurization

66

25

5

4

NA

NA

Subcutaneous Immune Globulin Vivaglobin 16%

US donors Plasmapheresis

IU

international units

NS

normal saline

RIA

radioimmunoassay

IVIG

intravenous immune globulin

NT

neutralization test

RSS

reduced space symbology

KS

Kawasaki syndrome

PEG

polyethylene glycol

RT

room temperature

LPS

lipopolysaccharide

PEI

Paul Ehrlich Institute International Units

SBV

Sindbis virus

PEV

porcine enterovirus (model for HAV)

SD

solvent detergent

PID

primary immunodeficiency

SQ

subcutaneous

PPV

porcine parvovirus

TSE

transmissible spongiform encephalopathy

PRV

pseudorabies virus

V-Z

varicella-zoster virus

MEV

mouse encephalomyelitis virus

MMV

mice minute virus (model for non-lipid DNA virus)

NA

information not available

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

3

Table 1. Therapeutic Considerations Streptococcus pneumoniae Producta

Type 1

Type 3

Haemophilus Influenzae Type B

(continued)

Streptolysin O

Viral Antibody Titers (Adenovirus)

CMV

HAV

HBV (Surface Antibody)

Herpes Simplex Type 1

Polio Type 2

Cytomegalovirus Intravenous Immune Globulin CytoGam

NA

NA

14.6 mcg/mL (EIA)

NA

NA

Antibody presenth,i

NA

2-3 IU/mL (RIA)

NA

0.46 (NT) type 1

Intravenous Immune Globulin Carimune NF

313 (EIA)

180 (EIA)

1:60 (CF)

300 IU/mL (HAI)

1:32 (CF)

1:512 (IFA); 1:2,560 (EIA)

1:348 (RIA)

1:64 (RIA)

1:128 (CF)

1:64 (NT)

Flebogamma 5% DIF

NA

NA

15±1 mg/L

NA

NA

30±6 PEI units/mL

21±4 IU/mL

48±27 IU/g Ig

NA

NA

Gammagard Liquid 10%

NA

21.2 mcg/mL (EIA)

1:2,320 (EIA)

NA

NA

68 PEI units/mL (EIA)

16.4 IU/mL (RIA)

≥0.20 IU/mL (EIA)

V-Z: 32 units/mL (NT)

Type 1: 1:190 mIU/mL (NT)

Gammagard S/D

17.5 mcgAbN/ mL (EIA)

8.5 mcg/mL (EIA)

11 mcg/mL (EIA)

1,150 IU (HH)

1:20 (EIA)

37 PEI mcg/mL (EIA); 1:2,480 (NT)

1:267 (RIA)

820 mIU/mL (RIA)

1:1,000 (EIA)

1:305 (NT)

Gamunex

87.4±22.2 mcg/mL

26.1±7.7 mcg/mL

13.0±2.4 mcg/mL

16,846± 13,648 Todd units/mL

NA

57 PEI units/mL

1:139

1:944

NA

1:22± 0.35

Octagam 5%

NA

NA

NA

600-800 IU/mL

NA

33-40 IU/mL

21-25 IU/mL

51 IU/g

1:8,192

1:1601:320 (NT)

Privigen 10%

NA

NA

36.1 (26.445.0) IU/mL

1,537 (1,2102,010) IU/mL

NA

76.4 (51.2116.8) IU/mL

21 (15-28) IU/mL

5.1 (3.0-10.1) IU/mL

NA

NA

NA

NA

NA

NA

30-50 IU/mL

NA

NA

NA

Subcutaneous Immune Globulin Vivaglobin 16%

4

NA

NA

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

Table 2. Cost Consideration Criteria Producta

Supply

Storage

24-Hour Service

Packaging/Labeling Enhancements

Shipping error; defective or damaged product; will NOT accept out-of-date products

Free

None

Distribution

Return Policy Warranty

2°C-8°C

Wholesaler or direct

Cytomegalovirus Intravenous Immune Globulin CytoGam

2.5 g

Intravenous Immune Globulin Carimune NF

3, 6, 12 g

≤30°C

Wholesaler or direct

Shipping error; defective or damaged product; will NOT accept out-of-date products

Free

Tamper-evident seal, RSS bar code, peel-off label with lot number/ expiration date

Flebogamma 5% DIF

0.5, 2.5, 5, 10, 20 g

2°C-25°C (36°F-77°F), 24 mo; do not freeze

Wholesaler or direct from Grifols USA (888) GRIFOLS

Limited

Free

Tamper-evident closure, laser-etched vials with individual vial information, bar-coded, peel-off label with product and lot number information; latex-free packaging

Gammagard Liquid 10%

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 9 mo

Direct from Baxter Healthcare Corp

No

Free

Tamper-evident cap, RSS bar code, peel-off label with lot number/ expiration date

Gammagard S/D

2.5, 5, 10 g

≤25°C; do not freeze

Direct from Baxter Healthcare Corp

No

Free

Tamper-evident cap, peel-off label with lot number/expiration date

Gamunex

1, 2.5, 5, 10, 20 g

2°C-8°C, 36 mo; ≤25°C, 6 mo; do not freeze

Wholesaler or direct

Limited

Free

Tamper-evident packaging, peel-off label with lot number/expiration date

Octagam 5%

1, 2.5, 5, 10, 25 g

2°C-8°C, 24 mo; 25°C, 24 mo

Wholesaler or direct

Shipping error; defective or damaged product; will NOT accept out-of-date products

Cost

Tamper-evident packaging, latex-free packaging, peel-off label with lot number/expiration date

Privigen 10%

5, 10, 20 g

Up to 25°C for 24 mo

Wholesaler or direct

Shipping error; defective or damaged product; will NOT accept out-of-date products

Free

Tamper-evident seal, RSS bar code; peel-off label with lot number/ expiration date

2°C-8°C; do not freeze

Wholesaler or direct

Shipping error; defective or damaged product; will NOT accept out-of-date products

Free

Latex-free packaging

Subcutaneous Immune Globulin Vivaglobin 16%

3, 10, 20 mL

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

5

Table 3. Pharmaceutical Considerations Producta

Method of Preparation

Form

Gamma Globulin, %

Liquid

99

≥95 monomers + dimers

Monomers, %

IgM Content

Albumin

PEG

Trace

10 mg/mL (1%)

0

Cytomegalovirus Intravenous Immune Globulin CytoGam

Cohn-Oncleyj ultrafiltration; SD treatment

Intravenous Immune Globulin Carimune NF

Kistler-Nitschmannj; pH 4.0 + trace pepsin; nanofiltration

Lyophilized

≥96

92

<20 mcg/mL

0

0

Flebogamma 5% DIF

Cohn-Oncleyj; PEG precipitation; ion-exchange chromatography; acid pH treatment; pasteurization; SD, dual nanofiltration (35+20 nm)

Liquid

99.6±0.2b

>99.8 monomers + dimersb (specification value: ≥95 monomers + dimers)

<2 mcg/mL

<2 mcg/mL

≤3 mg/mL

Gammagard Liquid 10%

Cohn-Oncleyj SD treatment; anion-exchange chromatography; nanofiltration; ultrafiltration; low pH incubation

Liquid

≥98

≥95 monomers + dimers

Trace

NA

Not detectable

Gammagard S/D

Cohn-Oncleyj; ultrafiltration; anion-exchange chromatography; SD treatment

Lyophilized

≥90

96.4

Trace

<3 mg/mL

<2 mg/mL

Gamunex

Cold ethanol fractionation; anion-exchange chromatography; caprylate chromatography purified; low pH incubation

Liquid

≥98

100 monomers + dimers

Trace

<20 mcg/mL

0

Octagam 5%

Cohn-Oncleyj; ultrafiltration; anion-exchange chromatography; SD treatment

Liquid

≥96

>99 monomers + dimers

≤0.1 mg/mL

0

0

Privigen 10%

Cold ethanol fractionation; octanoic acid precipitation; anion-exchange chromatography; pH 4.0 incubation; depth filtration, nanofiltration (20 nm)

Liquid

≥98

≥98 monomers + dimers

Trace

Measured values: 0.1-0.9 (specification: ≥2.0)

0

Liquid

>96

NA

NA

NA

NA

Subcutaneous Immune Globulin Vivaglobin 16%

6

Cold ethanol fractionation; pasteurization

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

Table 3. Pharmaceutical Considerations

Producta

Sodium Content (at 5% Concentration)

Sugar Content

Reconstitution Time

Osmolality

Shelf Lifek

Administrationl

5% sucrose

>206-222 mOsm/kg

24 mo

Not applicable (liquid solution)

0.2- to 15-mcm filter required; compatible with NaCl, D5W; 60 mg/kg/h or 75 mL/h maximum rate

Cytomegalovirus Intravenous Immune Globulin CytoGam

1-1.5 mEq/ 50 mL

Intravenous Immune Globulin Carimune NF

0% water; 0.9% saline

5% sucrose

In sterile water: 3%, 192 mOsm/kg; 6%, 384 mOsm/kg; 12%, 768 mOsm/kg In NS: 3%, 498 mOsm/kg; 6%, 690 mOsm/kg; 12%, 1,074 mOsm/kg

24 mo

Several minutes

No filter required; compatible with NaCl, D5W, sterile water

Flebogamma 5% DIF

<3.2 mmol/L

5% sorbitol (polyol)

240-370 mOsm/L

24 mo RT

Not applicable (liquid solution)

15- to 20-mcm filter recommended; lV, first 30 min: 0.01 mL/kg/min; if tolerated, gradually increase rate up to 0.1 mL/kg/min

Gammagard Liquid 10%

Not detectable

No sugar

240-300 mOsm/kg

36 mo refrigerated; 9 mo RT

Not applicable (liquid solution)

No filter required; compatible with D5W; not compatible with NaCl

Gammagard S/D

0.85%

2% glucose

5%, 636 mOsm/L; 10%, 1,250 mOsm/Lm

24 mo

<5 min at RT; >20 min if cold

Filter required; compatible with sterile water

Gamunex

Trace

No sugar

258 mOsm/kg

36 mo refrigerated; 6 mo RT

Not applicable (liquid solution)

No filter required; avoid NaCl even in evacuated containers; 0.08 mL/kg/min maximum rate

Octagam 5%

0

10% maltosen

310-380 mOsm/kg

24 mo

Not applicable (liquid solution)

No filter required; compatible with D5W, NS, sterile water; latex-free

Privigen 10%

â&#x2030;¤0.05 mmol/L (â&#x2030;¤1 mmol/L at 10% IgG)

No sugar

240-440 mOsm/kg

24 mo RT

NA

No filter required; compatible with D5W, 0.9% NaCl

No sugar

NA

24 mo

Not applicable (liquid solution)

SQ administration only; check prescribing information for dosing information; SQ rate: <20 mL/h; infusion pump: <15 mL per site

Subcutaneous Immune Globulin Vivaglobin 16%

0.3%

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

7

Table 4. Log Reduction Factor Comparisonso Enveloped Viruses HIV Producta

Nonenveloped Virus

Models for HCV SBV

Model for Large DNA BVDV

PRV

NA

>11

>19

5.8 (MEV)

Cytomegalovirus Intravenous Immune Globulin CytoGam

>16 (HIV-1)

Intravenous Immune Globulin Carimune NF

>26

>19

>9

>25

>19 (BEV)

Flebogamma 5% DIF

≥20.30

≥6.49

≥11.92

≥18.19

15.04 (PPV); 13.33 (EMCV)

Gammagard Liquid 10%

>14.8

NA

>16.8

>16.9

5.7 (HAV); >7.7 (EMCV); 5.1 (MMV)

Gammagard S/D

18.3 (HIV-1); 5.7 (HIV-2)

5.1

6.2

12.3

8 (HAV)

Gamunex

14

Not applicable

16.3

12.2

5.0 (HAV)

Octagam 5%

≥14.6

≥16.7

NA

≥21.1

≥9.2 (PPV)

Privigen 10%

≥16.0

NA

≥9.4

≥12.2

≥7.9 (EMCV); ≥7.8 (MMV)

NA

14.0

14.1

10.4 (PEV); 9.0 (CPV)

Subcutaneous Immune Globulin Vivaglobin 16%

12.7

FOOTNOTES a

All agents are contraindicated for IgA deficiency with antibodies to IgA.

b

Average of sample lots.

j

Under appropriate storage conditions.

c

For patients with known reactions to IgA or IgA deficiency with antibodies; special request only.

k

Unless specific compatibility information is available, do not mix with other drugs or solutions.

d

Varies with disease state, immune status, and age of the patient.

l

e

Average of sample lots; variable range in all IgG classes.

Kistler-Nitschmann is the specific cold ethanol fractionation method used by the manufacturer (CSL Behring); Cohn-Oncley is another method of cold ethanol fractionation.

f

8-24 h post-transplant; contact manufacturer for additional information.

m

Limit infusion rate to <3.3 mg IgG/kg/min (2 mL/kg/h) for 10% solutions.

n

Maltose may cause false elevations in blood glucose testing with glucose dehydrogenase-pyrroloquinolone quinone enzyme test strips; may cause problems with patients allergic to corn. See package insert for complete details.

o

Log reduction factor values obtained through prescribing information; most are available on respective Web sites.

g

antibody titer (≥7,000 IU/mL) that is determined using a proprietary EIA to meet or exceed FDA standards for CytoGam.

In contrast to serum IgG levels observed with monthly IVIG treatment (rapid peaks followed by decline), the serum IgG levels in subjects receiving weekly SQ Vivaglobin were relatively stable in 2 studies.

h

Data on file at CSL Behring.

i

All donors are selected based on a predetermined minimum

8

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

The PROOF is everywhere you look GAMUNEX is the IGIV therapy supported by robust clinical trials ■

Proven efficacy and patient outcomes in more FDA-approved indications (CIDP, PI, and ITP)* than any other liquid IGIV1

■

The most clinically studied liquid IGIV, with >600 patients and >4100 infusions2

The most common drug-related adverse reactions observed at a rate ≥5% were headache, fever, chills, hypertension, rash, nausea, and asthenia (in CIDP); headache, cough, injection-site reaction, nausea, pharyngitis, and urticaria (in PI); and headache, vomiting, fever, nausea, back pain, and rash (in ITP).

The most serious adverse reactions observed in clinical study subjects receiving GAMUNEX were pulmonary embolism (PE) in one subject with a history of PE (in CIDP), an exacerbation of autoimmune pure red cell aplasia in one subject (in PI), and myocarditis in one subject that occurred 50 days post–study drug infusion and was not considered drug related (in ITP). *CIDP=chronic inflammatory demyelinating polyneuropathy; PI=primary immunodeficiency; ITP=idiopathic thrombocytopenic purpura.

References: 1. Data on file. Talecris Biotherapeutics, Inc. 2. GAMUNEX [package insert]. Research Triangle Park, NC: Talecris Biotherapeutics; 2008.

Important Safety Information — Gamunex, Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified, is indicated for the treatment of primary humoral immunodeficiency disease (PI), idiopathic thrombocytopenic purpura (ITP), and chronic inflammatory demyelinating polyneuropathy (CIDP). Gamunex is contraindicated in individuals with known anaphylactic or severe systemic response to Immune Globulin (Human).

Immune Globulin Intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis and death.

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.

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. Gamunex does not contain sucrose. Glycine, a natural amino acid, is used as a stabilizer.

There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Lung Injury (TRALI)], hemolytic anemia, and aseptic meningitis in patients administered with IGIV. Thrombotic events have been reported in association with IGIV. Patients at risk for thrombotic events may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. Hyperproteinemia, increased serum viscosity, and hyponatremia may occur in patients receiving IGIV therapy.

Gamunex is made from human plasma. Because this product 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.

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

Please see adjacent page for brief summary of GAMUNEX full Prescribing Information.

Evidence based. Patient proven.

To get GAMUNEX call 1-888-MY-GAMUNEX (694-2686) ©2009 Talecris Biotherapeutics, Inc.

All rights reserved.

USA Customer Service 1-800-243-4153 www.gamunex.com

Clinical Communications 1-800-520-2807 September 2009

Reimbursement Help line 1-877-827-3462 GX214-0809

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to I Hyperproteinemia, increased serum viscosity and hyponatremia use GAMUNEX®, Immune Globulin Intravenous (Human), 10% occur in patients receiving IGIV therapy.

Caprylate/Chromatography Purified, safely and effectively. See I Thrombotic events have occurred in patients receiving IGIV therapy. full prescribing information for GAMUNEX. Monitor patients with known risk factors for thrombotic events; GAMUNEX (Immune Globulin Intravenous [Human], 10% Caprylate/ consider baseline assessment of blood viscosity for those at risk of Chromatography Purified) 10% Liquid Preparation hyperviscosity.

Initial U.S. Approval: 2003 I Aseptic Meningitis Syndrome has been reported with GAMUNEX and other IGIV treatments, especially with high doses or rapid infusion.

WARNING: ACUTE RENAL DYSFUNCTION and FAILURE I Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration.

See full prescribing information for complete boxed warning.

I IGIV recipients should be monitored for pulmonary adverse reactions I Renal dysfunction, acute renal failure, osmotic (TRALI). nephrosis, and death may be associated with Immune Globulin Intravenous (Human) (IGIV) products I The product is made from human plasma and may contain in predisposed patients. infectious agents, e.g., viruses and, theoretically, the CreutzfeldtJakob disease agent.

I Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing ADVERSE REACTIONS sucrose. GAMUNEX does not contain sucrose.

I Administer IGIV products at the minimum concentration I PI – Most common drug related adverse reactions during clinical available and the minimum infusion rate practicable. trials were headache and cough.

I ITP – Most common drug related adverse reactions during clinical INDICATIONS AND USAGE trials were headache, vomiting, fever, and nausea.

GAMUNEX is an immune globulin intravenous (human), 10% liquid I CIDP – Most common drug related adverse reactions during clinical indicated for treatment of: trials were headache and fever.

I Primary Humoral Immunodeficiency (PI) To report SUSPECTED ADVERSE REACTIONS, contact Talecris I Idiopathic Thrombocytopenic Purpura (ITP) Biotherapeutics, Inc. at 1-800-520-2807 or FDA at 1-800-FDA-1088 I Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) or www.fda.gov/medwatch.

CONTRAINDICATIONS DRUG INTERACTIONS I Anaphylactic or severe systemic reactions to human immunoglobulin I IgA deficient patients with antibodies against IgA and a history of I The passive transfer of antibodies may interfere with the response to live viral vaccines. hypersensitivity I The passive transfer of antibodies may confound the results of WARNINGS AND PRECAUTIONS serological testing.

I

IgA deficient patients with antibodies against IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions. USE IN SPECIFIC POPULATIONS Epinephrine should be available immediately to treat any acute I In patients over age 65 or in any patient at risk of developing renal severe hypersensitivity reactions. insufficiency, do not exceed the recommended dose, and infuse I Monitor renal function, including blood urea nitrogen, serum GAMUNEX at the minimum infusion rate practicable. creatinine, and urine output in patients at risk of developing acute renal failure.

I Pregnancy: no human or animal data. Use only if clearly needed.

Talecris Biotherapeutics, Inc. Research Triangle Park, NC 27709 USA U.S. License No. 1716

08939392/08939393-BS Revised: October 2008

Hem/Onc Pharmacy 31

Pharmacy Practice News • January 2010

In Focus Imatinib

Nilotinib 300 mg bid

Nilotinib 400 mg bid

35

continued from page 28

either nilotinib arm relative to imatinib.)

The CCyR rates at 12 months were 80% for 300 mg bid nilotinib (P<0.0001 vs. imatinib), 78% for 400 mg bid nilotinib (P=0.0005 vs. imatinib) and 65% for imatinib. Only two patients (0.7%) in the 300-mg nilotinib arm (P<0.001 vs. imatinib) and only one patient (0.4%) in the 400-mg nilotinib arm (P<0.004 vs. imatinib) entered AP or BC within 12 months compared with 11 patients (3.9%) in the imatinib arm.

Both nilotinib and imatinib were relatively well tolerated, but there were differences in the types of side effects.

Whereas grade 3 or 4 myelosuppression was generally low overall, imatinib was associated with higher rates of grade 3/4 neutropenia (20% vs. 12% and 10% for the 300- and 400-mg bid doses of nilotinib, respectively). Grade 3 or 4 nonhematologic side effects were uncommon in all groups, but when imatinib was compared with 300- or 400-mg bid nilotinib for specific side effects of any grade, rates were higher for imatinib for nausea (31% vs. 12% and 20%), muscle spasm (24% vs. 7% and 6%), diarrhea (21% vs. 8% and 7%) and vomiting (14% vs. 5% and 9%). In contrast, rash (11% vs.

31% and 26%) and headache (8% vs. 14% and 21%) were more frequently reported in the two nilotinib arms (Figure).

Edema and weight gain were also more common in the imatinib arm, although overall rates were low. The most common type of edema was peripheral (any grade), reported in 14% of patients taking imatinib and 5% taking either dose of nilotinib. Grade 3 and 4 laboratory abnormalities were also observed at a low frequency overall. Although grade 3 or 4 total bilirubin elevations were more common with nilotinib than imatinib (4%

BEVACIZUMAB continued from page 22

physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York City, pointed out that the updated AVADO study also presented at SABCS showed that the addition of bevacizumab to docetaxel as second-line therapy in patients with MBC improved PFS and overall response rate, but at 25 months, no difference in overall survival was seen.

She agreed with Dr. Perez’s conclusion.

“Based on results from two studies, clinicians may consider bevacizumab in combination with their choice of second-line chemotherapy for patients with metastatic breast cancer who have not received bevacizumab in the firstline setting,” Dr. Dickler said.

31

31

% of Patients

NILOTINIB

30 26

24

25

21

20

21

20 14

14

15

12

11 7

10

8 6

9

8

7 5

0 Nausea

Muscle spasm

Diarrhea

Vomiting

Rash

Headache

Figure. Comparison rates of nonhematologic side effects.

‘Based on these results, we strongly believe that nilotinib may become the new standard of care in newly diagnosed CML.’ —Giuseppe Saglio, MD and 8% vs. <1%) and lipase abnormalities were more common with nilotinib (6% in either arm vs. 3% with imatinib), there was one discontinuation for nilotinib and one for imatinib due to pancreatitis. No clinically significant QTc abnormalities were observed in any group.

Nearly 30% of the patients enrolled in this study were in a high Sokal risk classification, with the remaining patients relatively evenly divided between low and intermediate risk. When rates of MMR were stratified by Sokal risk, nilotinib was consistently more effective in all risk groups. Regardless of therapy, the study supported other evidence that patients with a better response, characterized by CCyR, are less likely to progress in CML. The researchers said the greater efficacy of nilotinib can be attributed to a greater specificity for the molecular target, producing a greater likelihood of an MMR. This response predicts protection from progression, which was more common for imatinib by the end of the study (4% vs. <1% for either nilotinib dose).

Confusing Picture Laura Boehnke Michaud, PharmD, BCOP, FASHP, manager of clinical pharmacy services at M.D. Anderson Cancer Center in Houston, said the results of RIBBON-2 “confuse the picture” of how to manage patients with advanced and metastatic breast cancer. A previous large randomized Phase 3 trial found no advantage in PFS for the addition of bevacizumab to capecitabine in women with advanced breast cancer who had progressed on an anthracycline and a taxane (J Clin Oncol 2005;23:792-799). Secondly, none of the trials to date with bevacizumab plus chemotherapy in breast cancer has demonstrated significant improvements in overall survival. These issues, coupled with the difficult-to-manage side effects of hypertension and blood

“We know that despite excellent results we can achieve with imatinib, progression can still occur in a small proportion of patients, and progression is associated with a poor outcome,” Dr. Saglio said. Based on these results, nilotinib further reduces the risk for progression relative to imatinib.

More Data Needed Asked to comment on the study, Richard M. Stone, MD, director of the Adult Leukemia Program at Dana-Farber Cancer Institute, in Boston, characterized the results as “encouraging,” but he did not agree with the conclusion that the study establishes nilotinib as the new standard of care in CML. He noted that nilotinib has only demonstrated superiority on the surrogate markers of MMR and CCyR. Although the responses of both parameters likely predict a decreased risk for disease progression, patients who take somewhat longer to attain the desired end points may still do well. According to Dr. Stone, the

clots, raise concern that the addition of bevacizumab may provide only modest, transient benefits for patients with MBC, Dr. Michaud suggested.

“Further, recent preclinical data indicate that tumors relapsing while on antiangiogenic therapies appear to be more invasive, which may be one reason why the addition of bevacizumab has not had a positive effect on [overall] survival. These data, of course, need to be confirmed in clinical trials, but bring to light significant concerns with this agent,” she said.

“Everyone is grappling with how to apply results of RIBBON-2 and to decide what is in the best interest of patients,” Dr. Michaud added. “I have some concerns about giving a clearly toxic drug to potentially compromised patients that does not extend survival.

decreased rate of progression to AP disease was the most compelling finding in favor of nilotinib over imatinib.

“The story is complicated, and it is not clear that this study has generated the type of data that warrants an immediate change in practice. We need longer follow-up that continues to show meaningful clinical differences, such as risk for progression, beyond the surrogate end points,” Dr. Stone said. “These are strong findings that do predict nilotinib has the potential to emerge as the better firstline agent, but we are not there yet.”

Hem/Onc Pharmacist Urges Caution Asked for his comment, Casey B. Williams, PharmD, hematology/oncology clinical coordinator and residency director, Kansas University Medical Center, Kansas City, concurred with Dr. Stone. “I am also not convinced that this data warrants an immediate change in practice.

We have at least eight years of followup information to go on with imatinib from the IRIS trial and the results have been quite impressive. Overall survival is approximately 85% with imatinib, and actually climbs to around 93% when only CML-related deaths and those prior to stem cell transplant are considered,” Dr. Williams reported.

From the pharmacy perspective, one variable of interest is price. Dr. Williams noted that nilotinib “is a lot more expensive than imatinib,” but these results may change pricing for both imatinib and nilotinib. Pricing strategies are particularly difficult to predict because the same pharmaceutical company, Novartis, markets both drugs. In any event, Dr. Williams characterized nilotinib as “a promising alternative to imatinib as a first-line agent,” but “I am not ready to change my practice just yet.”

—Ted Bosworth

The drug is going to be studied as maintenance therapy in this population, which is also of concern, but should be systematically studied.”

Dr. Michaud also stated that the decision to add bevacizumab should be individualized and discussed fully with each appropriate patient, including mention of all the concerns she cited.

The bottom line is that bevacizumab has difficult-to-manage toxicities, does not prolong survival, and is also expensive. Dr. Michaud is not convinced that this drug should be used second-line, as in the RIBBON-2 trial. “However, each patient should be presented with the available information and given the opportunity to decline or accept the therapy.”

—Alice Goodman

32

Hem/Onc Pharmacy

Pharmacy Practice News • January 2010

In Focus

Denosumab Trumps Zoledronic Acid for Bone Metastases T

wo studies support the first-line use of denosumab (Prolia, Amgen) rather than zoledronic acid (Zometa, Novartis) for cancer patients with bone metastases. The studies were presented at the recent joint meeting of the European CanCer Organisation and the European Society for Medical Oncology (ECCO-ESMO). Amgen says it is evaluating when to apply for FDA approval for denosumab.

“I don’t see any downside of using [denosumab] first-line whatsoever. It’s more efficacious, has less toxicity, has no renal monitoring and is more convenient,” said Alison Stopeck, MD, associate professor of medicine, Arizona Cancer Center, University of Arizona Health Sciences Center, Tucson. She presented results from a study comparing the use of the two drugs in patients with breast cancer. Dr. Stopeck noted that up to 80% of patients with stage IV breast cancer develop bone metastases at some point during the course of their disease.

“In breast cancer, unlike some of the other solid tumors, patients live years with metastatic disease, so treating or palliating bone metastases is actually a very important part of what I do,” Dr. Stopeck said.

In the international trial (abstract LBA2), investigators enrolled 2,046 patients with advanced breast cancer and bone metastases and randomized them to 120 mg subcutaneous denosumab and an IV infusion of placebo, or 4 mg IV zoledronic acid plus a subcutaneous injection of placebo. Patients who had prior IV bisphosphonate administration for bone metastases were excluded from the study; however, patients were eligi-

ble if they had received bisphosphonates for osteopenia or osteoporosis. Patients taking zoledronic acid had their renal function monitored and their drug dose reduced if creatinine levels indicated a need, per the prescribing information for zoledronic acid. The investigators found that denosumab was 18% better than zoledronic acid in delaying the time to first on-study skeletal-related events (SREs)—fracture, radiation to bone, surgery to bone, or spinal cord

compression—or hypercalcemia (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.71-0.95; P=0.01). Denosumab was 23% better than zoledronic acid at delaying the time to first and subsequent on-study SRE (HR, 0.77; 95% CI, 0.66-0.89; P=0.001).

“On average, patients were in the study 26.5 months when they were in the Zometa arm before they developed a skeletal-related event and on denosumab, it hadn’t been reached,”

A trusted source brings Tacrolimus Capsules to your shelf.

WARNING Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression.

Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe Tacrolimus Capsules. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

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

Fluorodeoxyglucose positron emission tomography image depicting bone metastases in a patient with inflammatory breast cancer.

Dr. Stopeck said. “Not even 50% of the patients in the denosumab arm had had a skeletal-related event.”

Rates of adverse events and infectious serious events were similar, but patients taking denosumab had a lower incidence of renal toxicity (4.9% vs. 8.5%). In a prespecified exploratory analysis, patients receiving denosumab reported worsening of pain later than those on zoledronic acid (88 vs. 64 days, respectively; HR, 0.87; 95% CI, 0.79-0.97; P=0.009).

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

Prograf® is a registered trademark of Astellas Pharma Inc.

www.us.sandoz.com a Novartis company © 2009 Sandoz Inc. SDZ0045

Look beyond the bottle ▲ Tacrolimus Capsules are AB rated to Prograf® Capsules ▲ Offered in .5 mg, 1 mg and 5 mg capsules ▲ Sandoz is a member of the Novartis family of companies — a name you can trust for quality and reliability

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Hem/Onc Pharmacy 33

Pharmacy Practice News • January 2010

In Focus Osteonecrosis of the jaw was infrequent in both treatment groups (20 patients receiving denosumab [2%] compared with 14 patients [1.4%] receiving zoledronic acid, but this difference was not statistically significant). Overall survival (HR, 0.95; 95% CI, 0.81-1.11; P=0.50) and time to cancer progression (HR, 0.99; 95% CI, 0.891.11; P=0.90) were balanced between treatment arms.

In a second randomized, double-blind trial presented at ECCO-ESMO (abstract 5187), investigators enrolled 1,776 cancer patients with solid tumors or multiple

Tacrolimus Capsules WARNING Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe tacrolimus capsules.

Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

INDICATIONS AND USAGE Tacrolimus capsules is indicated for the prophylaxis of organ rejection in patients receiving allogeneic liver or kidney transplants. It is recommended that tacrolimus capsules be used concomitantly with adrenal corticosteroids. In kidney transplant recipients, it is recommended that tacrolimus capsules be used in conjunction with azathioprine or mycophenolate mofetil (MMF). The safety and efficacy of the use of tacrolimus capsules with sirolimus has not been established.

CONTRAINDICATIONS Tacrolimus capsules are contraindicated in patients with a hypersensitivity to tacrolimus.

WARNINGS (See boxed WARNING) Post-Transplant Diabetes Mellitus Insulin-dependent post-transplant diabetes mellitus (PTDM) was reported in 20% of tacrolimus-treated kidney transplant patients without pretransplant history of diabetes mellitus in the Phase III study. The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at one year and in 50% at 2 years post transplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM. Insulin-dependent post-transplant diabetes mellitus was reported in 18% and 11% of tacrolimus-treated liver transplant patients and was reversible in 45% and 31% of these patients at 1 year post transplant, in the U.S. and European randomized studies, respectively. Hyperglycemia was associated with the use of tacrolimus in 47% and 33% of liver transplant recipients in the U.S. and European randomized studies, respectively, and may require treatment (see ADVERSE REACTIONS).

Nephrotoxicity Tacrolimus capsules can cause nephrotoxicity, particularly when used in high doses. Nephrotoxicity was reported in approximately 52% of kidney transplantation patients and in 40% and 36% of liver transplantation patients receiving tacrolimus capsules in the U.S. and European randomized trials, respectively (see ADVERSE REACTIONS). More overt nephrotoxicity is seen early after transplantation, characterized by increasing serum creatinine and a decrease in urine output. Patients with impaired renal function should be monitored closely as the dosage of tacrolimus capsules may need to be reduced. In patients with persistent elevations of serum creatinine who are unresponsive to dosage adjustments, consideration should be given to changing to another immunosuppressive therapy. Care should be taken in using tacrolimus with other nephrotoxic drugs. In particular, to avoid excess nephrotoxicity, tacrolimus capsules should not be used simultaneously with cyclosporine. Tacrolimus capsules or cyclosporine should be discontinued at least 24 hours prior to initiating the other. In the presence of elevated tacrolimus capsules or cyclosporine concentrations, dosing with the other drug usually should be further delayed.

Hyperkalemia Mild to severe hyperkalemia was reported in 31% of kidney transplant recipients and in 45% and 13% of liver transplant recipients treated with tacrolimus capsules in the U.S. and European randomized trials, respectively, and may require treatment (see ADVERSE REACTIONS).

Serum potassium levels should be monitored and potassium-sparing diuretics should not be used during tacrolimus capsules therapy (see PRECAUTIONS).

Neurotoxicity Tacrolimus capsules can cause neurotoxicity, particularly when used in high doses. Neurotoxicity, including tremor, headache, and other changes in motor function, mental status, and sensory function were reported in approximately 55% of liver transplant recipients in the two randomized studies. Tremor occurred more often in tacrolimus capsulestreated kidney transplant patients (54%) compared to cyclosporinetreated patients. The incidence of other neurological events in kidney transplant patients was similar in the two treatment groups (see ADVERSE REACTIONS). Tremor and headache have been associated with high whole-blood concentrations of tacrolimus and may respond to dosage adjustment. Seizures have occurred in adult and pediatric patients receiving tacrolimus capsules (see ADVERSE REACTIONS). Coma and delirium also have been associated with high plasma concentrations of tacrolimus.

‘It clearly appears that denosumab has activity and may be better than zoledronic acid in delaying the onset of skeletal-related events in patients with breast cancer metastatic to bone.’

—Sarah L. Scarpace, PharmD myeloma who had bone metastases and were naïve to IV bisphosphonates; the study excluded patients with breast or prostate cancer. Patients were randomized to receive subcutaneous denosumab 120 mg and an IV placebo, or 4 mg IV

Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). Symptoms indicating PRES include headache, altered mental status, seizures, visual disturbances and hypertension. Diagnosis may be confirmed by radiological procedure. If PRES is suspected or diagnosed, blood pressure control should be maintained and immediate reduction of immunosuppression is advised. This syndrome is characterized by reversal of symptoms upon reduction or discontinuation of immunosuppression.

Malignacy and Lymphoproliferative Disorders As in patients receiving other immunosuppressants, patients receiving tacrolimus capsules are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. A lymphoproliferative disorder (LPD) related to Epstein-Barr Virus (EBV) infection has been reported in immunosuppressed organ transplant recipients. The risk of LPD appears greatest in young children who are at risk for primary EBV infection while immunosuppressed or who are switched to tacrolimus capsules following long-term immunosuppression therapy. Because of the danger of oversuppression of the immune system which can increase susceptibility to infection, combination immunosuppressant therapy should be used with caution.

Latent Viral Infections Immunosuppressed patients are at increased risk for opportunistic infections, including latent viral infections. These include BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML) which have been observed in patients receiving tacrolimus. These infections may lead to serious, including fatal, outcomes.

PRECAUTIONS General Hypertension is a common adverse effect of tacrolimus therapy (see ADVERSE REACTIONS). Mild or moderate hypertension is more frequently reported than severe hypertension. Antihypertensive therapy may be required; the control of blood pressure can be accomplished with any of the common antihypertensive agents. Since tacrolimus may cause hyperkalemia, potassium-sparing diuretics should be avoided.

While calcium-channel blocking agents can be effective in treating tacrolimus-associated hypertension, care should be taken since interference with tacrolimus metabolism may require a dosage reduction (see Drug Interactions).

Renally and Hepatically Impaired Patients For patients with renal insufficiency some evidence suggests that lower doses should be used. The use of tacrolimus capsules in liver transplant recipients experiencing post-transplant hepatic impairment may be associated with increased risk of developing renal insufficiency related to high whole-blood levels of tacrolimus. These patients should be monitored closely and dosage adjustments should be considered. Some evidence suggests that lower doses should be used in these patients.

Myocardial Hypertrophy Myocardial hypertrophy has been reported in association with the administration of tacrolimus capsules, and is generally manifested by echocardiographically demonstrated concentric increases in left ventricular posterior wall and interventricular septum thickness. Hypertrophy has been observed in infants, children and adults. This condition appears reversible in most cases following dose reduction or discontinuance of therapy. In a group of 20 patients with pre- and post-treatment echocardiograms who showed evidence of myocardial hypertrophy, mean tacrolimus whole blood concentrations during the period prior to diagnosis of myocardial hypertrophy ranged from 11 to 53 ng/mL in infants (N=10, age 0.4 to 2 years), 4 to 46 ng/mL in children (N=7, age 2 to 15 years) and 11 to 24 ng/mL in adults (N=3, age 37 to 53 years).

In patients who develop renal failure or clinical manifestations of ventricular dysfunction while receiving tacrolimus therapy, echocardiographic evaluation should be considered. If myocardial hypertrophy is diagnosed, dosage reduction or discontinuation of tacrolimus should be considered.

Information for Patients Patients should be informed of the need for repeated appropriate laboratory tests while they are receiving tacrolimus capsules. They should be given complete dosage instructions, advised of the potential risks during pregnancy, and informed of the increased risk of neoplasia. Patients should be informed that changes in dosage should not be undertaken without first consulting their physician.

Patients should be informed that tacrolimus capsules can cause diabetes mellitus and should be advised of the need to see their physician if they develop frequent urination, increased thirst or hunger.

As with other immunosuppressive agents, owing to the potential risk of malignant skin changes, exposure to sunlight and ultraviolet (UV) light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

zoledronic acid and a subcutaneous placebo. Patients were encouraged to take daily supplemental calcium and vitamin D. Treatment groups were well balanced.

Investigators found that denosumab

Laboratory Tests Serum creatinine, potassium, and fasting glucose should be assessed regularly. Routine monitoring of metbolic and hematologic systems should be performed as clinically warranted.

Drug Interactions Due to the potential for additive or synergistic impairment of renal function, care should be taken when administering tacrolimus capsules with drugs that may be associated with renal dysfunction.

These include, but are not limited to, aminoglycosides, amphotericin B, and cisplatin. Initial clinical experience with the co-administration of tacrolimus and cyclosporine resulted in additive/synergistic nephrotoxicity. Patients switched from cyclosporine to tacrolimus should receive the first tacrolimus capsules dose no sooner than 24 hours after the last cyclosporine dose. Dosing may be further delayed in the presence of elevated cyclosporine levels.

Drugs that May Alter Tacrolimus Concentrations Since tacrolimus is metabolized mainly by the CYP3A enzyme systems, substances known to inhibit these enzymes may decrease the metabolism or increase bioavailability of tacrolimus as indicated by increased whole blood or plasma concentrations. Drugs known to induce these enzyme systems may result in an increased metabolism of tacrolimus or decreased bioavailability as indicated by decreased whole blood or plasma concentrations. Monitoring of blood concentrations and appropriate dosage adjustments are essential when such drugs are used concomitantly.

Drugs that may increase tacrolimus blood concentrations: Calcium Channel Blockers: diltiazem, nicardipine, nifedipine, verapamil; Antifungal Agents: clotrimazole, fluconazole, itraconazole, ketoconazole, voriconazole; Macrolide Antibiotics: clarithromycin, erythromycin, troleandomycin; Gastrointestinal Prokinetic Agents: cisapride, metoclopramide; Other Drugs: bromocriptine, chloramphenicol, cimetidine, cyclosporine, danazol, ethinyl estradiol, methylprednisolone, omeprazole, pretease inhibitors, nefazodone, magnesium-aluminum-hydroxide.

Drugs that may decrease tacrolimus blood concentrations: Anticonvulsants: carbamazepine, Phenobarbital, penytoin; Antimicrobials: rifabutin, caspofungin, rifampin; Herbal Preparations: St. John’s Wort; Other Drugs: sirolimus This list is not all-inclusive.

St. John’s Wort (Hypericum perforatum) induces CYP3A4 and P-glycoprotein. Since tacrolimus is a substrate for CYP3A4, there is the potential that the use of St. John’s Wort in patients receiving tacrolimus capsules could result in reduced tacrolimus levels.

Interaction studies with drugs used in HIV therapy have not been conducted. However, care should be exercised when drugs that are nephrotoxic (e.g., ganciclovir) or that are metabolized by CYP3A (e.g., nelfinavir, ritonavir) are administered concomitantly with tacrolimus. Tacrolimus may affect the pharmacokinetics of other drugs (e.g., phenytoin) and increase their concentration. Grapefruit juice affects CYP3A-mediated metabolism and should be avoided.

Following co-administration of tacrolimus and sirolimus (2 or 5 mg/ day) in stable renal transplant patients, mean tacrolimus AUC0-12 and Cmin decreased approximately by 30% relative to tacrolimus alone. Mean tacrolimus AUC0-12 and Cmin following co-administration of 1 mg/day of sirolimus decreased approximately 3% and 11%, respectively.

The safety and efficacy of tacrolimus used in combination with sirolimus for the prevention of graft rejection has not been established and is not recommended.

Other Drug Interactions Immunosuppressants may affect vaccination. Therefore, during treatment with tacrolimus capsules, vaccination may be less effective. The use of live vaccines should be avoided; live vaccines may include, but are not limited to measles, mumps, rubella, oral polio, BCG, yellow fever, and TY 21a typhoid.1 At a given MMF dose, mycophenolic acid (MPA) exposure is higher with tacrolimus capsules co-administration than with cyclosporine co-administration due to the differences in the interruption of the enterohepatic recirculation of MPA. Clinicians should be aware that there is also a potential for increased MPA exposure after crossover from cyclosporine to tacrolimus in patients concomitantly receiving MMF or MPA. Carcinogenesis, Mutagenesis, Impairment of Fertility An increased incidence of malignancy is a recognized complication of immunosuppression in recipients of organ transplants. The most common forms of neoplasms are non-Hodgkin’s lymphomas and carcinomas of the skin. As with other immunosuppressive therapies, the risk of malignancies in tacrolimus recipients may be higher than in the normal, healthy population. Lymphoproliferative disorders associated with Epstein-Barr Virus infection have been seen. It has been reported that reduction or discontinuation of immunosuppression may cause the lesions to regress.

delayed the time to first on-study SRE (pathologic fracture, radiation therapy or surgery to bone, or spinal cord compression) and was noninferior to zoledronic acid (HR, 0.84; 95% CI, 0.71-0.98; P=0.0007). The median time to first onstudy SRE was 20.6 months for patients taking denosumab and 16.3 months for those taking zoledronic acid. Although numerically greater, the delay in time to first on-study SRE with denosumab was not superior to zoledronic acid based on statistical analysis. “At 0.06, it was very close to being superior, but did

•

see DENOSUMAB, page 34

34

Hem/Onc Pharmacy

Pharmacy Practice News • January 2010

In Focus

DENOSUMAB continued from page 33

not reach statistical significance,” said David Henry, MD, clinical professor of medicine at Pennsylvania Hospital, Philadelphia. Time to first and subsequent SRE was also numerically greater for denosumab, but not statistically significant (HR, 0.90; 95% CI, 0.77-1.04; P=0.14). Both drugs were equivalent at decreasing pain over time, but denosumab was superior when it came to how long it took for patients’ pain to get worse (57 days with denosumab vs.

No evidence of genotoxicity was seen in bacterial (Salmonella and E. coli) or mammalian (Chinese hamster lung-derived cells) in vitro assays of mutagenicity, the in vitro CHO/HGPRT assay of mutagenicity, or in vivo clastogenicity assays performed in mice; tacrolimus did not cause unscheduled DNA synthesis in rodent hepatocytes.

Carcinogenicity studies were carried out in male and female rats and mice. In the 80-week mouse study and in the 104-week rat study no relationship of tumor incidence to tacrolimus dosage was found. The highest doses used in the mouse and rat studies were 0.8 - 2.5 times (mice) and 3.5 - 7.1 times (rats) the recommended clinical dose range of 0.1 - 0.2 mg/kg/day when corrected for body surface area.

No impairment of fertility was demonstrated in studies of male and female rats. Tacrolimus, given orally at 1 mg/kg (0.7 - 1.4X the recommended clinical dose range of 0.1 - 0.2 mg/kg/day based on body surface area corrections) to male and female rats, prior to and during mating, as well as to dams during gestation and lactation, was associated with embryolethality and with adverse effects on female reproduction. Effects on female reproductive function (parturition) and embryolethal effects were indicated by a higher rate of preimplantation loss and increased numbers of undelivered and nonviable pups. When given at 3.2 mg/kg (2.3 - 4.6X the recommended clinical dose range based on body surface area correction), tacrolimus was associated with maternal and paternal toxicity as well as reproductive toxicity including marked adverse effects on estrus cycles, parturition, pup viability, and pup malformations.

Pregnancy: Category C In reproduction studies in rats and rabbits, adverse effects on the fetus were observed mainly at dose levels that were toxic to dams. Tacrolimus at oral doses of 0.32 and 1 mg/kg during organogenesis in rabbits was associated with maternal toxicity as well as an increase in incidence of abortions; these doses are equivalent to 0.5 - 1X and 1.6 - 3.3X the recommended clinical dose range (0.1 - 0.2 mg/kg) based on body surface area corrections. At the higher dose only, an increased incidence of malformations and developmental variations was also seen.

Tacrolimus, at oral doses of 3.2 mg/kg during organogenesis in rats, was associated with maternal toxicity and caused an increase in late resorptions, decreased numbers of live births, and decreased pup weight and viability. Tacrolimus, given orally at 1 and 3.2 mg/kg (equivalent to 0.7 - 1.4X and 2.3 - 4.6X the recommended clinical dose range based on body surface area corrections) to pregnant rats after organogenesis and during lactation, was associated with reduced pup weights.

No reduction in male or female fertility was evident.

There are no adequate and well-controlled studies in pregnant women.

Tacrolimus is transferred across the placenta. The use of tacrolimus during pregnancy has been associated with neonatal hyperkalemia and renal dysfunction. Tacrolimus capsules should be used during pregnancy only if the potential benefit to the mother justifies potential risk to the fetus.

Nursing Mothers Since tacrolimus is excreted in human milk, nursing should be avoided.

Pediatric Patients Experience with tacrolimus in pediatric kidney patients is limited.

Successful liver transplants have been performed in pediatric patients (ages up to 16 years) using tacrolimus capsules. Two randomized trials of tacrolimus capsules in primary liver transplantation included 56 pediatric patients. Thirty-one patients were randomized to tacrolimusbased and 25 to cyclosporine-based therapies. Additionally, a minimum of 122 pediatric patients were studied in an uncontrolled trial of tacrolimus in living related donor liver transplantation. Pediatric patients generally required higher doses of tacrolimus capsules to maintain blood trough concentrations of tacrolimus similar to adult patients.

ADVERSE REACTION Liver Transplantation The principal adverse reactions of tacrolimus are tremor, headache, diarrhea, hypertension, nausea, and abnormal renal function. These occur with oral and IV administration of tacrolimus and may respond to a reduction in dosing. Diarrhea was sometimes associated with other gastrointestinal complaints such as nausea and vomiting.

Hyperkalemia and hypomagnesemia have occurred in patients receiving tacrolimus therapy. Hyperglycemia has been noted in many patients; some may require insulin therapy (see WARNINGS).

Kidney Transplantation The most common adverse reactions reported were infection, tremor, hypertension, abnormal renal function, constipation, diarrhea, headache, abdominal pain and insomnia.

Less Frequently Reported Adverse Reactions The following adverse events were reported in either liver and/or kidney transplant recipients who were treated with tacrolimus in clinical trials.

36 days with Zometa), however, this did not reach statistical significance.

Adverse events, progression-free survival and overall survival were equivalent in the two groups.

“Denosumab met the primary end point of this trial. It was not inferior to Zometa when looking to prevent or delay first on-study SRE. … Pain improvement was a little better in the denosumab arm. There was no difference in overall survival, disease progression, or adverse-event rates.

There was a little more renal toxicity and acute phase reactions in the Zometa arm and there was a little more hypocalce-

Nervous System (see WARNINGS) Abnormal dreams, agitation, amnesia, anxiety, confusion, convulsion, crying, depression, dizziness, elevated mood, emotional lability, encephalopathy, haemorrhagic stroke, hallucinations, headache, hypertonia, incoordination, insomnia, monoparesis, myoclonus, nerve compression, nervousness, neuralgia, neuropathy, paresthesia, paralysis flaccid, psychomotor skills impaired, psychosis, quadriparesis, somnolence, thinking abnormal, vertigo, writing impaired Special Senses Abnormal vision, amblyopia, ear pain, otitis media, tinnitus Gastrointestinal Anorexia, cholangitis, cholestatic jaundice, diarrhea, duodenitis, dyspepsia, dysphagia, esophagitis, flatulence, gastritis, gastroesophagitis, gastrointestinal hemorrhage, GGT increase, GI disorder, GI perforation, hepatitis, hepatitis granulomatous, ileus, increased appetite, jaundice, liver damage, liver function test abnormal, nausea, nausea and vomiting, oesophagitis ulcerative, oral moniliasis, pancreatic pseudocyst, rectal disorder, stomatitis, vomiting Cardiovascular Abnormal ECG, angina pectoris, arrhythmia, atrial fibrillation, atrial flutter, bradycardia, cardiac fibrillation, cardiopulmonary failure, cardiovascular disorder, chest pain, congestive heart failure, deep thrombophlebitis, echocardiogram abnormal, electrocardiogram QRS complex abnormal, electrocardiogram ST segment abnormal, heart failure, heart rate decreased, hemorrhage, hypotension, peripheral vascular disorder, phlebitis, postural hypotension, syncope, tachycardia, thrombosis, vasodilatation Urogenital (see WARNINGS) Acute kidney failure, albuminuria, BK nephropathy, bladder spasm, cystitis, dysuria, hematuria, hydronephrosis, kidney failure, kidney tubular necrosis, nocturia, oliguria, pyuria, toxic nephropathy, urge incontinence, urinary frequency, urinary incontinence, urinary retention, vaginitis Metabolic/Nutritional Acidosis, alkaline phosphatase increased, alkalosis, ALT (SGPT) increased, AST (SGOT) increased, bicarbonate decreased, bilirubinemia, BUN increased, dehydration, edema, GGT increased, gout, healing abnormal, hypercalcemia, hypercholesterolemia, hyperkalemia, hyperlipemia, hyperphosphatemia, hyperuricemia, hypervolemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactic dehydrogenase increase, peripheral edema, weight gain Endocrine (see PRECAUTIONS) Cushing’s syndrome, diabetes mellitus Hemic/Lymphatic Coagulation disorder, ecchymosis, haematocrit increased, haemoglobin abnormal, hypochromic anemia, leukocytosis, leukopenia, polycythemia, prothrombin decreased, serum iron decreased, thrombocytopenia Miscellaneous Abdomen enlarged, abdominal pain, abscess, accidental injury, allergic reaction, asthenia, back pain, cellulitis, chills, fall, feeling abnormal, fever, flu syndrome, generalized edema, hernia, mobility decreased, pain, peritonitis, photosensitivity reaction, sepsis, temperature intolerance, ulcer Musculoskeletal Arthralgia, cramps, generalized spasm, joint disorder, leg cramps, myalgia, myasthenia, osteoporosis Respiratory Asthma, bronchitis, cough increased, dyspnea, emphysema, hiccups, lung disorder, lung function decreased, pharyngitis, pleural effusion, pneumonia, pneumothorax, pulmonary edema, respiratory disorder, rhinitis, sinusitis, voice alteration

mia in the denosumab arm that was not clinically significant. ONJ [osteonecrosis of the jaw] is an infrequent event and not different between the two arms,” Dr. Henry said.

“I think the most important [message], when I take this home and play it out in the clinic to patients, is that you can give denosumab monthly subcutaneously, much [easier] than having to have an IV started,” said Dr. Henry.

“While superiority was statistically not met, to me the convenience of the drug and lack of renal monitoring is such a winner for patients that it moves in my

Gastrointestinal Bile duct stenosis, colitis, enterocolitis, gastroenteritis, gastrooesophageal reflux disease, hepatic cytolysis,hepatic necrosis, hepatotoxicity, impaired gastric emptying, liver fatty, mouth ulceration, pancreatitis haemorrhagic, pancreatitis necrotizing, stomach ulcer, venoocclusive liver disease Hemic/Lymphatic Disseminated intravascular coagulation, neutropenia, pancytopenia, thrombocytopenic purpura, thrombotic thrombocytopenic purpura Metabolic/Nutritional Glycosuria, increased amylase including pancreatitis, weight decreased Miscellaneous Feeling hot and cold, feeling jittery, hot flushes, multi-organ failure, primary graft dysfunction Nervous System Carpal tunnel syndrome, cerebral infarction, hemiparesis, leukoencephalopathy, mental disorder, mutism, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), quadriplegia, speech disorder, syncope Respiratory Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, respiratory distress, respiratory failure Skin Stevens-Johnson syndrome, toxic epidermal necrolysis Special Senses Blindness, blindness cortical, hearing loss including deafness, photophobia Urogenital Acute renal failure, cystitis haemorrhagic, hemolytic-uremic syndrome, micturition disorder.

There have been rare spontaneous reports of myocardial hypertrophy associated with clinically manifested ventricular dysfunction in patients receiving tacrolimus therapy (see PRECAUTIONS-Myocardial Hypertrophy).

Please see current package insert for complete adverse events information.

OVERDOSAGE Limited overdosage experience is available. Acute overdosages of up to 30 times the intended dose have been reported. Almost all cases have been asymptomatic and all patients recovered with no sequelae.

Occasionally, acute overdosage has been followed by adverse reactions consistent with those listed in the ADVERSE REACTIONS section except in one case where transient urticaria and lethargy were observed. Based on the poor aqueous solubility and extensive erythrocyte and plasma protein binding, it is anticipated that tacrolimus is not dialyzable to any significant extent; there is no experience with charcoal hemoperfusion. The oral use of activated charcoal has been reported in treating acute overdoses, but experience has not been sufficient to warrant recommending its use. General supportive measures and treatment of specific symptoms should be followed in all cases of overdosage.

Asked to comment on the study, Sarah L. Scarpace, PharmD, BCOP, assistant professor, acting vice chair, Department of Pharmacy Practice, Albany College of Pharmacy and Health Sciences, said, “it clearly appears that denosumab has activity and may be better than zoledronic acid in delaying the onset of skeletal-related events in patients with breast cancer metastatic to bone.”

Dr. Scarpace added, however, that “the true implications and role of denosumab therapy will depend highly on the apparent survival advantage that zoledronic acid has shown (over placebo) in this population, independent of its effects on skeletal-related events.

The cost of these therapies also is a consideration in terms of where it will ultimately rest in the role of drug therapy for this population.”

Both studies were supported by Amgen.

—Kate O’Rourke

What’s Your View?

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POST MARKETING

Cardiovascular Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, Torsade de Pointes, venous thrombosis deep limb, ventricular extrasystoles, ventricular fibrillation

Pharmacist’s Perspective

REFERENCE: 1 CDC: Recommendations of the Advisory Committee on Immunization Practices: Use of vaccines and immune globulins in persons with altered immunocompetence. MMWR 1993;42(RR-4):1-18.

Skin Acne, alopecia, exfoliative dermatitis, fungal dermatitis, herpes simplex, herpes zoster, hirsutism, neoplasm skin benign, skin discoloration, skin disorder, skin ulcer, sweating

Post Marketing Adverse Events The following adverse events have been reported from worldwide marketing experience with tacrolimus.

mind to first position.”

Catherine Van Poznak, MD, an assistant professor of internal medicine specializing in breast oncology at the University of Michigan Medical School, Ann Arbor, said the studies show progress is being made. “The results of these Phase III studies suggest that future studies will be needed to define the optimal use [of ] osteoclast inhibitors. We do not yet know if subsets of patients may benefit more from one drug over another and we haven’t yet got data on the use of combination or sequential therapy,” Dr. Van Poznak said. “Our ability to decrease SREs is improved with the inhibition of osteoclast activity. For example, in the placebo arm of the earlier bisphosphonate studies, patients may have experienced an SRE three to four times within a year. The median time to first SRE in the study of metastatic breast cancer, NCT00321464, was over two years. Clearly, the field is making progress.”

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Are clinicians at your oncology department aware of the new denosumab data? If so, how are the data impacting practice? Do you feel this drug should get the nod over zoledronic acid for metastatic breast cancer?

Send replies to

ppneditor@mcmahonmed.com

Hem/Onc Pharmacy 35

Pharmacy Practice News â&#x20AC;˘ January 2010

In Focus

Clinical Pearl

Rapid Infusion of Rituximab Works in Community Setting R

ituximab (Rituxan, Genentech/ Biogen Idec) is generally well tolerated by patients with non-Hodgkinâ&#x20AC;&#x2122;s lymphoma (NHL), but the probability of infusion-related toxicities still exists.

Due to the risk for these toxicities, the manufacturer of rituximab recommends a slow standard administration schedule, requiring an average of five to six hours during the initial infusion and three to four hours during subsequent infusions. Rituximabâ&#x20AC;&#x2122;s long infusion times and expanding indications have increased nursing resource and time demands in community-based outpatient infusion clinics that could potentially lead to administration errors and increased patient stress. To help alleviate some of these concerns, we implemented a rapid rituximab infusion protocol in an effort to decrease infusion times along with nursing and patient stress.

From September 2008 to June 2009, we initiated a 90-minute rapid rituximab infusion protocol at three community-based outpatient infusion clinics located in Gainesville, Ga. Study participants were diagnosed with CD20-positive NHL and were allowed to enter the trial at any point in their treatment cycle.

Patients received the standard rituximab dose of 375 mg/m2 over 90 minutes (20% of the dose during the first 30 minutes and 80% over the subsequent 60 minutes) in a total volume of 250-mL normal saline. Premedications were not standardized and could vary per facility protocol. We used a strict safety monitoring algorithm, measuring blood pressure, heart rate and respiratory rate before the infusion and at 15, 30, 60 and 90 minutes to monitor respiratory or cardiac symptoms. We also monitored temperature prior to the infusion and questioned patients about adverse reactions throughout the infusion and at each visit. Sixteen patients were enrolled and treated with a total of 51 rapid rituximab infusions. The median number of infusions each patient received was three (range, one to seven). Most of the patients were younger than 60 and male. Three patients experienced minor adverse reactions which were expected with rituximab administration. The total infusion time saved compared with

standard infusion rates was 2,925 minutes (49 hours; 57 minutes per infusion). Patient and nursing satisfaction, assessed through surveys, was extremely high in all but one statement.

We report excellent safety and tolerability using a 90-minute rapid rituximab infusion in our community outpatient infusion clinics. The results of this study support other reports of success with decreased rituximab infusion time.

Patients and nurses preferred the rapid infusion to the standard infusion rate because of the time saved with this

regimen. Nursing staff, however, did feel that the intense monitoring schedule in this trial required equal attention to that of the standard infusion. If medical oncologists at these practice sites adopted this regimen as standard practice, an easier monitoring schedule should be employed to free up nursing time and resources.

We believe that most patients will tolerate the rapid rituximab infusion as long as no severe adverse reactions are seen on initial infusions. Other investigators have adopted this as the

standard of care and have had excellent results. Sehn et al reported the use of a 90-minute rapid rituximab infusion in more than 1,200 patients, with only one grade III reaction (Blood 2007;109:41714173). Furthermore, another study assessed a 60-minute rapid rituximab infusion without severe adverse reactions (Ann Oncol 2006;17:1027-1028). â&#x20AC;&#x201D;Chad J. Coulter, PharmD Assistant Professor of Clinical and Administrative Sciences Sullivan University College of Pharmacy Louisville, Ky.

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Send submissions (300-600 words) to ppneditor@ mcmahonmed.com.

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36 Clinical

Pharmacy Practice News • January 2010

Awards

Vote for the Best Clinical Abstract of 2009 P harmacy societies bestow the title “best” on at least one abstract presented at their annual meetings. But is there a “best of the best”? We identified 13 candidates from among the “best abstract” winners honored at major conferences over the past 12 months, with the stipulation that each could have an immediate impact on patient care. How much impact? You be the judge.

Vote for your choice at pharmacypracticenews.com/Awards09 and enter to win $250.

The chosen abstract—and the lucky winner—will be announced in the March 2010 issue.

Introducing Intravenous Interoperability: Expanding the Pharmacist’s Role in Medication Administration Amanda E. Prusch, PharmD, et al.

Lancaster General Health, Lancaster, Pa. Winner of ASHP Best Practices Award

L

ancaster General Health has successfully employed intravenous (IV) interoperability, or auto-programming, beyond a pilot phase to 18 nursing units (392 beds) to improve the safety of IV drug administration throughout their facility.

IV interoperability, which integrates intelligent infusion devices and other emerging technologies into a bar code–driven work flow, directly links the medication order to pump programming. The program allows pharmacists to directly affect bedside medication administration and provides two additional safety checks—pharmacist oversight of the infusion rate (first check) and independent validation of the auto-programmed rate by nurses (second check).

After IV interoperability was implemented at Lancaster General Health, compliance with the drug library during the first month of implementation increased by more than 30% (P<0.0001) in the facility’s telemetry units and by 83.4% (P<0.0001) in the medical/surgical nursing units compared with the same month one year before.

Violations of dose limits that prompted the nurse to “edit,” or reprogram, the pump decreased by 94% (P<0.0001) in telemetry units and 97% (P<0.0001) in medical/surgical units, according to the research team. A time and motion study was completed during the pilot phase that demonstrated a 24.8% (P<0.0001) reduction in nursing time and reduced pump programming steps by 58%.

The investigators concluded that “pioneering IV interoperability with pharmacist oversight has brought recognition that safe IV medication administration does not rest solely with the nurse at the bedside, thereby strengthening the collaborative partnership between pharmacy and nurs-

ing and providing our patients with a safer medication experience.”

The initiative was done in conjunction with Hospira, Inc., and Cerner.

Enhancing Antimicrobial Therapy through a PharmacistManaged Culture Review Process in an Emergency Department Setting Timothy C. Randolph, PharmD, et al.

Carolinas Medical Center-North East, Concord, N.C. Winner of ASHP Best Practices Award

T

o combat inappropriate antibiotic prescribing and dosing at their facility, Carolinas Medical Center-North East began a program of pharmacist-managed review of cultures. As part of the program, the medical center’s emergency department (ED) pharmacist received daily culture and susceptibility reports and compared patients’ empiric antimicrobial regimens with the culture and sensitivity data. If the patients were not receiving the appropriate therapy, the ED pharmacist consulted with an ED physician and the regimen was adjusted accordingly. The ED pharmacist also contacted and counseled the patients about their culture results and treatment.

The investigators compared one year of physician-managed cultures (June 30, 2007 to June 30, 2008; n=2,278) with one year of pharmacist-managed cultures (July 1, 2008 to July 1, 2009; n=2,361) and evaluated the number of antimicrobial regimens modified, unplanned readmissions within 96 hours of initial culture review and reasons for unplanned readmission within 96 hours of culture review. They found that patients whose cultures were managed by pharmacists had a reduced rate of unplanned readmissions due to treatment failure, noncompliance and allergic reactions (P<0.05).

The investigators concluded that “it is clear that the ED pharmacists at our institution have made a significant impact on patient care through the implementation of a pharmacistmanaged culture review process.”

Safety and Efficacy Analysis of an Inpatient Collaborative Drug Therapy Management Service for Direct Thrombin Inhibitors Heather Kokko, PharmD, et al.

Medical University of South Carolina Medical Center (MUSCMC), Charleston, S.C. Winner of ASHP Best Practices Award

M

USCMC developed a pharmacistdriven direct thrombin inhibitor (DTI) protocol to establish guidelines for the use and monitoring of DTIs and a collaborative drug therapy management (CDTM) service with pharmacy dosing to reduce medication errors related to the monitoring and adjusting of DTI dosages.

After implementation of the protocol and CDTM service, the team evaluated 50 patients: 25 patients treated pre-implementation and 25 treated post-implementation. They found that patients treated after implementation achieved therapeutic activated partial thromboplastin time more rapidly than patients treated before implementation (3.4 vs. 7.7 hours; P=0.009); patients treated under the new program also maintained a therapeutic aPTT more consistently than those treated before it was initiated (93% vs. 81%; P=0.001).

The team found that errors in DTI prescribing or administration occurred in 12% of patients treated under the new protocol, compared with 40% of patients treated before the program was implemented (P=0.05). The investigators reported that “the most notable difference in the incidence of medication errors was in the prevalence of prescribing errors.” They noted that before the protocol and CDTM service were initiated, prescribing errors occurred in 24% of the patients receiving DTI therapy. In contrast, after the program was implemented, “prescribing errors were completely eliminated (P=0.02).”

Improving Patient Care Through a Collaborative and Innovative Antimicrobial Stewardship Program Catherine Baker, PharmD, et al.

Providence St. Vincent Medical Center, Portland, Ore. Winner of ASHP Best Practices Award

I

n response to the increasing recognition that inappropriate antimicrobial

use contributes to greater morbidity, mortality and health care costs, Providence St. Vincent Medical Center expanded its collaborative efforts to improve antimicrobial use.

Over the past decade, the healthsystem’s antimicrobial stewardship program evolved, most recently with a broader role for clinical pharmacists in its multidisciplinary Antimicrobial Monitoring Service (AMS), which develops guidelines for antimicrobial use and consults on twice-weekly antimicrobial patient rounds. Another recent enhancement to the program was the implementation of computerized systems to identify patients for potential antimicrobial intervention.

The medical center’s program was successful in reducing antimicrobial expenditures. In the first five years after the AMS was put into place, antimicrobial expenditures declined as a proportion of total pharmaceutical expenditures (from 13.8% to 12.9%). The most recent data suggested a combined direct cost savings and cost avoidance of more than $300,000 annually associated with antimicrobial interventions.

The investigators concluded that their program used “a multifaceted approach to antimicrobial stewardship, incorporating both traditional and innovative roles for improving patient care.”

The Successful Implementation of a Collaborative Sepsis Bundle at a Community Hospital Gita Wasan Patel, PharmD, et al.

Medical Center of Plano, Texas Winner of ASHP Best Practices Award

R

ecognition of a need for improvement in sepsis mortality rates led a multidisciplinary team at the Medical Center of Plano to design and implement a sepsis bundle program. The team developed and implemented the twopart program made up of an emergency department (ED) screening tool and diagnosed sepsis admission orders.

One year after implementation, they retrospectively compared clinical outcomes and mortality for all adult patients diagnosed with severe sepsis or septic shock in 2006, before the sepsis bundles were in place, with patients from 2007, who were treated with the full sepsis bundles. The team found that mortality was 61.1% in 2006 versus 20% in 2007 (P<0.0001). In addition, median time to cultures, time to the first dose of

Clinical 37

Pharmacy Practice News • January 2010

Awards antibiotics, time to transfer to the ICU, percentage of patients initiated on vasopressors or dialysis, median days on vasopressors and median milliliters of fluid administered within the first 24 hours were all lower in the sepsis bundle group.

Demographics, blood glucose, drotrecogin use, steroid use, ICU/hospital lengths of stay, ventilator use and ventilator days did not differ significantly between patients treated in 2006 and in 2007.

The investigators concluded that the program “yielded a positive impact on clinical outcomes and mortality in the septic patients in our nonacademic, community hospital setting.”

Protecting Our Most Vulnerable Patients Cynthia Brown, RPh Women and Children’s Hospital of Buffalo (WCHOB), part of Kaleida Health System, Buffalo, N.Y. Winner of ASHP Foundation Award for Excellence in Medication-Use Safety

A

fter realizing that the smart pump technology their institution was using was not ideal for its pediatric patients, pharmacists at WCHOB set out to develop a new IV delivery system that would meet the needs of both pediatric and adult patients.

The WCHOB pharmacists established a multidisciplinary team to develop an IV medication delivery system and training program that would include an infusion pump with software to maximize safety, a customized drug library, standardized dosing and limited drug concentrations.

The system also needed to have safeguards to prevent applications that could get around the technology, be able to adjust to diverse patient populations, and have wireless capability “to provide realtime updates and data for continuous quality improvement.”

The system they developed included an intelligent infusion pump and drug library with more than 300 medication entries. The library was developed through extensive testing by practitioners who attempted to circumvent the system to uncover areas that could contribute to errors. The team used evidence-based references and standards of care to establish appropriate dosing limits, indications and concentrations.

WCHOB’s Pharmacy and Therapeutics Committee provided assistance on certain medications, particularly when the literature did not provide clear guidance.

The team found a 99% compliance rate for the use of the library, which was 60% higher than rates at other facilities in the Kaleida Health system, the largest health care provider in western New York. Data generated via hard- and soft-limit alerts during the first year of implementation showed that the system prevented errors. With further refine-

ment of the drug library, preventable errors decreased by 50%.

The WCHOB team concluded that this study showed how crucial it is that pharmacists, nurses and physicians work together to design systems to ensure that new technology is optimized for all patient populations.

Stop the Traveling Clot Jane Hughes, BS Pharm, MBA, et al.

Rex Healthcare, Raleigh, N.C. Finalist for ASHP Foundation Award for Excellence in Medication-Use Safety

T

o decrease the incidence of venous thromboembolism (VTE) in their hospital network, a multidisciplinary team at Rex Healthcare implemented a program that incorporated education of health care providers and use of a unique VTE assessment tool. The tool, which included a risk scoring system and recommendations for preventing VTE, is used for all patients at the time of hospital admission and repeated 72 hours later, and at any change in level of care. The results of the assessments are part of the electronic medical record and are easily accessible to all providers.

The program’s “dramatic increase in assessment and prevention of VTE resulted in improved prophylaxis and a demonstrated reduction of morbidity for hospitalized patients,” according to the team. After implementation of the program, 100% of medical inpatients and 97.6% of surgical patients who were at risk for VTE received pharmacologic prophylaxis within 24 hours of assessment. The Rex Healthcare team observed a 53% increase in the use of mechanical prophylaxis for VTE and a 43% increase in the use of pharmacologic prophylaxis after the program was implemented. The number of VTE readmissions within 30 days also decreased by 12% after the program was put into place.

The investigators concluded that the program’s “dramatic increase in assessment and prevention of VTE resulted in improved prophylaxis and a demonstrated reduction of morbidity for hospitalized patients.”

Improving Safety Through a Pharmacist-Directed Anticoagulation Service James S. Kalus, PharmD Henry Ford Hospital, Detroit, Mich.

Finalist for ASHP Foundation Award for Excellence in Medication-Use Safety

T

o reduce the risks for prescribing errors associated with anticoagulants, pharmacists at Henry Ford Hospital led a multidisciplinary team that planned and implemented a pharmacistdirected anticoagulation service throughout the hospital and health system. The team identified several areas in need of improvement in the medication-use process for anticoagulants: dosing, monitor-

ing, patient education and patient transition from inpatient to outpatient settings.

The team found that the pharmacistled service significantly improved the safety and efficiency of anticoagulant use.

Patient international normalized ratio (INR) values greater than 5 declined by 80% during an 18-month period after implementation (P<0.05). Patients discharged through the service required 80% fewer adjustments at their first outpatient anticoagulation clinic visit (P<0.001). The investigators also found a 26% reduction in all-cause readmissions within 30 days of discharge among patients cared for by the pharmacist-led service (P=NS). There were also trends suggesting that patients treated through the service were more likely to achieve an INR greater than 2 during their inpatient stay (58.7% vs.

52%) and more likely to achieve a therapeutic INR prior to discharge (50.8% vs.

41.4%) than patients treated by a multidisciplinary rounding team.

The investigators concluded that the service “produces significant improvement in patient safety with regard to the use of anticoagulants and improves hospital efficiency.” They suggested that the model they used could be adjusted to meet the needs of smaller or larger hospitals or health systems.

Safety and Efficacy of a FishOil–Based Fat Emulsion in the Treatment of Parenteral Nutrition–Associated Liver Disease Kathleen M. Gura, PharmD, et al.

Children’s Hospital Boston (CHB), Harvard Medical School, Boston, Mass.

Winner of the ASHP Foundation Drug Therapy Research Award

A

fter successfully treating a teenager who had a soy allergy with a fish-oil–based total parenteral nutrition (TPN) formula, investigators at CHB wanted to investigate whether a fish-oil–based emulsion could treat the potentially fatal liver disease that occurs in patients on TPN. To assess the safety and efficacy of the fish-oil–based fat emulsion, the investigators evaluated 18 infants with short-bowel syndrome who developed cholestasis while receiving a soybean emulsion and compared the findings with a historical cohort of 21 infants with short-bowel syndrome who also developed cholestasis while receiving the soybean emulsion.

The investigators found that the median time to reversal of cholestasis was 9.4 weeks in the infants receiving the fish-oil–based TPN versus 44 weeks in the historical cohort (Pediatrics 2008;121:e678-e686). Reversal of cholestasis occurred 4.8 times faster in those who received the fish-oil–based emulsion compared with those who received the soybean emulsion. The investigators

reported that the fish-oil–based TPN was safe and not associated with side effects such as hypertriglyceridemia, coagulopathy and delayed growth. They concluded that the fish-oil–based fat emulsion is a safe and potentially effective treatment for TPN-associated liver disease.

Enhanced Photoemission Spectroscopy for Verification of High-Risk IV Medications Yaman Kaakeh, PharmD, BCPS, BCNSP, et al.

University of Michigan Health System (UMHS),* Ann Arbor Winner of the ASHP Foundation Pharmacy Practice Research Award

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o improve the safety of high-risk medications compounded for pediatric patients, investigators at UMHS evaluated the sensitivity and specificity of enhanced photoemission spectroscopy (EPS) for automated verification of compounded IV admixtures.

The investigators used a tabletop EPS device to test samples of pharmacy-compounded drug-diluent combinations of the following drugs: epinephrine, gentamicin, hydromorphone, insulin, lorazepam, morphine and vancomycin (Am J Health-Syst Pharm 2008;65:49-54). The investigators tested samples consisting of dilutions ranging from 10-fold above to 10-fold below the targeted concentration, for each drug. They found that the EPS device was able to detect errors of 20% or greater deviation from the target concentration with a sensitivity of 95% or higher. The specificity of the device for differentiating the seven drugs at the target concentrations was 100%.

The team concluded that the “device demonstrated acceptable sensitivity and specificity for validating the identity and concentrations of selected high-risk IV medications” and that “the device may help prevent clinically important medication errors caused by inaccurate compounding.” *At the time of the study, all of the authors were affiliated with the University of Michigan Health System.

Implementing After-Hours Pharmacy Coverage for Critical Access Hospitals in Northeast Minnesota Timothy P. Stratton, PhD, et al.

University of Minnesota College of Pharmacy, St. Luke’s Hospital, Duluth Winner of the ASHP Foundation Award for Innovation in Pharmacy Practice

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o optimize patient safety at several critical access hospitals in rural Minnesota, administrators, pharmacists

•

see BEST ABSTRACT, page 38

38 Clinical

Pharmacy Practice News • January 2010

Awards

BEST ABSTRACT continued from page 37

and nurses enhanced after-hours pharmacy coverage using an Internet-based health information technology (IT) system. The system enabled the pharmacy staff at the hub hospital, St. Luke’s, in Duluth, to remotely enter pharmacy orders into the electronic medical records of patients at eight participating critical access hospitals (Am J Health-Syst Pharm 2008; 65:1727-1734).

Capabilities included medication order processing, drug interaction checking, medication dispensing via automated dispensing cabinets at the remote hospitals, and formulary and inventory management. If a medication was not available in the automated dispensing cabinets at the remote location, it was obtained via a locked pharmacy cabinet by a nurse supervisor.

Noting that the rural hospitals achieved nearly 24-hour coverage for their patients using this system, the investigators concluded that the remote IT system “helped ensure that those patients received safe and effective medication therapy.”

Remember to Vote!

Immunologic Response to Hepatitis B (Hep B) Vaccination in Human Immunodeficiency Virus (HIV)-Infected Patients Bernadette Johnson, PharmD, et al.

University of New Mexico Health Sciences Center, Albuquerque, Southwest Care Clinic, Santa Fe, N.M. ACCP Best Paper Finalist

A

lthough current guidelines recommend that all HIV-infected patients receive the Hep B vaccine regardless of CD4 count, investigators in New Mexico

conducted a study to describe Hep B response rates in HIV-infected patients considering their CD4 counts, and determine whether there is a CD4 level that could be used as a cutoff for deferring vaccination.

The investigators included 69 patients from two clinics, which serve most of the HIV-infected population in New Mexico, in the retrospective study. The overall response rate to Hep B vaccination was 50.7%. Patients with a CD4 count of 200 cells/mm3 or lower had a response rate of 29.4% versus a response of 57.7% among those with a CD4 count higher

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than 200 cells/mm3 (P=0.04).

The researchers found that adequate response to the Hep B vaccine was more likely in patients who had CD4 counts higher than 200 cells/mm3. They recommended that deferment of vaccination should be considered in patients with CD4 cell counts of 200 cells/mm3 or lower.

—Sarah Tilyou

Quality of Depression Care in Kentucky Sheila R. Botts, PharmD, et al.

University of Kentucky College of Pharmacy, University of Kentucky Healthcare, Lexington ACCP Best Paper Finalist

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nvestigators from the University of Kentucky retrospectively studied Medicaid patients of all ages with newly diagnosed depression to determine the extent of and variables associated with depression treatment.

Same Name. New Size.

Introducing 3 mL of Humalog® and Humulin® R U-100 in a Smaller Vial*

They found that of the 49,301 depression episodes evaluated, 25% of the patients received antidepressant therapy and 16% received some form of psychotherapy. Patients were less likely to have received antidepressant therapy (odds ratio [OR], 0.87; P<0.01) and more likely to receive psychotherapy (OR, 2.1; P<0.001) if they were treated at a community mental health center. In contrast, patients who were seen for recommended follow-up visits (OR, 1.47; P<0.001) and patients with comorbid diabetes (OR, 1.29; P<0.001) were more likely to have received adequate antidepressant treatment. The investigators concluded that less than 20% of Medicaid enrollees received adequate depression treatment.

The New Smaller Vial, Another Insulin Delivery Option Intended To: Give hospitals more flexibility when evaluating insulin storage and distribution (floor stock vs individual patient supply), in addition to the 10 mL vial and Humalog® KwikPen™.

Indication Humalog is for use in patients with diabetes mellitus for the control of hyperglycemia. Humalog should be used with longer-acting insulin, except when used in combination with sulfonylureas in patients with type 2 diabetes.

• Same Bar-Coding Technique, New Size • Same Color-Differentiating System, New Size • National Drug Code (NDC) Humalog - NDC Number - 0002-7510-17 Humulin R U-100 - NDC Number - 0002-8215-17

Select Safety Information Hypoglycemia is the most common adverse effect associated with insulins, including Humalog.

When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal.

*3 mL of Humalog and Humulin R U-100 are in a 5 mL vial.

Pens are for single-patient use only and should not be shared among patients.

Please see Important Safety Information on adjacent page and accompanying Brief Summary of full Prescribing Information.

Up Front 39

Pharmacy Practice News • January 2010

Late-Breaker

TRANSPLANT DRUGS

Pharmacists: Data Not New, But Still ‘Important’

continued from page 3

The Mayo Clinic findings “don’t really break any significantly new ground,” commented Kwaku Marfo, PharmD, an organ transplant pharmacist at Montefiore Medical Center, in New York City.

Multiple studies in recent years, he noted, have shown that these drugs can boost the risk for cancer not only in heart transplant patients but also in those receiving other solid organs, such as pancreas, kidneys and livers, “in order of highest risk,” he said.

“But it’s still an important study, if only to remind us how vigilant we need to be when counseling these patients.”

• decreased awareness of skin cancer risk • a history of a non-melanoma skin cancer As far as the mechanism behind the increased cancer risk, Dr. Brewer said it is largely due to the profound druginduced immunosuppression that occurs in transplant patients. “A part of the immune system that is involved in tumor surveillance may be blunted with these drugs,” he explained. “As a result, precancerous cells are more likely to turn into a full-blown malignancy.”

During those interactions, Dr. Marfo said, “I definitely stress the need to follow adequate sun protection practices.

It’s a message that solid organ transplant pharmacists can really help deliver.”

Jennifer N. Fosnot, PharmD, clinical specialist-solid organ transplantation, Vanderbilt University Medical Center, Nashville, Tenn., said she also counsels patients on the need for using sunscreens. Male patients in particular “need to be given more attractive options for sunscreen use, since they seem the most averse to using sunscreen and lip balm products,” she said. “In our quarterly patient newsletter that went out to heart transplant patients last spring, we includ-

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

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

Humalog differs from regular human insulin by its rapid onset of action as well as a shorter duration of action.

Therefore, when used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal.

Due to the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an insulin pump). Glucose monitoring is recommended for all patients with diabetes.

The safety and effectiveness of Humalog in patients less than 3 years of age have not been established. There are no adequate and well-controlled clinical studies of the use of Humalog in pregnant or nursing women.

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

Hypoglycemia Hypoglycemia is the most common adverse effect associated with insulins, including Humalog. Hypoglycemia can happen suddenly, and symptoms may be different for each person and may change from time to time.

Severe hypoglycemia can cause seizures and may be life-threatening.

Other Side Effects Other potential side effects associated with the use of insulins include: hypokalemia, weight gain, lipodystrophy, and hypersensitivity. Systemic allergy is less common, but may be life-threatening. Because of the difference in action of Humalog, care should be taken in patients in whom hypoglycemia or hypokalemia may be clinically relevant (eg, those who are fasting, have autonomic neuropathy or renal impairment, are using potassium-lowering drugs, or taking drugs sensitive to serum potassium level).

For additional safety profile and other important prescribing considerations, see accompanying Brief Summary of full Prescribing Information.

Please see full user manual that accompanies the pen.

Humalog® is a registered trademark of Eli Lilly and Company and is available by prescription only.

Humalog® KwikPen™ is a trademark of Eli Lilly and Company and is available by prescription only.

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

HI59950-3

1109 PRINTED IN USA

©2009, LILLY USA, LLC. ALL RIGHTS RESERVED.

ed an article, in patient-friendly language, addressing this topic.”

Clinicians don’t have to take it on faith that such educational measures can be effective. A recent British prospective study (Br J Dermatol 2009;161 [Suppl 3]:78-84) showed that counseling immunosuppressed organ transplant patients on the proper use of sunscreens helped prevent some skin cancers. For example, of the 120 patients in the study, eight developed squamous cell carcinomas, and all of those lesions occurred in a control group of patients who did not receive the sunscreen counseling (P<0.01).

—David Bronstein

40 Operations & Management

Pharmacy Practice News • January 2010

Joint Commission

Hospitals Hone Their Medication Reconciliation Skills Studies at ASHP document improved safety, cost savings and the potential for better Joint Commission compliance

I

mplementing medication reconciliation has proven a challenge for many hospitals, but those that have opted to do so have found that their decisions can pay off in fewer medication errors and less risk for adverse events for patients.

“The biggest benefit gained by medication reconciliation is coordination of care,” said Bona E. Benjamin, RPh, director of medication use quality

improvement at the American Society of Health-System Pharmacists’ (ASHP) Practice Development Division. “Medication therapy can be constantly evaluated and updated, giving every caregiver a current and accurate record of what the patient should be taking.”

The addition of a pharmacist can enhance the process. “They really are the experts in medication use therapy,”

Ms. Benjamin said. “Pharmacists have the ability to interview a patient in such a way as to get a complete and accurate drug list. This takes time, but once the list is known, the pharmacist is able to compare it to what has been prescribed in the new care setting and detect any possible interactions, duplications of therapy, or dose changes and intervene by calling the physician to

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

INDICATIONS AND USAGE: Humalog is an insulin analog that is indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia. Humalog has a more rapid onset and a shorter duration of action than regular human insulin. Therefore, in patients with type 1 diabetes, Humalog should be used in regimens that include a longer-acting insulin. However, in patients with type 2 diabetes, Humalog may be used without a longer-acting insulin when used in combination therapy with sulfonylurea agents.

Humalog may be used in an external insulin pump, but should not be diluted or mixed with any other insulin when used in the pump. Humalog administration in insulin pumps has not been studied in patients with type 2 diabetes.

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

WARNINGS: This human insulin analog differs from regular human insulin by its rapid onset of action as well as a shorter duration of activity. When used as a mealtime insulin, the dose of Humalog should be given within 15 minutes before or immediately after the meal. Because of the short duration of action of Humalog, patients with type 1 diabetes also require a longer-acting insulin to maintain glucose control (except when using an external insulin pump).

External Insulin Pumps: When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin. Patients should carefully read and follow the external insulin pump manufacturer’s instructions and the “PATIENT INFORMATION” leaflet before using Humalog.

Physicians should carefully evaluate information on external insulin pump use in the Humalog physician package insert and in the external insulin pump manufacturer’s instructions. If unexplained hyperglycemia or ketosis occurs during external insulin pump use, prompt identification and correction of the cause is necessary. The patient may require interim therapy with subcutaneous insulin injections (see PRECAUTIONS, For Patients Using External Insulin Pumps, and DOSAGE AND ADMINISTRATION).

Hypoglycemia is the most common adverse effect associated with the use of insulins, including Humalog. As with all insulins, the timing of hypoglycemia may differ among various insulin formulations. Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using an external insulin pump.

Any change of insulin should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type (eg, regular, NPH, analog), species, or method of manufacture may result in the need for a change in dosage.

PRECAUTIONS: General—Hypoglycemia and hypokalemia are among the potential clinical adverse effects associated with the use of all insulins. Because of differences in the action of Humalog and other insulins, care should be taken in patients in whom such potential side effects might be clinically relevant (eg, patients who are fasting, have autonomic neuropathy, or are using potassium-lowering drugs or patients taking drugs sensitive to serum potassium level). Lipodystrophy and hypersensitivity are among other potential clinical adverse effects associated with the use of all insulins.

As with all insulin preparations, the time course of Humalog action may vary in different individuals or at different times in the same individual and is dependent on site of injection, blood supply, temperature, and physical activity.

Adjustment of dosage of any insulin may be necessary if patients change their physical activity or their usual meal plan.

Insulin requirements may be altered during illness, emotional disturbances, or other stress.

Hypoglycemia—As with all insulin preparations, hypoglycemic reactions may be associated with the administration of Humalog. Rapid changes in serum glucose concentrations may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as long duration of diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control.

Renal Impairment—The requirements for insulin may be reduced in patients with renal impairment.

Hepatic Impairment—Although impaired hepatic function does not affect the absorption or disposition of Humalog, careful glucose monitoring and dose adjustments of insulin, including Humalog, may be necessary.

Allergy—Local Allergy—As with any insulin therapy, patients may experience redness, swelling, or itching at the site of injection. These minor reactions usually resolve in a few days to a few weeks. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique.

Systemic Allergy—Less common, but potentially more serious, is generalized allergy to insulin, which may cause rash (including pruritus) over the whole body, shortness of breath, wheezing, reduction in blood pressure, rapid pulse, or sweating. Severe cases of generalized allergy, including anaphylactic reaction, may be life-threatening. Localized reactions and generalized myalgias have been reported with the use of cresol as an injectable excipient. In Humalog-controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving Humulin R® (N=2969) and 30 patients receiving Humalog (N=2944) (P=.053).

Antibody Production—In large clinical trials, antibodies that cross-react with human insulin and insulin lispro were observed in both Humulin R- and Humalog-treatment groups. As expected, the largest increase in the antibody levels during the 12-month clinical trials was observed with patients new to insulin therapy.

Usage of Humalog in External Insulin Pumps—The infusion set (reservoir syringe, tubing, and catheter), Disetronic® D-TRON®2,3 or D-TRONplus®2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced and a new infusion site selected every 48 hours or less. Humalog in the external insulin pump should not be exposed to temperatures above 37°C (98.6°F).

In the D-TRON ®2,3 or D-TRONplus ®2,3 pump, Humalog 3 mL cartridges may be used for up to 7 days. However, as with other external insulin pumps, the infusion set should be replaced and a new infusion site should be selected every 48 hours or less.

When used in an external insulin pump, Humalog should not be diluted or mixed with any other insulin (see INDICATIONS AND USAGE, WARNINGS, PRECAUTIONS, For Patients Using External Insulin Pumps, Mixing of Insulins, DOSAGE AND ADMINISTRATION, and Storage).

Information for Patients—Patients should be informed of the potential risks and advantages of Humalog and alternative therapies. Patients should also be informed about the importance of proper insulin storage, injection technique, timing of dosage, adherence to meal planning, regular physical activity, regular blood glucose monitoring, periodic hemoglobin A1C testing, recognition and management of hypoglycemia and hyperglycemia, and periodic assessment for diabetes complications.

Patients should be advised to inform their physician if they are pregnant or intend to become pregnant.

Refer patients to the “PATIENT INFORMATION” leaflet for timing of Humalog dosing (<_15 minutes before or immediately after a meal), storing insulin, and common adverse effects.

For Patients Using Insulin Pen Delivery Devices: Before starting therapy, patients should read the “PATIENT INFORMATION” leaflet that accompanies the drug product and the User Manual that accompanies the delivery device. They should also reread these materials each time the prescription is renewed. Patients should be instructed on how to properly use the delivery device, prime the Pen to a stream of insulin, and properly dispose of needles. Patients should be advised not to share their Pens with others.

For Patients Using External Insulin Pumps: Patients using an external infusion pump should be trained in intensive insulin therapy and in the function of their external insulin pump and pump accessories. Humalog was tested in the MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested in the Disetronic ®2 H-TRONplus ® V100 insulin pump (with plastic 3.15 mL insulin reservoir), and the Disetronic D-TRON ®2,3 and D-TRONplus ®2,3 insulin pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets.

The infusion set (reservoir syringe, tubing, catheter), D-TRON®2,3 or D-TRONplus ®2,3 cartridge adapter, and Humalog in the external insulin pump reservoir should be replaced, and a new infusion site selected every 48 hours or less. Humalog in the external pump should not be exposed to temperatures above 37°C (98.6°F).

A Humalog 3 mL cartridge used in the D-TRON ®2,3 or D-TRONplus ®2,3 pump should be discarded after 7 days, even if it still contains Humalog. Infusion sites that are erythematous, pruritic, or thickened should be reported to medical personnel, and a new site selected.

Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump.

Laboratory Tests—As with all insulins, the therapeutic response to Humalog should be monitored by periodic blood glucose tests. Periodic measurement of hemoglobin A1C is recommended for the monitoring of long-term glycemic control.

Drug Interactions—Insulin requirements may be increased by medications with hyperglycemic activity, such as corticosteroids, isoniazid, certain lipid-lowering drugs (eg, niacin), estrogens, oral contraceptives, phenothiazines, and thyroid replacement therapy (see CLINICAL PHARMACOLOGY).

Insulin requirements may be decreased in the presence of drugs that increase insulin sensitivity or have hypoglycemic activity, such as oral antidiabetic agents, salicylates, sulfa antibiotics, certain antidepressants (monoamine oxidase inhibitors), angiotensin-converting-enzyme inhibitors, angiotensin II receptor blocking agents, beta-adrenergic blockers, inhibitors of pancreatic function (eg, octreotide), and alcohol. Beta-adrenergic blockers may mask the symptoms of hypoglycemia in some patients.

Mixing of Insulins—Care should be taken when mixing all insulins as a change in peak action may occur. The American Diabetes Association warns in its Position Statement on Insulin Administration, “On mixing, physiochemical changes in the mixture may occur (either immediately or over time). As a result, the physiological response to the insulin mixture may differ from that of the injection of the insulins separately.” Mixing Humalog with Humulin® N or Humulin® U does not decrease the absorption rate or the total bioavailability of Humalog. Given alone or mixed with Humulin N, Humalog results in a more rapid absorption and glucose-lowering effect compared with regular human insulin.

Pregnancy—Teratogenic Effects—Pregnancy Category B—Reproduction studies with insulin lispro have been performed in pregnant rats and rabbits at parenteral doses up to 4 and 0.3 times, respectively, the average human dose (40 units/day) based on body surface area. The results have revealed no evidence of impaired fertility or harm to the fetus due to Humalog. There are, however, no adequate and well-controlled studies with Humalog in pregnant women. Because

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

Although there are limited clinical studies of the use of Humalog in pregnancy, published studies with human insulins suggest that optimizing overall glycemic control, including postprandial control, before conception and during pregnancy improves fetal outcome. Although the fetal complications of maternal hyperglycemia have been well documented, fetal toxicity also has been reported with maternal hypoglycemia. Insulin requirements usually fall during the first trimester and increase during the second and third trimesters. Careful monitoring of the patient is required throughout pregnancy. During the perinatal period, careful monitoring of infants born to mothers with diabetes is warranted.

Nursing Mothers—It is unknown whether Humalog is excreted in significant amounts in human milk. Many drugs, including human insulin, are excreted in human milk. For this reason, caution should be exercised when Humalog is administered to a nursing woman. Patients with diabetes who are lactating may require adjustments in Humalog dose, meal plan, or both.

Pediatric Use—In a 9-month, crossover study of prepubescent children (n=60), aged 3 to 11 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 minutes before meals 8.4%, Humalog immediately before meals 8.4%, and Humalog immediately after meals 8.5%. In an 8-month, crossover study of adolescents (n=463), aged 9 to 19 years, comparable glycemic control as measured by A1C was achieved regardless of treatment group: regular human insulin 30 to 45 minutes before meals 8.7% and Humalog immediately before meals 8.7%. The incidence of hypoglycemia was similar for all 3 treatment regimens. Adjustment of basal insulin may be required. To improve accuracy in dosing in pediatric patients, a diluent may be used. If the diluent is added directly to the Humalog vial, the shelf life may be reduced (see DOSAGE AND ADMINISTRATION).

Geriatric Use—Of the total number of subjects (n=2834) in 8 clinical studies of Humalog, 12% (n=338) were 65 years of age or over. The majority of these were patients with type 2 diabetes. A1C values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Humalog action have not been performed.

ADVERSE REACTIONS: Clinical studies comparing Humalog with regular human insulin did not demonstrate a difference in frequency of adverse events between the 2 treatments.

Adverse events commonly associated with human insulin therapy include the following: Body as a Whole—allergic reactions (see PRECAUTIONS).

Skin and Appendages—injection site reaction, lipodystrophy, pruritus, rash.

Other—hypoglycemia (see WARNINGS and PRECAUTIONS).

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

DOSAGE AND ADMINISTRATION: Humalog is intended for subcutaneous administration, including use in select external insulin pumps (see DOSAGE AND ADMINISTRATION, External Insulin Pumps). Dosage regimens of Humalog will vary among patients and should be determined by the healthcare provider familiar with the patient’s metabolic needs, eating habits, and other lifestyle variables. Pharmacokinetic and pharmacodynamic studies showed Humalog to be equipotent to regular human insulin (ie, one unit of Humalog has the same glucose-lowering effect as one unit of regular human insulin), but with more rapid activity. The quicker glucose-lowering effect of Humalog is related to the more rapid absorption rate from subcutaneous tissue. An adjustment of dose or schedule of basal insulin may be needed when a patient changes from other insulins to Humalog, particularly to prevent premeal hyperglycemia.

When used as a mealtime insulin, Humalog should be given within 15 minutes before or immediately after a meal.

Regular human insulin is best given 30 to 60 minutes before a meal. To achieve optimal glucose control, the amount of longer-acting insulin being given may need to be adjusted when using Humalog.

The rate of insulin absorption and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables. Humalog was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 U/kg regular human insulin or Humalog at abdominal, deltoid, or femoral sites, the 3 sites often used by patients with diabetes. When not mixed in the same syringe with other insulins, Humalog maintains its rapid onset of action and has less variability in its onset of action among injection sites compared with regular human insulin (see PRECAUTIONS). After abdominal administration, Humalog concentrations are higher than those following deltoid or thigh injections. Also, the duration of action of Humalog is slightly shorter following abdominal injection, compared with deltoid and femoral injections. As with all insulin preparations, the time course of action of Humalog may vary considerably in different individuals or within the same individual. Patients must be educated to use proper injection techniques.

Humalog in a vial may be diluted with STERILE DILUENT for Humalog, Humulin N, Humulin R, Humulin 70/30, and Humulin® R U-500 to a concentration of 1:10 (equivalent to U-10) or 1:2 (equivalent to U-50). Diluted Humalog may remain in patient use for 28 days when stored at 5°C (41°F) and for 14 days when stored at 30°C (86°F). Do not dilute Humalog contained in a cartridge or Humalog used in an external insulin pump.

Parenteral drug products should be inspected visually before use whenever the solution and the container permit. If the solution is cloudy, contains particulate matter, is thickened, or is discolored, the contents must not be injected. Humalog should not be used after its expiration date. The cartridge containing Humalog is not designed to allow any other insulin to be mixed in the cartridge or for the cartridge to be refilled with insulin.

External Insulin Pumps—Humalog was tested in MiniMed®1 Models 506, 507, and 508 insulin pumps using MiniMed®1 Polyfin®1 infusion sets. Humalog was also tested in the Disetronic ®2 H-TRONplus ® V100 insulin pump (with plastic 3.15 mL insulin reservoir) and the Disetronic D-TRON ®2,3 and D-TRONplus ®2,3 pumps (with Humalog 3 mL cartridges) using Disetronic Rapid®2 infusion sets. Humalog should not be diluted or mixed with any other insulin when used in an external insulin pump.

HOW SUPPLIED: Humalog (insulin lispro injection, USP [rDNA origin]) is available in the following package sizes (with each presentation containing 100 units insulin lispro per mL [U-100]): 10 mL vials NDC 0002-7510-01 (VL-7510) 3 mL vials NDC 0002-7510-17 (VL-7533) NDC 0002-7516-59 (VL-7516) 5 x 3 mL cartridges 3 5 x 3 mL prefilled insulin delivery devices (Pen) NDC 0002-8725-59 (HP-8725) 5 x 3 mL prefilled insulin delivery devices (Humalog® KwikPen™ ) NDC 0002-8799-59 (HP-8799)

1 2 3

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

Other product and company names may be the trademarks of their respective owners.

Storage —Unopened Humalog should be stored in a refrigerator (2° to 8°C [36° to 46°F]), but not in the freezer. Do not use Humalog if it has been frozen. Unrefrigerated (below 30°C [86°F]) 12 vials, cartridges, Pens, and KwikPens must be used within 28 days or be discarded, even if they still contain Humalog. Protect from direct heat and light.

Use in an External Insulin Pump—A Humalog 3mL cartridge used in the D-TRON®2,3 or D-TRONplus®2,3 should be discarded after 7 days, even if it still contains Humalog. Infusion sets, D-TRON ®2,3 and D-TRONplus ®2,3 cartridge adapters, and Humalog in the external insulin pump reservoir should be discarded every 48 hours or less.

Literature revised December 7, 2009 KwikPens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA. Pens manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Lilly France, F-67640 Fegersheim, France.

Vials manufactured by Eli Lilly and Company, Indianapolis, IN 46285, USA or Hospira, Inc., Lake Forest, IL 60045, USA or Lilly France, F-67640 Fegersheim, France.

Cartridges manufactured by Lilly France, F-67640 Fegersheim, France for Eli Lilly and Company, Indianapolis, IN 46285, USA. www.humalog.com Copyright © 1996, 2008, Eli Lilly and Company. All rights reserved.

resolve the discrepancies.”

At the ASHP Midyear Clinical Meeting in December, more than a halfdozen poster studies focused on how pharmacy oversight can improve the medication reconciliation process.

The studies come at a time when the Joint Commission is considering new revisions of National Patient Safety Goal (NPSG) No. 8, which centers on the requirement for accurate and complete medication lists to accompany patients as they travel from home through various levels of hospital care and then back into their communities.

It has been estimated that inadequate medication reconciliation accounts for 46% of medication errors and as many as 20% of adverse drug events (Am J Health-Syst Pharm 2007;64:850-854).

“We’ve been working on how best to revise the medication reconciliation NPSG to help the field improve medication safety, but also be pragmatic,” said Ann Blouin, a Joint Commission spokeswoman. Although the goal and its elements of performance remain in place during the Joint Commission’s re-evaluation, organizations are not yet being scored for compliance failures, according to Joint Commission sources.

VA Hospital Efforts Pay Off Some of the more active efforts to draw pharmacists into the process have taken place at Veterans Affairs (VA) hospitals. At the Ralph H. Johnson VA Medical Center in Charleston, S.C., for example, pharmacists’ interventions during medication reconciliation have prevented hundreds of errors, according to a study presented at the ASHP meeting.

To evaluate the impact of medication reconciliation on patient safety, the VA pharmacist-researchers retrospectively examined records of patients admitted to or discharged from their facility during a three-month period from September to December 2008, and compared the findings with those of a similar evaluation two years earlier.

During the latest study period, researchers found that pharmacists’ interventions prevented 345 medication errors, or approximately 1.3% of prescriptions filled. Two years earlier, however, pharmacist interventions prevented 540 errors (2.1% of prescriptions filled). The reason for the decrease, the researchers said, was “mostly likely” pharmacist education efforts over the two years. “As providers became more educated, the need for pharmacists to discontinue duplicate or unnecessary

Operations & Management 41

Pharmacy Practice News • January 2010

Joint Commission

‘The point of discharge is where the greatest number of medication errors are likely to occur.’

—Michael T. Nowicki, PharmD the inclusion of medications that had been discontinued at admission, giving patients the impression, Dr. Nowicki said, “that they should still take them.

This was something the pharmacist was able to clarify with both the provider and patient.”

One of the challenges of medication reconciliation is the amount of time it can take. Dr. Nowicki’s study found that the discharge process required an average of 60 minutes. “A lot of that was wait time,” he said, “waiting for physicians to get back to you and for patients to get back to their rooms so you could talk to them,” he said. “I was concerned that it was taking too long, but when I compared it with other studies, I found that it was about the same.”

Dr. Nowicki was a resident when he conducted the study last February. Now he is working in the inpatient pharmacy at the VA medical center.

Big Gains Achieved At Smaller Facility Even small hospitals can benefit from pharmacist interventions in the medication reconciliation process. At Medical Park Hospital, a 22-bed facility in Winston Salem, N.C. that specializes in elective surgery, the pharmacy department launched a prospective

•

see RECONCILIATION, page 42

In the treatment of patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible

Making the Case for INFeD

®

prescriptions declined,” they noted.

Pharmacist interventions also led to cost avoidance, according to the study.

In 2008, pharmacists discontinued 684 duplicate or unnecessary medications for a saving of just over $98,000. Two years earlier, pharmacists discontinued 1,080 prescriptions for a cost avoidance of more than $185,000. The probable reason for the decline, researchers noted, was not only the reduced need to discontinue medications but also lower prescription costs.

Most of the errors involved omission of medications—57% in 2006 and 50% in 2008. This was followed by incorrect drugs (17% in 2006 and 23% in 2008) and incorrect dosages (19% in both 2006 and 2008). Most of the medication errors were prevented at discharge (340 of the 540 in 2006 and 246 of the 345 in 2008).

At Another VA Facility, Discharge Medications Targeted for Savings The prevention of discharge medication errors was the focus of a study at the San Francisco VA Medical Center.

“The point of discharge is where the greatest number of medication errors are likely to occur,” said Michael T. Nowicki, PharmD, the clinical pharmacist who led the study. “We wanted to see the impact of a pharmacist fully dedicated to performing medication reconciliation and counseling at discharge.” During a three-week period, they indentified 136 discrepancies requiring interventions.

The largest proportion of discrepancies (61.8%) concerned the omission of medications from the patient’s discharge medication list. Others involved

Many years of clinical use

Proven safety profile of iron dextran

Potentially significant cost savings

Iron dextran products differ in chemical characteristics and may differ in clinical effects.

Iron dextran products are not interchangeable1 Allows for FDA-approved treatment of a wide range of patients with documented iron deficiency anemia1 INFeD® has a BP rating by the FDA and as such, the FDA has not approved any therapeutically equivalent products2 More than 10 years of approved clinical use in the US2 In a retrospective analysis of 841,252 doses of IV iron dextran, dyspnea, hypotension, and neurological symptoms were the most common major adverse drug events (ADEs)3 – The most common minor ADEs were nausea, vomiting, flushing, and pruritus3 – INFeD® had a low rate of ADEs with a high frequency of use (55 ADEs in 675,024 administrations over 6 months)3 Serious adverse events are rare – In a nonuremic population, 3 serious adverse events occurred in 481 patients (0.6%) receiving 2099 iron dextran injections (0.1%), with no fatalities reported4 – In a retrospective analysis of 61,950 hemodialysis patients, the incidence of reactions to INFeD® requiring resuscitative medications was 0.0016% (5 episodes in 317,097 exposures)5 A test dose of INFeD® is required prior to the first therapeutic dose1 In a 6-month randomized control trial, epoetin doses steadily decreased in patients whose TSAT was maintained between 30% and 50% with INFeD®6 – Patients maintained at a TSAT between 30% and 50% with INFeD® potentially save $109/month, or $1308/year6 Iron dextrans provide 33%-69% cost savings compared to other IV iron products7

Important Safety Information1

Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection. A test dose should be administered prior to the first therapeutic dose, followed by the full therapeutic dose if no signs or symptoms of anaphylactic-type reactions are seen. Resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions must be readily available during all INFeD® administrations.

Patients should be observed for signs or symptoms of anaphylactic-type reactions during all INFeD® administrations. Fatal reactions have followed the test dose and have also occurred in situations where the test dose was tolerated. Use INFeD® only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy. Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphylactic-type reactions. INFeD® should be used with caution in individuals with histories of significant allergies and/or asthma, and is contraindicated in patients with hypersensitivity to the product and patients with all anemias not associated with iron deficiency. INFeD® should be used with extreme care in patients with serious impairment of liver function, and should not be used during the acute phase of infectious kidney disease. Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis, which is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias.

Please see next page for references and brief summary of full Prescribing Information.

www.infed.com

© 2009, Watson Pharma, Inc., Morristown, NJ 07960. All rights reserved. 06108 11/09

42 Operations & Management

Pharmacy Practice News • January 2010

Joint Commission

RECONCILIATION continued from page 41

pharmacist review of nurse-obtained medication reconciliation lists during preanesthesia visits in an effort to improve the accuracy and efficiency of the process.

Rather than hire a pharmacist, pharmacy manager Kathy L. Doub, RPh, reassigned a pharmacist to the hospital’s preanesthesia visit area, where nurses collect medication lists for the nearly 12,000 patients who undergo surgical procedures each year, most

of them on an outpatient basis. The job of the pharmacist was simply to review the admission medications while the patient was still awake and able to resolve any problems. Before the change, the pharmacy had to rely on information from third parties 95% of the time.

The study found that of the 2,685 medication lists obtained by nurses during the third quarter of 2008, 901 (34%) had discrepancies that required pharmacist interventions. Sixty-five percent of the time, the patient was available to answer questions, reducing

the need to call providers. The pharmacist’s ability to ensure accurate and complete medication lists had a secondary benefit: It reduced order entry time by 15% compared with the same period a year earlier.

“The pharmacists doing order entry in the main pharmacy love the change because it used to be such a problem trying to figure things out while the patient was asleep,” said Ms. Doub, who added that “special credit” needed to go to Susan Wilson, RPh, the clinical pharmacy specialist who “developed and spearheaded the process.”

References: 1. INFeD® full Prescribing Information. Watson Pharma, Inc. September 2009. 2. FDA, Approved Drug Products with Therapeutic Equivalence Evaluations, 29th Edition. 3. Fletes R, Lazarus JM, Gage J, Chertow GM. Suspected iron dextran-related adverse drug events in hemodialysis patients. Am J Kidney Dis. 2001;37:743-749. 4. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. JAMA. 1980; 243:1726-1731.

5. Walters BAJ, Van Wyck DB. Benchmarking iron dextran sensitivity: reactions requiring resuscitative medication in incident and prevalent patients. Nephrol Dial Transplant. 2005;20:1438-1442. 6. Besarab A, Amin N, Ahsan M, et al.

Optimization of epoetin therapy with intravenous iron therapy in hemodialysis patients. J Am Soc Nephrol. 2000;11:530-538. 7. First Data Bank & Medispan WAC Pricing, August 2009.

Drug/Laboratory Test Interactions: Large doses of iron dextran (5 mL or more) have been reported to give a brown color to serum from a blood sample drawn 4 hours after administration.

The drug may cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium.

Serum iron determinations (especially by colorimetric assays) may not be meaningful for 3 weeks following the administration of iron dextran.

Serum ferritin peaks approximately 7 to 9 days after an intravenous dose of INFeD and slowly returns to baseline after about 3 weeks.

BRIEF SUMMARY: For full Prescribing Information, see package insert.

WARNING: RISK FOR ANAPHYLACTIC-TYPE REACTIONS

Examination of the bone marrow for iron stores may not be meaningful for prolonged periods following iron dextran therapy because residual iron dextran may remain in the reticuloendothelial cells.

Bone scans involving 99m Tc-diphosphonate have been reported to show a dense, crescentic area of activity in the buttocks, following the contour of the iliac crest, 1 to 6 days after intramuscular injections of iron dextran.

Anaphylactic-type reactions, including fatalities, have followed the parenteral administration of iron dextran injection.

Have resuscitation equipment and personnel trained in the detection and treatment of anaphylactictype reactions readily available during INFeD administration.

Bone scans with 99m Tc-labeled bone seeking agents, in the presence of high serum ferritin levels or following iron dextran infusions, have been reported to show reduction of bony uptake, marked renal activity, and excessive blood pool and soft tissue accumulation.

Administer a test INFeD dose prior to the first therapeutic dose. If no signs or symptoms of anaphylactic-type reactions follow the test dose, administer the full therapeutic INFeD dose.

Pregnancy: Pregnancy Category C: Iron dextran has been shown to be teratogenic and embryocidal in mice, rats, rabbits, dogs, and monkeys when given in doses of about 3 times the maximum human dose.

During all INFeD administrations, observe for signs or symptoms of anaphylactic-type reactions.

Fatal reactions have followed the test dose of iron dextran injection. Fatal reactions have also occurred in situations where the test dose was tolerated.

No consistent adverse fetal effects were observed in mice, rats, rabbits, dogs and monkeys at doses of 50 mg iron/kg or less. Fetal and maternal toxicity has been reported in monkeys at a total intravenous dose of 90 mg iron/kg over a 14 day period. Similar effects were observed in mice and rats on administration of a single dose of 125 mg iron/kg. Fetal abnormalities in rats and dogs were observed at doses of 250 mg iron/kg and higher. The animals used in these tests were not iron deficient. There are no adequate and well-controlled studies in pregnant women. INFeD should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Use INFeD only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy.

Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphylactic-type reactions to INFeD. INDICATIONS AND USAGE: Intravenous or intramuscular injections of INFeD are indicated for treatment of patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible.

CONTRAINDICATIONS: Hypersensitivity to the product. All anemias not associated with iron deficiency.

WARNINGS: Risk for Anaphylactic-type Reactions: Anaphylactic-type reactions, including fatalities have followed the parenteral administration of iron dextran. Always have resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions readily available during INFeD administration. Prior to the first therapeutic dose, administer a test INFeD dose of 0.5 mL. (See DOSAGE AND ADMINISTRATION.) Although reactions are usually evident within a few minutes, observe patients for at least one hour before administering the therapeutic dose. During all INFeD administrations, observe patients for signs or symptoms of anaphylactic-type reactions. Fatal reactions have followed the test dose of iron dextran and have also occurred in situations where the test dose was tolerated. Use INFeD only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy.

The factors that affect the risk for anaphylactic-type reactions to iron dextran products are not fully known but limited clinical data suggest the risk may be increased among patients with a history of drug allergy or multiple drug allergies.

Additionally, concomitant use of angiotensin-converting enzyme inhibitor drugs may increase the risk for reactions to an iron dextran product. The extent of risk for anaphylactic-type reactions following exposure to any specific iron dextran product is unknown and may vary among the products.

Iron dextran products differ in chemical characteristics and may differ in clinical effects. Iron dextran products are not clinically interchangeable.

Delayed Reactions: Large intravenous doses, such as used with total dose infusions (TDI), have been associated with an increased incidence of adverse effects. The adverse effects frequently are delayed (1-2 days) reactions typified by one or more of the following symptoms: arthralgia, backache, chills, dizziness, moderate to high fever, headache, malaise, myalgia, nausea, and vomiting. The onset is usually 24-48 hours after administration and symptoms generally subside within 3-4 days. The etiology of these reactions is not known. The potential for a delayed reaction must be considered when estimating the risk/benefit of treatment.

Carcinogenesis, Mutagenesis, Impairment Of Fertility: See WARNINGS.

Placental Transfer: Various animal studies and studies in pregnant humans have demonstrated inconclusive results with respect to the placental transfer of iron dextran as iron dextran. It appears that some iron does reach the fetus, but the form in which it crosses the placenta is not clear.

Nursing Mothers: Caution should be exercised when INFeD is administered to a nursing woman. Traces of unmetabolized iron dextran are excreted in human milk.

Pediatric Use: Not recommended for use in infants under 4 months of age. (See DOSAGE AND ADMINISTRATION.) ADVERSE REACTIONS: Severe/Fatal: Anaphylactic reactions have been reported with the use of iron dextran injection; on occasions these reactions have been fatal. Such reactions, which occur most often within the first several minutes of administration, have been generally characterized by sudden onset of respiratory difficulty and/or cardiovascular collapse.

Because fatal anaphylactic reactions have been reported after administration of iron dextran injection, the drug should be given only when resuscitation techniques and treatment of anaphylactic and anaphylactoid shock are readily available.

(See BOXED WARNING and PRECAUTIONS: General, pertaining to immediate availability of epinephrine.)

Cardiovascular: Chest pain, chest tightness, shock, cardiac arrest, hypotension, hypertension, tachycardia, bradycardia, flushing, arrhythmias. (Flushing and hypotension may occur from too rapid injections by the intravenous route.)

Pharmacy Intern Eyes Charts for Red Flags At Spectrum Health, a multihospital system in Grand Rapids, Mich., a pharmacist-led study demonstrated how a modest investment in time prior to patients’ admission for a planned procedure could significantly improve the accuracy and completeness of their medication lists and speed their treatments once they entered the hospital.

To obtain baseline data, the research team reviewed the medication orders of 75 randomly selected patients at Spectrum Health’s Blodgett and Butterworth Hospitals. They found that 55% of the medication profiles required clarification at admission.

During a three-month study period in 2008, a pharmacy intern at the pre-procedure planning (PPP) facility was assigned to review charts and to flag those needing clarification. Of the 220 charts that were reviewed over 10 days, 99 (45%) required clarification.

Of those, 37 were clarified by contacting the patient or a family member. The rest were flagged in a note written into the multidisciplinary communication tool and/or the medication sheet.

The intern spent anywhere from one to 30 minutes reviewing the charts (mean: five minutes). Most of the clarifications centered on medication dose and frequency. More than half (59%) involved prescription medications.

As a result of the program, the number of profiles requiring clarification fell from 55% to 31%. The researchers concluded that pharmacy interns could be valuable in resolving medication issues prior to patient admission.

—Bruce and Joan Buckley

Dermatologic: Urticaria, pruritus, purpura, rash, cyanosis.

Gastrointestinal: Abdominal pain, nausea, vomiting, diarrhea.

Hematologic/lymphatic: Leucocytosis, lymphadenopathy.

Musculoskeletal/soft tissue: Arthralgia, arthritis (may represent reactivation in patients with quiescent rheumatoid arthritis – See PRECAUTIONS: General), myalgia; backache; sterile abscess, atrophy/fibrosis (intramuscular injection site); brown skin and/or underlying tissue discoloration (staining), soreness or pain at or near intramuscular injection sites; cellulitis; swelling; inflammation; local phlebitis at or near intravenous injection site.

Neurologic: Convulsions, seizures, syncope, headache, weakness, unresponsiveness, paresthesia, febrile episodes, chills, dizziness, disorientation, numbness, unconsciousness.

Respiratory: Respiratory arrest, dyspnea, bronchospasm, wheezing.

Urologic: Hematuria.

Delayed reactions: Arthralgia, backache, chills, dizziness, fever, headache, malaise, myalgia, nausea, vomiting. (See WARNINGS.)

Educational & Commercial Reprints

The maximum daily dose should not exceed 2 mL undiluted iron dextran.

Miscellaneous: Febrile episodes, sweating, shivering, chills, malaise, altered taste.

Risk in Patients with Underlying Conditions: INFeD should be used with extreme care in patients with serious impairment of liver function. It should not be used during the acute phase of infectious kidney disease.

OVERDOSAGE: Overdosage with iron dextran is unlikely to be associated with any acute manifestations. Dosages of iron dextran in excess of the requirements for restoration of hemoglobin and replenishment of iron stores may lead to hemosiderosis. Periodic monitoring of serum ferritin levels may be helpful in recognizing a deleterious progressive accumulation of iron resulting from impaired uptake of iron from the reticuloendothelial system in concurrent medical conditions such as chronic renal failure, Hodgkins disease, and rheumatoid arthritis. The LD50 of iron dextran is not less than 500 mg/kg in the mouse.

Reprints of Pharmacy Practice News articles are available in minimum quantities of 500.

Rx Only

Reprints can be ordered in black & white or 4-color versions and printed on 80-lb. glossy stock.

Adverse reactions experienced following administration of INFeD may exacerbate cardiovascular complications in patients with pre-existing cardiovascular disease.

Carcinogenesis: A risk of carcinogenesis may attend the intramuscular injection of iron-carbohydrate complexes. Such complexes have been found under experimental conditions to produce sarcoma when large doses or small doses injected repeatedly at the same site were given to rats, mice, and rabbits, and possibly in hamsters.

The long latent period between the injection of a potential carcinogen and the appearance of a tumor makes it impossible to measure accurately the risk in man. There have, however, been several reports in the literature describing tumors at the injection site in humans who had previously received intramuscular injections of ironcarbohydrate complexes.

PRECAUTIONS: General: Unwarranted therapy with parenteral iron will cause excess storage of iron with the consequent possibility of exogenous hemosiderosis. Such iron overload is particularly apt to occur in patients with hemoglobinopathies and other refractory anemias that might be erroneously diagnosed as iron deficiency anemias.

INFeD should be used with caution in individuals with histories of significant allergies and/or asthma.

Revised: September 2009 Address medical inquiries to: WATSON Medical Communications P.O. Box 1953 Morristown, NJ 07962-1953 800-272-5525

Anaphylaxis and other hypersensitivity reactions have been reported after uneventful test doses as well as therapeutic doses of iron dextran injection. Therefore, administer a test dose prior to the first therapeutic dose of INFeD. (See BOXED WARNING and DOSAGE AND ADMINISTRATION: Administration.)

Epinephrine should be immediately available in the event of acute hypersensitivity reactions. (Usual adult dose: 0.5 mL of a 1:1000 solution, by subcutaneous or intramuscular injection.) Note: Patients using beta-blocking agents may not respond adequately to epinephrine. Isoproterenol or similar beta-agonist agents may be required in these patients.

Patients with rheumatoid arthritis may have an acute exacerbation of joint pain and swelling following the administration of INFeD. Reports in the literature from countries outside the United States (in particular, New Zealand) have suggested that the use of intramuscular iron dextran in neonates has been associated with an increased incidence of gramnegative sepsis, primarily due to E. Coli.

Information For Patients: Patients should be advised of the potential adverse reactions associated with the use of INFeD.

Standard turnaround time is 4 weeks.

For specific price quotes,

Distributed by: Watson Pharma, Inc. Morristown, NJ 07962 Manufactured by: Patheon Italia S.p.A. Ferentino, Italy 03013 251279 S0909

call Dave Kaplan at (212) 957-5300 x912.

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Operations & Management 45

Pharmacy Practice News • January 2010

Infectious Disease

Antibiotic Therapy Outcomes Boosted by Stewardship Plans Las Vegas—Inappropriate antibiotic use fell sharply and pharmacy costs were reduced at several hospitals after the launch of pharmacist-managed antimicrobial stewardship programs, according to studies presented at the American Society of Health-System Pharmacists’ (ASHP) Midyear Clinical Meeting in December 2009.

The studies reflect the growing trend toward infectious disease (ID) pharmacists and physicians working together to enhance patient outcomes and restrain the emergence of microbial resistance by optimizing the selection, doses and duration of the medications.

HealthEast Bethesda Hospital At HealthEast Bethesda Hospital, a 142-bed long-term acute care hospital in St. Paul, Minn., annual antibiotic acquisition costs decreased by $305,000, or 43%, without any negative impact on patient survival after an antimicrobial stewardship program was initiated, according to Paul F. Glynn, PharmD, BCPS, CGP, who led the yearlong study.

“The typical length of stay at Bethesda is right around 30 to 35 days,” Dr. Glynn said. “There are a lot of patients who have multiple chronic disease states, longterm urinary catheterization, or who are on ventilators, so as you can imagine it is a very high-risk environment for multidrug-resistant organisms.”

Prior to the program’s launch, the research team found that “antibiotics were routinely ordered by staff physicians for positive wound, respiratory and urinary cultures, regardless of symptoms. Infections were often not documented with appropriate cultures or x-rays. Appropriate lab monitoring was not always ordered.” The result, Dr. Glynn said, “was a significant amount of inappropriate antibiotics” being used.

In April 2007, he said, St. Paul Infectious Disease Associates began to round at Bethesda. As part of the group’s agreement with the hospital, an antibiotic stewardship team made up of a clinical pharmacist, an infectious disease specialist, and frequently a pharmacy student and/or resident initiated twice-weekly rounds of patients receiving antimicrobial therapy. Among the indicators highlighted for review were positive blood cultures, antibiotics with a high potential for adverse drug events, broad-spectrum and high-cost agents, multidrug-resistant organisms such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, complex disease states and antibiotics without stop dates.

As a prelude to rounds, clinical pharmacists spent an average of five hours per week assembling information on

‘We’re doing the right thing, saving a lot of money, minimizing collateral damage.

We’re not causing resistance and patients are doing just fine.’

—Michael Serra, PharmD

patient demographics, medical histories, laboratory results, cultures and imaging studies.

Using that information, Dr. Glynn said, “we would make recommendations for more appropriate antibiotic use—better coverage based on culture results—or for discontinuing antibiotic use, among other [interventions].”

At the outset, the recommendations sometimes were rejected. Only 162 of 307 (53%) were accepted in the first year.

Despite the low acceptance rate, antibiotic costs per patient-day decreased to $10.05 from $17.31 in the previous year, and daily defined doses per 1,000 patient-days declined 43% to 203 from 353. Almost half of the accepted recommendations (48%) involved discontinuing antibiotics. Others included requests for additional diagnostic tests (19%), simplifying or narrowing antibiotic regimens (12%) and changing to more effective agents (9%).

In addition to improving therapy and reducing costs, the stewardship team wanted to make sure the interventions were not having a negative impact on patient survival. After a year, they were able to show a trend toward lower mortality per 100 patient-days, despite an increase in patient acuity as measured by case mix index. The decrease in mortality was not statistically significant, Dr. Glynn said, “but we were able to show that the program did not adversely affect patient outcomes.”

Physician acceptance improved after the first year’s results were in. “I think the physicians started to realize the value of the program. The acceptance rate now hovers between 80% and 90%, so things have definitely improved at that site,” said Dr. Glynn, who recently became the clinical pharmacy manager at Abbott Northwestern Hospital in Minneapolis. “We’re very proud of the work we’ve done there.”

St. Joseph’s Regional Medical Center At St. Joseph’s Regional Medical Center in Paterson, N.J., a team of clinical ID pharmacists and physicians had several goals in mind when they created an antibiotic stewardship program in January 2009.

The first was to meet the Joint Com-

mission’s National Patient Safety Goal provision (7.03.01) to reduce the risk for health care–associated infections by preventing the emergence of multidrugresistant organisms through appropriate antibiotic use.

A secondary aim, said Nan Hong, PharmD, was to reduce antibiotic costs, “because as we all know, it is a huge expenditure for pharmacy.” At St. Joseph’s, a 651-bed tertiary academic medical center, antibiotic purchases account for more than 30% of the pharmacy budget.

To accomplish the goals, the team inaugurated a series of steps starting in December 2008 when Dr. Hong was hired as an ID pharmacist to jumpstart the stewardship program by the following month. Dr. Fong and an ID physician established a list of restricted antibiotics and an approval process for their use. A revised physician order form was created to incorporate the changes. A new protocol spelled out when antibiotics could be de-escalated or discontinued and when IV antibiotics could be switched to oral agents. An antibiotic stewardship queue was installed in the pharmacy digital ordering system to give Dr. Fong the ability to review restricted antibiotic orders in real time. Dr. Fong scheduled a series of educational sessions to explain the changes to pharmacists, nurses and physicians. She also began to round with the ID physician three times per week in the intensive care unit.

The measures appear to have worked, at least in terms of cost savings. In the first five months of the stewardship program, Dr. Hong made 509 interventions, 465 of which involved de-escalating or discontinuing antibiotics and the remaining 44 conversions from intravenous to oral agents. The actions were judged to have saved or avoided costs of more than $86,000.

After completing the calculations for the ASHP study, though, Dr. Hong told Pharmacy Practice News that she had “crunched new numbers” covering the first eight months of the program, which showed savings on acquisition costs of restricted antibiotics of $168,000.

Now she is intent on discovering if the stewardship program has reduced hospital length of stay and had an impact on antibiotic susceptibility as reflected in

the hospital’s antibiogram. “This is my goal: looking at how stewardship affects the patients,” she said.

Morristown Memorial Hospital Improving patient outcomes and lowering antibiotic costs were also the goals of an antimicrobial stewardship program at Morristown Memorial Hospital, a 700-bed tertiary care community facility in Morristown, N.J. After several attempts over the past few years, the hospital finally launched a successful pharmacist-managed stewardship program in the latter part of 2008, according to Michael Serra, PharmD, BCPS, the clinical pharmacist and lead author of a study describing the program’s results for January through June 2009.

To get the program under way, a team of clinical pharmacists, ID physicians, nurses and microbiologists sat down and developed guidelines to promote optimal antibiotic use. As part of that effort, two levels of agents were created. The first level consisted of antibiotics approved for use by all ID physicians. The second level was reserved for broad-spectrum agents such as daptomycin (Cubicin, Cubist Pharmaceuticals), tigecycline (Tygacil, WyethAyerst) and linezolid (Zyvox, Pfizer) that required review by a stewardship officer—either Dr. Serra or another clinical pharmacist—before dispensing.

“We found that we were able to curtail the use of these level 2 drugs significantly,” said Dr. Serra, “and when we looked at the impact on length of stay and mortality, there was really no difference between the two time periods [before and after program implementation]. Anecdotally, we’re seeing improvement in our antibiogram. We haven’t had time to collect all that data yet, but we’re seeing the right trends that we expected to see.”

The biggest impact occurred in the use of three restricted agents. The number of daptomycin vials used in the six-month study period decreased from 1,040 to 430 compared with the same period the previous year. For tigecycline, the reduction was from 1,250 to 280 vials. The largest decrease came in the use of linezolid, which was lowered to 890 vials during the study period, from 2,720 a year earlier.

Costs for the three drugs also declined sharply. Looking at acquisition costs on an annualized basis, the research team found that reducing the use of linezolid alone saved the hospital more than $312,000, a decrease of more than twothirds compared with the previous year.

Savings on tigecycline and daptomycin were $92,104 (74.9% lower than the year

•

see STEWARDSHIP, page 46

46 Operations & Management

Pharmacy Practice News • January 2010

Infectious Disease

rare and potentially lethal strain of methicillin-resistant Staphylococcus aureus (MRSA) has raised alarms at one Detroit hospital. Of the 16 patients infected with the USA600 strain over a three-year period, eight died within 30 days. The strain also was more resistant to vancomycin than more common strains, according to researchers who tracked the patients.

“The mortality rate was pretty high compared to what’s previously been reported in the literature,” said lead author Carol Moore, PharmD, a research investigator in infectious diseases at the Henry Ford Health System, where the cases emerged. “In the few studies that have been published on MRSA bloodstream infections, mortality ranges from 10% to 30%.”

Dr. Moore cautioned that the study’s small size and the fact that patients with the USA600 strain were sicker and older than those in a control group may have contributed to the poorer outcomes. However, she added that the potential for the spread of this “virulent and resistant strain and its associated mortality” underscores the need for more research, and perhaps for the development of better measures to manage USA600 outbreaks.

In a nested case–control study, Dr.

Moore and her colleagues assessed the epidemiology, clinical characteristics and risk for early mortality of the USA600 strain. They evaluated 16 consecutive cases of USA600 that had occurred over a three-year period and compared the outcomes with a random sample of 64 non-USA600 cases drawn from 420 consecutive MRSA infections. The mean APACHE II score of the USA600 patients was 20, compared with 13 for patients with other MRSA strains (P<0.01), and the mean ages of the cohorts were 64 and 52 years, respectively.

Fifty percent of patients infected with the USA600 group died within 30 days, compared with 11% of patients infected with other MRSA strains (P<0.001).

Thirty-eight percent of patients with the new strain had positive blood cultures for 10 days or longer, compared with only 2% of the controls (P<0.001).

Half of USA600 isolates were heteroresistant to vancomycin, compared with 6% of the controls (P<0.001).

USA600 was universally resistant to erythromycin and clindamycin, considerably less susceptible to trimethoprimsulfamethoxazole and gentamicin, and more tolerant of vancomycin than were other strains (P=0.03).

“It’s too soon to tell what the findings mean,” said Dr. Moore, whose team

STEWARDSHIP

pharmacy team led by an ID specialist rounded on adult patients identified in a daily census report as receiving any one of 10 antibiotics that were deemed susceptible to misuse: aztreonam (Azactam, Elan Corp), ciprofloxacin, gentamicin, imipenem/cilastatin, levofloxacin (Levaquin, Ortho-McNeil), meropenem (Merrem, AstraZeneca), piperacillin, piperacillin/tazobactam, tobramycin and vancomycin.

The rounding team’s main goal was to ensure each patient was receiving optimal therapy. They reviewed drug selection, dose and duration to make sure they were appropriate and that the risk for toxicity was minimal. When applicable, they made recommendations for de-escalation of therapy or a switch from an intravenous to oral medication.

The team recommended a total of 69 therapy changes for 50 patients during the study period. “About 67% were accepted and an additional 10% were accepted with some kind of modification,” said Megan Fletcher, PharmD, the ID pharmacist who led the study. A modification, she explained, might be the substitution of a different fluoroquinolone for the one recommended by the team.

Of the recommendations made, approximately 42% involved de-escalating to an agent with a narrower

continued from page 45

before) and $13,990 (–7.6%), respectively.

The team also looked at hospital length of stay and patient mortality.

“We did see some positive trends,” Dr. Serra said, “but they were not statistically significant.”

He said the team had made some additions to the program since the study ended. “We’re looking at other drugs including the carbapenems. We streamlined the use of our carbapenem agents and were actually able to gain some ground in improving our antibiogram.

Anecdotally, Pseudomonas sensitivity is again improving.”

“The hospital is very pleased with the initiative,” Dr. Serra said. “We’re doing the right thing, saving a lot of money, minimizing collateral damage. We’re not causing resistance and patients are doing just fine.”

Munson Medical Center Pharmacists at Munson Medical Center, a 391-bed community hospital in Traverse City, Mich., carried out a shorter study to demonstrate the cost-effectiveness of their pharmacist-managed antimicrobial stewardship program.

During Feb. 6 to March 3, 2009, a

presented the results at the annual meeting of the Infectious Diseases Society of America in Philadelphia last fall. “We have to conduct further studies in a larger set of patients to fully understand what’s happening with this strain.” Plans for further investigation are under way, she noted.

‘Frightening’ Strain Bears Watching

Photo Credit: Janice Carr, Centers for Disease Control and Prevention

Rare MRSA Strain Raises Alarm A

Scanning electron micrograph image depicting methicillin-resistant Staphylococcus aureus (MRSA) bacteria.

Despite the study’s limitations, Robert Rapp, PharmD, professor of pharmacy and surgery emeritus at the University of Kentucky Medical Center, Lexington, thinks it’s worth paying attention to. “I certainly agree with the authors that this strain demonstrates characteristics that are frankly frightening if it were to become more widespread,” he said.

“It’s also important to note that these cases are bacteremic isolates,” which underscores the potential potency of the strain. “We can only hope the Detroit outbreak is somewhat of an aberration and does not come forth in other areas of the United States.”

But he added that the small number, greater age and greater acuity of the USA600 patients must be considered when evaluating the results. “The difference in APACHE II scores between the two cohorts is remarkable,” Dr. Rapp

said. “Like a lot of infections that we see, the more ill you are, the more immunosuppressed you usually are, and therefore the more open to infection.”

The Centers for Disease Control and Prevention (CDC), which tracks invasive MRSA isolates, has found no evidence to suggest that USA600 is more virulent or less resistant to antibiotics than other MRSA strains it has encountered, according to Brandi Limbago, PhD, a molecular biologist in the CDC’s Division of Healthcare Quality Promotion in Atlanta. “USA600 is not a very common strain. Among MRSA isolates we’ve received, it has not been associated with unusually severe cases or with any unusually severe outcomes,” she said. “I don’t think hospitals need to be on the lookout for it specifically yet.”

spectrum of activity. For example, Dr. Fletcher said, a patient might be receiving an antibiotic for pneumonia caused by methicillin-resistant Staphylococcus aureus, when the culture had shown methicillin susceptibility. Twenty-eight percent of the recommendations were for changing to an oral agent.

A cost analysis showed that the changes resulted in savings of $5,944, or $129.21 per recommendation. The researchers concluded that on an annualized basis, daily rounding by an ID pharmacist could result in savings of $114,181 in antibiotic acquisition costs alone.

important principles and issues guiding appropriate antimicrobial prescribing.”

Ms. Caruso said that “many administrators are shortsighted in evaluating programs and focus on drug cost savings to justify stewardship salaries, with members viewed upon as the ‘antibiotic police.’

“With limited antimicrobials under development,” she added, “the true benefit of the stewardship is to minimize the development of multidrugresistant organisms, optimize empiric therapy, incorporate local susceptibility data when determining most effective therapy, and limit the development of antimicrobial adverse events such as Clostridium difficile infection.

“At Maimonides,” Ms. Caruso said, “our stewardship has effectively curtailed the mismanagement of bacteremia with tigecycline, introduced the concept of extended infusions of meropenem and piperacillin/tazobactam to treat infections caused by organisms with higher minimum inhibitory concentrations, and educated the medical staff to evaluate laboratory data for the presence of extended-spectrum β-lactamases and carbapenemases. Our cost for antimicrobials has also decreased.”

Collaboration Is Key Patricia Caruso, MS, RPh, infectious disease clinical pharmacy manager at Maimonides Medical Center in New York City, noted that “hospitals throughout the country have embraced the antimicrobial stewardship model, based upon an interdisciplinary approach to appropriate antibiotic management.

“I personally have found that collaboration between the stewardship pharmacist and stewardship physician followed by an individual case discussion with the patient’s physician to be our most effective strategy. Not only does the patient immediately benefit, but the clinician is now educated to the

—Steve Frandzel

—Bruce and Joan Buckley

48 Operations & Management

Pharmacy Practice News • January 2010

Leadership in Action

Influencing the Profession of Pharmacy I recently attended the ASHP Midyear Clinical Meeting in Las Vegas (alongside a strikingly large crowd of about 20,000 other pharmacists). This was the first meeting I had attended in my new role as system vice president of pharmacy at Caritas Christi Health Care System, in Boston, which is why I approached this meeting so much differently from the others I have attended over the past 32 years. This year, I had a new mission: to meet people who hold corporate

roles similar to my own new post. I also wanted to familiarize the pharmacy profession with my new organization.

I was slated to give two presentations, participate in a roundtable discussion for students, be a panelist at a discussion on health care reform and facilitate a session for multihospital health-system pharmacy leaders. At the latter session, I told the 75 attendees how I had selfishly asked ASHP to host the meeting (so that I could network with as many people

as I could who held positions similar to my own). This would give me a new list of “go to” people. I hope those who attended were as pleased with our new network as I was and am. I am always amazed at the level of talent and commitment I see in our profession.

My participation in the meeting this year was all about increasing my sphere of influence among my colleagues. I recently read a paper entitled “Leading a Life of Intentional Influence” by John C.

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.

“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

Maxwell.1 This article was recommended to the Section of Pharmacy Practice Managers in a newsletter a few months ago, and it resonated deeply with me. In fact, I found that I have been unknowingly following Maxwell’s principles for many years. Maxwell states there are

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.

Operations & Management 49

Pharmacy Practice News • January 2010

Leadership in Action three basic truths about influence: 1. We all have influence in one way or another. He estimates that even the shiest of individuals influences more than 10,000 people in his or her lifetime. I think that in the pharmacy profession, influence is our business. We influence hospital administrators, physicians, patients, nurses, other pharmacy colleagues, members of Congress, the media and so forth.

Then, there is the influence we have on our family and friends. The list goes on and on. Over the course of a lifetime, we influence and shape the

There are two marks of an effective leader—succession planning and seeking feedback by which to learn and grow. lives of tens of thousands of people.

2. We choose the nature of the influence that we exert over others. The way that others see us is a reflection of who we are, by way of the choices that we make (the big ones as well as the little ones). The way we treat individuals on a daily basis reflects who we are to those around us. We

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

are known by our choices.

3. We must work to earn the influence we desire to have. As Maxwell states, “While everyone exercises influence, the size and strength of our influence depends upon our effort.” Exerting our influence does take a conscious effort on our part. As we grow professionally and personal-

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

Table 1. Adverse Events Occurring with an Incidence of > 15% Adverse Event

Number of AEs

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

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

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

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

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

Table 2. Summary of Infusions with Mild, Moderate, and Severe TreatmentRelated Adverse Events Severity of AE Mild Moderate Severe

No. Infusions 58 25 1

Adjusted % a with AE 7.9 3.6 0.1

Confidence Intervalb 10.4 4.9 0.3

a. Adjusted % = average of the % of infusions with a treatment-related adverse event for each individual subject. b. The 95% upper bound for the adjusted % of infusions for which at least 1 treatmentrelated adverse event was reported was derived by using the t-statistic.

The number and percent of subjects with treatment-emergent rises in AST or ALT are in Table 3.

Table 3. Number (%) of Subjects with Treatment-Emergent Rises in AST or ALT (N = 46) Laboratory Test AST ALT

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

n 3 1

% 6.5 2.2

a. ULN = upper limit of normal.

None of these subjects had a concomitant treatment-emergent rise in total bilirubin.

Reported adverse reactions with Flebogamma® 5% DIF and other IGIV products include: headache, chills, fever, shaking, fatigue, malaise, anxiety, back pain, muscle cramps, abdominal cramps, blood pressure changes, chest tightness, palpitations, tachycardia, nausea, vomiting, cutaneous reactions, wheezing, rash, arthralgia, and edema, often beginning within 60 minutes of the start of the infusion.

Rarely, Immune Globulin Intravenous (Human) can induce a severe fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with IGIV. In the case of shock, the current standard medical treatment for shock should be implemented.

Manufactured by INSTITUTO GRIFOLS, S.A. Barcelona - Spain U.S. License No. 1181 Distributed by GRIFOLS BIOLOGICALS INC. Los Angeles - CA 90032 Phone: 888-GRIFOLS (888-474-3657)

ly, our spheres of influence expand. I am constantly encouraging and helping people grow in our profession of pharmacy. It benefits the profession and the person.

Next, Maxwell lists five ways to gain the influence you want to have. These principles resonate deeply with me, as I have tried for years to share these goals in what I write and in the way I speak to people: 1. Know what is important. If we are going to be influencers, we must first focus on what brings meaning and purpose to our own lives. Our personal values must be deeply rooted for us to stay true to them as changing tides and storms rage around us. People must see character that they are willing to be influenced by, or they will turn away. We need to be willing to give to others, to serve them, to help them be successful in what they do. We must be willing to teach those life principles that we know work. Much of this comes from our desire to learn and grow, but also through the lessons we have learned through life’s “hard knocks.”

2. Live what is important. The great quote here is “influence happens through actions, not intentions.” We can have the best of intentions, but it is only when we put the walk to the talk that our influence is felt. If we do not live up to our own expectations, we lose self-respect. If we lose self-respect, it becomes difficult for us to stay motivated and for others to respect us.

3. Leverage our influence. We are the leaders in our profession, which means we influence others both formally (as in when we make professional presentations) and informally (as we conduct our daily lives). One area that I’m working on is to listen with my eyes and my ears. Showing attentiveness says that we care and catalyzes influence.

4. Choose those who can best multiply your influence over others, in order to develop successors. We speak frequently in pharmacy about the development of the next leaders as many of the current leaders retire from their leadership positions. As Ken Blanchard states,2 there are two marks of an effective leader—succession planning and seeking feedback by which to learn and grow. So who are the future leaders whom you are helping to develop? Future leaders are those who will make things happen in our profession. They aim to lead, not merely follow. They have a high degree of emotional intelligence, including relationship skills.

They praise others and add value. We need to teach these new leaders how

•

see INFLUENCE, page 53

50 Operations & Management

Pharmacy Practice News • January 2010

Staffing

Working at Home, Pharmacists Stay on the Job Las Vegas—Writers and artists and small-business entrepreneurs can all work productively at home, but for pharmacists it’s a different story. They need to be close to the center of pharmacy activity—the computers, the medication shelves, the automated dispensing cabinets and the flow of medicine to units throughout the hospital.

That may be true for many institutions, but not The Cleveland Clinic. There, the pharmacy department has recruited a cadre of work-at-home pharmacists to verify and process medication orders. In doing so, the pharmacy has been able to free up many of its large staff of in-house pharmacists for more clinical tasks.

As a secondary benefit, the work-athome program has provided a boost to the pharmacy’s recruitment efforts, according to Samuel V. Calabrese, MBA, RPh, director of inpatient pharmacy services. “I think we’ve been able to recruit more pharmacists because we could offer that clinical role. We were able to hire over 30 pharmacists the first year and about 25 this past year,” Mr. Calabrese told Pharmacy Practice News at an ASHP Midyear Clinical Meeting poster presentation describing the work-athome program (poster 3-006).

In 2007, the national pharmacist shortage was posing serious staffing issues for the clinic’s pharmacy, Mr. Calabrese said. “We had pharmacists working extra shifts and mandatory overtime, and we needed to do something,” he explained.

“That’s when we thought about the stayat-home moms and dads who had family issues but still wanted to keep up their clinical skills and practice.”

The pharmacy mailed out recruitment

vv

postcards to pharmacists who might be available for part-time work at home.

“On the bottom of the card were three little words—‘Work at Home’— and it took off,” Mr. Calabrese said. In a little over two years, the program has expanded to the point where 11 full- and part-time home-based pharmacists now provide around-the-clock verification and order entry services.

Recruitment and retention were also part of the motive for another Cleveland Clinic initiative—a pharmacist career ladder introduced by the pharmacy department about a year ago (poster 3-008). The idea, according to Morton P. Goldman, PharmD, BCPS, director of pharmacotherapy services, was to offer advancement opportunities and rewards based on the pharmacists’ varying levels of knowledge, skills and leadership.

The career ladder has six rungs, going from Pharmacist 3, the lowest level, up to Pharmacist 1, and then from Clinical Specialist 3 up to 1. “New staff pharmacists start at 3,” said Dr. Goldman.

“If they go into a specialized satellite service or a nursing unit program, they can advance to level 2. If they show great skills in teaching and mentoring other pharmacists, they can reach the Pharmacist 1 level.”

Advancement has other requirements, including a robust portfolio application process and peer review by the Professional Practice of Pharmacy Council. The council, made up of pharmacy leadership, pharmacists and clinical specialists, determines if a candidate has the qualifications to advance if an opening develops.

Not all possible advancements have

taken place in the past year, but Dr. Goldman said, “theoretically a Pharmacist 1 could become a Clinical Specialist 3, if they are able to train residents, if they are working on projects, and if they are performing the functions of a clinical pharmacist,” he added. “They can actually work their way all the way up to Clinical Specialist 1.” Credentials like board certification and specialty residencies are also weighed in the evaluation process.

During the initial phase of the program, four of 67 pharmacists reached level 1, while 33 and 30, respectively, were at levels 2 and 3. Of the 19 clinical specialists, 11 were at level 1, six at 2, and none at 3. Each advancement brings an incremental increase in income.

At Cleveland Clinic, “we’re a lot about recognition and reward,” Dr. Goldman said, “and this is really a great retention tool. Over the past year, we’ve had a pretty significant decline in our turnover.”

Technology Support In the work-at-home program, telecommuting pharmacists are provided with computers, telephones and any reference material not available online, said Mr. Calabrese. “The only thing the pharmacists have to supply is the DSL line. We don’t pay for their Internet connection.”

Pharmacists who work at home are paid 2% less than those at the hospital, Mr. Calabrese said, “because they don’t have travel costs and other commuting expenses. We make sure productivity is monitored. We feel their productivity should be higher than that of pharmacists on site because they have fewer interruptions and they don’t have to

check final products.”

The goal for home-based pharmacists is approximately 45 orders per hour, compared to between 22 and 30 per hour for on-site pharmacists. “That has been consistent over the years that the program has been implemented.”

Once each quarter, work-at-home pharmacists are brought in for an eight-hour education session. “We do clinical pearls and any required informatics training, just so they are up to speed and we can see their faces once in a while,” he said. Once a month, he added, the pharmacy schedules a conference call to go over any issues that might have arisen.

Patient privacy was a concern at the outset. “We contacted the State Board of Pharmacy,” Mr. Calabrese said, and the board raised certain issues regarding compliance with the Health Insurance Portability and Accountability Act. For example, work-at-home pharmacists can’t have a printer hooked up to the computer, and they need to sign on using fingerprint biometrics. If there is no online activity for a short period, the computer automatically shuts down.

The pharmacy department also provided the telecommuters with Alltel wireless phones. “We disabled their call waiting, phone messaging, e-mail and voice mail,” Mr. Calabrese said. “We also gave them fake six-digit internal numbers, so if the pharmacists paged physicians, the physicians thought they were calling an in-house number. We’re now on CPOE [computerized prescriber order entry], so we don’t need that connect system anymore.”

Mr. Calabrese said on-site pharmacists “are happy with the program, because now they are able to do the clinical functions they were taught in school. They don’t feel chained to the basement anymore, and that was a big improvement for pharmacy practice at The Cleveland Clinic.”

A Similar Strategy Domenic A. Caselnova III, BS, MHA, director of pharmacy at Benefis Health System, a 56-bed facility based in Great Falls, Mont., also has instituted an aggressive recruitment and retention program, with a multitiered career advancement plan similar to the one employed at The Cleveland Clinic. Coupled with other strategies, such as flex schedules and employee recognition, Benefis has virtually eliminated staff turnover over the past few years, Mr. Caselnova reported during a poster session at the 2009 ASHP Summer Meeting (July 2009 PPN, page 1). Before the program was initiated, turnover had peaked at 22%.

—Bruce and Joan Buckley

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An expert editorial team has brought together a panel of contributors to produce this beautifully illustrated guide to the major infectious diseases that a clinician is likely to meet. Topics include avian influenza, SARS, hMPV, other viral infections such as hepatitis and HIV/AIDS, infectious agents responsible for diarrhea disease in Western and developing countries and other infectious diseases such as malaria and tuberculosis.

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52 Operations & Management

Pharmacy Practice News • January 2010

Finance

How To Sift Through 340B Resources Katheryne Richardson, PharmD Senior Quality and Compliance Specialist

Danielle Mathers Communications Manager Health Resources and Services Administration, Pharmacy Services Support Center

T

here are various sources of information on the 340B Drug Pricing Program, and it can be hard to decipher what information is good and what information is not. This article outlines some of the organizations and resources available to help you with the 340B program.

Part 2 in a Series

T

his bimonthly series focuses on strategies for getting the most out of the federal 340B Drug Discount Program. The first article, “340B Drug Pricing Program: A Primer,” appeared in the November 2009 issue of Pharmacy Practice News. Future topics include: Split billing software. What does it do? How does it work? Plus tips on policies, procedures and practices, staffing, etc.

Optimizing savings. How to achieve full implementation; dealing with formulary changes; and more.

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.

The Pharmacy Services Support Center The Health Resources and Services Administration (HRSA) Pharmacy Services Support Center (PSSC) is the government-approved resource for all 340B information. PSSC operates through a contract between HRSA and the American Pharmacists Association (APhA). PSSC was created to help federally funded clinics and other health care safety net providers develop clinically and cost-effective pharmacy services. Central to this endeavor is optimal use of the 340B Drug Pricing Program, which is run by the Office of Pharmacy Affairs (OPA) in the HRSA Healthcare Systems Bureau. PSSC provides free information, education and technical assistance to increase patient access to affordable drugs and pharmacy services.

Reach out to the PSSC call center (800) 628-6297 for any questions concerning 340B. This free resource is available to help with all of your 340B inquiries. Staff, trained in the various issues relating to the 340B program, is on hand to answer questions or direct your calls to the appropriate people. The call center operates 9 a.m. to 4:30 p.m.

(Eastern Time). Or e-mail PSSC anytime at PSSC@aphanet.org.

In addition to the call center, PSSC manages a free technical assistance (TA) program, PharmTA, in partnership with OPA. This resource provides 340B-eligible entities solutions directly from expert pharmacist consultants. An objective-based work plan guides the process, and TA is delivered via phone, e-mail or site visit. Call (800) 628-6297 or e-mail PSSC@aphanet.org to request this service.

Table 1. 340B-Focused Organizations

The 340B Journey PSSC developed the 340B Journey, an extranet, as a place to put all of the most reliable 340B information. The 340B Journey is a collection of resources—links, documents, photos, videos,

a

Organizationa

Description

340B Prime Vendor Program (PVP) https:// www.340bpvp.com/ public/about/

The organization is responsible for the negotiation of pharmaceutical pricing below the 340B price as well as improving access to affordable medications by establishing a distribution network for pharmaceuticals to covered entities. The program is free and voluntary to facilities that are already 340B-eligible.

Safety Net Hospitals for Pharmaceutical Access (SNHPA) http://www.snhpa. org/public/index.cfm

SNHPA monitors, educates and serves as an advocate on federal legislative and regulatory issues related to 340B pricing and other pharmacy matters affecting safety net providers.

Other

The primary mission of these organizations is not 340B-specific, but they do stay engaged in 340B issues.

Pharmacy organizations

Some examples include the American Pharmacists Association (APhA), the American Society of HealthSystem Pharmacists (ASHP), the Academy of Managed Care Pharmacy (AMCP), the National Community Pharmacists Association (NCPA) and the National Association of Chain Drug Stores (NACDS).

Health care/policy organizations

Some examples include the National Conference of State Legislatures (NCSL), the National Association of Community Health Centers (NACHC), State and Regional Primary Care Associations, the National Governors Association (NGA), the National Rural Health Association (NRHA), the American College of Healthcare Executives (ACHE), the National Council for Prescription Drug Programs (NCPDP), the National Alliance of State and Territorial AIDS Directors (NASTAD), the National Family Planning & Reproductive Health Association (NFPRHA), the Child Health Corporation of America (CHCA), the National Association of Children’s Hospitals and Related Institutions (NACHRI) and the National Association of Children’s Hospitals (NACH).

Government programs

Each government program that is involved with eligible entities closely works with the Office of Pharmacy Affairs on 340B-related issues. Some examples include the HRSA Office of Pharmacy Affairs, the HRSA Bureau of Primary Healthcare, the HRSA Office of Rural Health Policy/Rural Assistance Center (RAC), the Indian Health Service, Centers for Disease Control and Prevention, and the FDA.

HRSA PSSC does not endorse or hold a position on any of the above stakeholders’ specific practices pertaining to 340B guidance.

tools and presentations. PSSC has sifted through all of the 340B information available on the Internet and vetted that information so that only the best and most accurate 340B resources were posted on the site.

The site is organized into the following sections: Tip of the week: This section changes on a weekly basis and contains general information that offers quick assistance to users.

Quick search: The quick search tool allows users to search the site for key terms. This tool also searches the entire APhA library for relevant information.

Getting started: This section contains comprehensive information for all entities in the 340B program. Folders are titled with all of the different entity types; users simply click on the folder of choice to find all of the information they need to enroll and implement the 340B program at the eligible site. Any entity-specific information also is listed in this section.

Policy and education: Users can find relevant PowerPoint presentations, 340B educational modules and the most current policy information. PSSC’s Policy Blast, a newsletter containing policy developments specific to the 340B program, can be found here.

Patient safety and quality initiatives: This section includes all of the latest information and resources relating the HRSA Patient Safety and Clinical

Operations & Management 53

Pharmacy Practice News • January 2010

Finance Pharmacy Services Collaborative and other federal and private sector programs relating to improving patient safety.

Resources: This section contains Access for All articles, recommended journal lists, PSSC presentations, links to other Web sites, PSSC’s tools and a page for consumers.

340B spotlight: Scrolling lists of breaking news and upcoming 340B meetings are presented in this section.

Links: This section highlights PSSC’s social networking group on LinkedIn, the 340B resource network.

All sections of this site are fully searchable and the information can be easily e-mailed or printed. This resource is continually updated as the PSSC staff discovers new resources available to assist the safety net community. So check back frequently for new updates.

To access the 340B Journey, go to the PSSC Web site (http://pssc.aphanet. org) and click on the luggage tag.

These include 340B-focused and other organizations. Table 1 offers additional information; however, it does not detail each organization due to space limitations. Any omission is unintentional.

Service Providers Over the last several years, the 340B marketplace has expanded exponen-

Table 2. 340B Member Organizationsa Service Providers

Consulting

✔

Americhoice AmerisourceBergen

A-S Medication Solutions

✔

✔

✔

Physician Dispensing

✔

✔

✔

✔

✔ ✔

✔

✔

✔

Centric Health Resources

✔

Coordinated Care Network CVS Caremark

Pharmacy Dispensing Services

✔

Capture Rx Cardinal

Disease Management (Services/ Software)

✔

APS Pharmacy

✔

✔

✔

✔

✔

✔

✔

✔

✔

Dispensing Solutions Inc eAudit Solutions

✔

eRx

✔

Equiscript

✔

Global Pharmaceutical Solutions

✔

✔

Good Health Systems Inc

✔

Hudson Headwaters

✔

INFLUENCE

Huron

continued from page 49

Innovation Associates

2. Blanchard K, Hodges P. Servant Leader. Nashville, TN: J. Countryman; 2003.

Data Management (Services/ Systems)

340B Partners Pharmacy, LLC

Leadership in Action

1. Maxwell JC. Leading a life of intentional influence. http://www.giantimpact.com/articles/ read/leading_a_life_of_intentional_influence.

Accessed December 28, 2009.

Pharmacy Operations (Software/ Hardware)

American Health Care

In the 340B environment, there are organizations that represent the voices of members and/or provide solutions to issues that impact 340B stakeholders.

References

Category of 340B Service

Distribution

340B Organizations

to be influential. As I have said many times, we need to have mentors and be mentors.

5. Prepare your team to perform in your absence. If you have been a steward, a delegator or a coach—giving both authority and responsibility to your people—your team should perform very well.

Keeping Maxwell’s assertions in mind, let’s return to my anecdote. I represented Caritas in my ASHP presentations.

Also, in the health care reform session, I was able to specifically address the unique efforts that Caritas, the secondlargest health system in Massachusetts, is making in working with a large insurance company to create a risk contract called “Alternative Quality Contract.”

Was the Midyear Clinical Meeting a success for me, as far as having intentional influence to introduce pharmacists to Caritas Christi Health System?

I think it was a good start.

brief due to space limitations, and the contents represent the results of an Internet search conducted in December 2009. Thus, the table may not include every possible vendor; any omission is unintentional.

For more information on resources available, contact PSSC at (800) 6286297 or PSSC@aphanet.org.

tially. There are a variety of vendors and consultants that offer 340B-related services (Table 2), ranging from assistance with 340B compliance to data management and capture. Many of the organizations that appear in Table 1 also offer 340B services, but are not repeated in Table 2. The descriptions in Table 2 have been kept intentionally

✔ ✔

Integrated Informatics McKesson

✔

Morris & Dickson

✔

✔

✔

✔

✔

Navigant ✔

✔

Net-Rx

✔

✔

✔

✔

✔

Pharmacy HealthCare Solutions

✔ ✔

✔

✔

RxStrategies

✔

✔

✔

✔

Sentry Data Systems

✔

✔

Speed Script

✔

S/T Health Group Consulting, Inc

a

✔

Ramsell Public Health Rx

✔

SunRx

✔

Talyst

✔

WellPartner

✔

Wilkinson Benefit Consultants

✔

✔

Pharmacy Services Support Center

ScriptPro

✔

✔

NEC Networks, LLC

Qs1

✔

✔

National Direct Home Pharmacy

PDX, Inc.

✔

✔

✔ ✔

HRSA PSSC does not endorse or hold a position on any of the above stakeholders’ specific practices pertaining to 340B guidance.

Category Key: Distribution: drug distribution and reverse distribution services (there are at least 13 regional/specialty distributors that were not included in this table due to space constraints; some are detailed on the Prime Vendor Program’s Web site under Agreements, Distributors); Pharmacy Operations (Software/Hardware): pharmacy dispensing software, interactive voice response systems, pharmacy automation systems, telepharmacy, central fill; Data Management (Services/Systems): split billing, pharmacy benefit management, contract pharmacy data services, overcharge recovery services; Consulting: 340B compliance, operational improvement assistance, program evaluation, legal advice; Disease Management (Services/Software): software, provision/administration of disease management services; Pharmacy Dispensing Services: contract pharmacy services; due to space constraints, only organizations that were easily identifiable via Internet searching appear here; there are a large number of potential contract pharmacies; Physician Dispensing: in-clinic medication, systems that allow dispensing by a non-pharmacist.

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