Pharmacy Practice News - August 2009 - Digital Edition by McMahon Group

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Volume 36 • Number 8 • August 2009 ❃

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Pharmacist-led Program For Smoking Cessation Can Double Quit Rates Miami—Pharmacists have a key role to play in helping people stop smoking and live longer and healthier lives, according to new research presented in posters at the 5th annual conference of the Hematology/Oncology Pharmacy Association. In one of the posters, pharmacists who were trained to provide intensive smoking cessation counseling and drug therapy were able to double the quit rates reported in several earlier trials. Lead investigator Jane Pruemer, PharmD, said the successful outcome illustrates that pharmacists can excel at promoting wellness in their patients. “As pharmacists, we have a responsibility to help prevent cancers, as well as to help treat them,” said Dr. Pruemer, professor of pharmacy at the James L. Winkle College of Pharmacy, University of Cincinnati, in Ohio. “We all know that smoking is one of the major causes of not

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see STOP SMOKING, page 34

McMahon Publishing

in this issue Clinical

In Brief ‘Artificial’ lung shows promise.

Hem/Onc Pharmacy Cancer surge poses challenge—and opportunity—for hem/onc pharmacists.

The case for and against vitamins in cancer.

Operations & Mgmt

Preparedness ASHP launches flu readiness resource center.

Pharmacy Heritage Scoville’s test for pepper heat marked an early success for pharmacist research.

Policy

Medication Safety FDA to study anesthesia risks in children.

Charge master often neglected

Hospitals May Be Letting Crucial Drug Pricing Tool Rust Rosemont, Ill.—In a national survey, more than one-half of hospitals said they reviewed and changed line-item drug products on their pricing lists quarterly or less often. Nearly one-third (28%) reported reviewing the list only once annually. The failure to adequately manage the list, known as a hospital pharmacy charge master, can result in reduced reimbursement that not only hurts health-systems individually; lax updating can also trigger artificially low national pay rates set by the Centers for Medicare & Medicaid Services, noted lead investigator Christine A. Pierce. The federal agency, Ms. Pierce explained, collects charge data from hospitals and then aggregates them to use in a formula for establishing national levels of payment.

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Technology

Closed-System Transfer Devices Lessen Worker Contamination—at a Cost Miami—The use of a closed-system transfer device (CSTD) to reduce the danger of contamination from chemotherapy drugs to the health care workers who compound and administer them is justified because of its potential safety benefits. However, there are other factors to consider when persuading your institution to budget for the use of these devices, according to pharmacists from The Ohio State University Medical Center Arthur G. James Cancer Hospital, in Columbus. There is no question that the use of the CSTDs cuts down significantly on exposures to dangerous chemotherapy drugs, said Ryan A. Forrey, PharmD,

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see CLOSED SYSTEM, page 12

see DRUG PRICING, page 40

E-Prescribing How to avoid CPOE growing pains in ambulatory oncology infusion settings.

Informatics Anticoagulation made easier via tracking software.

Product/Service Profiles Section begins on page

PP1

Educational Review Antimicrobial Efficacy Insert after page

Strategy bridges inpatient-to-outpatient care gap

Strong Medication Reconciliation Effort Lowers ADE Readmissions Rosemont, Ill.—Intensive pharmacist-provided postdischarge medication follow-up dramatically lowered the rate of readmissions for adverse drug events (ADEs) in a large health care system’s hospitals, according to presentations at the American Society of Health-System Pharmacists (ASHP) Summer Meeting. Pharmacists at Novant Health

found that patients enrolled in the health system’s SafeMed medication reconcilation program were 4.19 times more likely to be readmitted within 60 days and 1.74 times more likely to be readmitted within 30 days with an ADE than a control group not participating in the outreach program, reported Terri B.

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see RECONCILIATION, page 6

The Book Page Managing Anticoagulation Patients in the Hospital: The Inpatient Anticoagulation Service Michael Gulseth

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Up Front 3

Pharmacy Practice News • August 2009

Capsules In Brief

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AUGUST 2009

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1. Recruiting, Retaining Pharmacists May Hinge on Depth of Offerings 2. Drug Noncompliance Still Driving Health Care Costs 3. Mississippi Clinic Wins Fight Against Resistant Hypertension 4. Life Portfolio—The Work Continues, but at a New Venue 5. Should Tamoxifen Candidates Be Tested for CYP2D6? Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

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‘You can’t force the issue, but if we’re going to continue to push for provider status, then we are going to have to be accountable for what we do, and both of those goals go hand in hand.’

See Web exclusive section, pharmacypracticenews.com

‘Artificial’ Lung Researchers Encouraged by Initial Data

—Lynnae M. Mahaney, MBA, FASHP

low-resistance membrane oxygenator may serve as a lifesustaining bridge for critically ill patients awaiting lung transplantation, according to a new study. Patients diagnosed with end-stage respiratory failure often wait months for a replacement lung because of a donor shortage, and rely on artificial means of oxygenation to survive. Compounding the problem is that currently available ventilators can lead to severe injury—including ventilator-induced lung injury and multiple organ failure—and are not designed to support The iLA Membrane Ventilapatients for extended periods of time. tor system enhances the Researchers at University Hospital Regensburg in Germany oxygenation and healing tested the Novalung Interventional Lung Assist (iLA) Membrane capacity of the patient’s Ventilator (Novalung GmbH) on two patients waiting for lung own lungs by promoting transplants, with promising results. The first patient had pulmonary CO2 elimination and other veno-occlusive disease and survived 18 days before dying from aspects of respiration. severe sepsis. The second patient, diagnosed with primary pulmonary hypertension, survived 62 days until undergoing successful lung transplantation. “To date, the outcome of patients transplanted directly from a ventilator is not convincing,” said Daniele Camboni, MD, research fellow at the University of Michigan in Ann Arbor, and lead author of the study. “The iLA can help wean patients from the ventilator—even allowing ambulatory care.” The Novalung iLA works by enriching a patient’s blood with oxygen and removing carbon dioxide through diffusion, powered by the patient’s heartbeat. The device is nonsurgically inserted into a groin artery and vein at two vascular access sites. The device may be used in conjunction with a ventilator, allowing optimal protective settings by eliminating carbon dioxide concerns. Currently, it is approved in Europe and Canada for lung support up to 29 days. The Novalung iLA has been used successfully in more than 4,000 cases for critical care support, acute lung failure, exacerbated chronic obstructive pulmonary disease and tracheal surgery. To date, the FDA has not approved the device. Preparations are under way for submission of a 510(k) application for premarket notification, which Novalung does not expect to submit before 2010. The full study findings were published in the ASAIO (American Society for Artificial Internal Organs) journal (2009;55:304-306). —Seth Kandel

EDITORIAL BOARD

Dan Radebaugh, Director of Production and Technical Operations

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

Mark Neufeld, Production Manager

ANESTHESIOLOGY/PAIN

Volume 36 • Number 8 • August 2009 • pharmacypracticenews.com

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

James Prudden, Group Editorial Director

Susan Goodin, PharmD, BCOP, New Brunswick, NJ

Elizabeth Zhong, Associate Copy Chief

Van Velle, President, Partner

Robert Ignoffo, PharmD, San Francisco, CA

Brian Dunleavy, Editorial Director, Promotional Medical Education

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

C. Michael White, PharmD, Storrs, CT CNS/PSYCHIATRY Charles F. Caley, PharmD, Storrs, CT Lawrence Cohen, PharmD, BCPP, FASHP, FCCP, Spokane, WA Larry Ereshefsky, PharmD, San Antonio, TX COMPLEMENTARY AND ALTERNATIVE MEDICINE

PEDIATRICS Gretchen Brummel, PharmD, Hershey, PA REIMBURSEMENT Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO TECHNOLOGY Susanne E. Larrabee, RPh, Petoskey, MI

CRITICAL CARE

Thomas Van Hassel, RPh, Yuma, AZ

John W. Devlin, PharmD, BCPS, FCCM, Boston, MA Judi Jacobi, PharmD, FCCM, Indianapolis, IN Lynda Welage, PharmD, FCCM, Ann Arbor, MI

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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

Your Letters

Pharmacy Practice News • August 2009

In Brief FDA Advisory Panel Imposes Harsh Rules On Acetaminophen

How Renewable Is Pharmacy License? To the editor:

appreciate the advice provided by Carmen Catizone, as reported in the May 2009 article, “Staying on the Bench [page 3].” However, I feel compelled to comment from a personal experience. I followed the advice regarding licensure in the article and kept my original license from 1976 in Virginia “inactive,” as I have practiced in Rhode Island since 1979. My understanding was that to reactivate my license, all I needed to do other than pay fees was to submit continuing education (CEU) units back to 1993 when the CE law was enacted in Virginia. However, unknown to me, in 2007 the law in Virginia was changed so that if your license is “inactive” for five or more years, pharmacists have to retake the pharmacy law exam. I was going to reciprocate my license from Virginia to New Hampshire, where I plan to retire; however this now presents an additional hurdle. Pharmacists need to understand that state laws change over time, and to assume, as the article states, that keeping their license “inactive” is sufficient as long as they keep up with CEUs is not accurate for every state. In my case, to reciprocate I need to return to Virginia, take the law exam ($100), provide 60 CEUs and pay $45 to reactivate the license. According to Virginia law, an “inactive” license is now viewed the same as one that has lapsed or been suspended or revoked, except for the administrative fees required to reactivate. George A. Kenna, PhD, RPh Assistant Professor (Research) Department of Psychiatry and Human Behavior and Center for Alcohol and Addiction Studies Brown University Senior Scientific Advisor Program on Opioid Risk Management Tufts Health Care Institute, Boston, MA

pharmacypracticenews.com Visit our Web site for coverage of the latest developments in clinical medicine, technology, policy, and pharmacy operations & management.

n FDA advisory panel has voted in favor of several harsh restrictions on the currently recommended use of acetaminophen, unanimously recommending a black box warning for prescription medications that combine acetaminophen with another drug, and also recommending a reduction in the number of liquid doses of the medication available for sick children. By narrower margins, the advisory panel also voted in favor of lowering the maximum daily dose of acetaminophen to less than the current recommendation of 4,000 mg; lowering the maximum single adult dose from 1,000 to 650 mg; making the 500-mg pill obtainable by prescription only; and—in perhaps its most controversial decision of the meeting—eliminating all prescription products that combine acetaminophen with certain other drugs, like narcotics, from the market. The advisory committee reached these conclusions after a two-day hearing which took place in late June. It is as yet unclear if the FDA will accept the advisory panel’s recommendations, as the agency is not bound to the rulings of its advisory committees. The recommendations of the advisory committee come on the heels of a new FDA ruling that requires manufacturers of over-the-counter (OTC) painkillers and fever reducers to include a warning on their labels of the potential for stomach bleeding and liver damage. The agents targeted for the new labeling include acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs)—a class that includes aspirin, ibuprofen, naproxen and ketoprofen. Products that contain these agents alone or combined with other ingredients must clearly state so on both the packaging and bottle, along with language warning of the increased risk for liver damage with acetaminophen and stomach bleeding with NSAIDs. “The risks associated with their [NSAIDs and acetaminophen] use need to be clearly identified on the label so that consumers taking these drugs are fully aware of the potential harm they can cause,” said Charles Ganley, MD, director of the FDA’s Office of Nonprescription Drugs in the Center for Drug Evaluation and Research, in reporting the new rule. “It is important to know how to take these medications safely to reduce their risk.” Acetaminophen overdose is far and away the most common cause of acute

liver damage in the United States (Hepatology 2005;42:1364-1372; Hepatol Res 2008;38:S3-S5). Nearly 50% of all cases of acute liver failure in the United States are linked to the use of acetaminophen, while the mortality rate for acetaminophen-related acute liver failure has been reported to be as high as 30% (Hepatol Res 2008;38:S3-S5). Unintentional acetaminophen overdose is quite common, with one study reporting that almost 40% of patients with acute liver failure related to unintentional acetaminophen overuse were taking two or more preparations of the painkiller simultaneously (Hepatology 2005;42:1364-1372). “Consumers may not be aware that acetaminophen is present in many overthe-counter combination products, so they may unknowingly exceed the recommended acetaminophen dose if they take more than one acetaminophen product without knowing that both contain acetaminophen,” stated an FDA report dated May 27. “There is extensive evidence that hepatoxicity … caused by acetaminophen use may result from a lack of consumer awareness that acetaminophen can cause severe liver injury.” Indeed, a 2008 study on outcomes of acetaminophen overdose reported that 34% of patients hospitalized for acetaminophen overdose were abusers of alcohol, which can increase the likelihood of or worsen liver damage (Clin Gastroenterol Hepatol 2008;6:918-925). The FDA recently published a consumer update on acetaminophen and liver injury, which can be accessed online at www.fda.gov/downloads/ForConsumers/ ConsumerUpdates/UCM168940.pdf.

of heartburn-free days and nights compared with placebo among frequent heartburn sufferers over a 14-day course of treatment. In one study (abstract T1083) presented at DDW, both Prevacid 24HR and lansoprazole 30 mg were associated with significantly more heartburn-free nights compared with placebo (61.7% for Prevacid 24HR, 61.3% for lansoprazole 30 mg and 47.8% for placebo). Another DDW presentation (abstract M1924) showed that Prevacid 24HR was superior to placebo in treating frequent heartburn both day and night in a 14-day course of treatment; this pooled analysis of three randomized, double-blind, placebo-controlled trials revealed that the percentage of people with no heartburn was significantly higher every day over the 14-day treatment period with Prevacid 24HR compared with placebo. For more information about Prevacid 24HR, visit www.Prevacid24HR.com. —Based on a press release from Novartis

FDA’s Division of Drug Info Joins Twitter Age

—Cynthia J. Gordon, PhD, and Donald M. Pizzi

FDA OKs Rx-Strength Prevacid 24HR as OTC

ovartis has announced that Prevacid 24HR (15-mg lansoprazole delayedrelease capsules) has been approved by the FDA as the first over-the-counter (OTC) proton pump inhibitor (PPI) indicated for the treatment of frequent heartburn since 2003. According to Novartis, OTC Prevacid 24HR is the first OTC PPI approved in its original prescription formulation, and it is the only PPI containing lansoprazole to be approved for OTC treatment of frequent heartburn, which is defined as heartburn that occurs two or more days per week. Data presented at the 2009 Digestive Disease Week (DDW) meeting showed that Prevacid 24HR, in the form of 15-mg delayed-release capsules, significantly increased the percentage

he FDA has joined the likes of Miley Cyrus and MC Hammer and become a proud “tweeter” on the free “social messaging” Web site Twitter. As the Center for Drug Evaluation and Research’s focal point for public inquiries, the FDA’s Division of Drug Information (DDI) will now provide updated drug information at http://twitter.com/ fda_drug_info. “Tweets,” the commonly used term for messages posted on the fast-growing site, will coincide with new drug product information posted to the FDA Web site. “[The] DDI believes Twitter will be an invaluable resource to provide timely, accurate information to consumers, health care providers and industry,” the FDA stated in a news release. “We recognize that new communication tools like Twitter derive much of their value from the two-way conversations that they enable; however, [the] DDI is only able to send out informational updates.” Individuals interested in contacting the DDI can do so at druginfo@fda.hhs.gov. —Staff

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6 Clinical

Pharmacy Practice News • August 2009

Medication Safety

RECONCILIATION

Near-misses

Allergies

continued from page 1

Cardwell, PharmD, clinical pharmacist and SafeMed team leader. In addition to reducing ADE-related readmissions at 30 (2.0% vs. 3.4%; P<0.0074) and 60 days (0.6% vs. 2.5%; P<0.0001) during the evaluation period between January 2007 and October 2008, Novant’s pharmacist-led SafeMed team reduced overall readmissions at 30 (6.0% vs 13.1%; P<0.0001) and 60 days (2.7% vs 7.7%; P<0.0001). These results garnered Novant Health, which serves more than 5 million people in North and South Carolina and Virginia, a great deal of positive attention, including the ASHP Research and Education Foundation’s 2008 Award for Excellence in Medication-Use Safety. Congratulating the Novant pharmacists on the program during the question-and-answer session, Anne M. Bobb, RPh, clinical informatics pharmacist at Northwestern Memorial Hospital, in Chicago, said, “You’ve probably done more for our profession with this program than all of us have done in a long time.” In an interview with Pharmacy Practice News, Ms. Bobb said that one of the things that “jumped out” at her about the Novant program is the success it has had in “bridging from the inpatient to the outpatient setting. Most organizations don’t do that very well.” Novant started the SafeMed program in 2006 in response to increasing reports of ADE-related readmissions, particularly in elderly patients. A lack of communication between hospital caregivers, patients and their primary care providers (PCPs) was a major source of the problems, noted Dr. Cardwell. “Physicians often aren’t aware of what medications other providers are giving their patients,” she said. To address this, the team’s pharmacists contacted Novant’s PCPs and discussed the program’s objectives with them. “We wanted to be able to prevent hospitalizations. Ideally, we wanted physicians to refer patients to us before they went into the hospital,” but as a start, Novant wanted to try to prevent patients who were released from the hospital from having to be readmitted because of a medicationrelated problem, such as drug allergies, drug interactions and so on (Figure). The program now includes six clinical pharmacists, who work with more than 1,000 Novant providers. Pharmacists in the SafeMed program review medically complex patients discharged from all of Novant’s hospitals. The pharmacists obtain a weekly list of discharged patients and review the hospital database for details on inpatient stays, gathering information from admission notes, discharge summaries, etc., according to SafeMed clinical pharmacist Jennifer M. Rief, PharmD.

Idiosyncratic reactions Overdosing/ underdosing

Medication Errors

Adverse Drug Events (ADEs)

Drug interactions Omissions

Side effects

Preventable ADEs

Figure. Adverse events and medication errors.

The pharmacist assesses the patient’s medication regimen and compares the discharge medication list with the discharge summary. The pharmacist then reviews all medications for potential problems and reviews the patient’s laboratory results. The next step is to hone in on patients with specific factors that might put them at risk for ADEs, such as increased age, number of medications, disease state, increased hospital length of stay, frequent emergency department and/or inpatient visits over the previous 12 months, frequent falls or injuries, cognitive impairments, and cultural and linguistic challenges. The pharmacist also reviews diseasespecific factors that can contribute to ADEs. For example, the hospital pharmacist conducted the ADE Trigger Project, which targeted four areas responsible for a large percentage of ADEs—anticoagulation, potassium homeostasis, sedation and digoxin use. For anticoagulation, the triggers were an international normalized ratio greater than 3.0 or the use of vitamin K; for potassium homeostasis, the triggers were serum potassium levels greater than 6.0 mEq/L or the use of sodium polystyrene sulfonate (Kayexalate, Sanofi-Aventis); for sedation, the triggers were the use of naloxone or flumazenil (Romazicon, Roche); and for digoxin, the trigger was a level greater than 2 ng/mL. These triggers help the SafeMed pharmacist target patients in need of intervention.

Armed with all of that information, the patient is contacted via telephone “within seven days of discharge,” said Dr. Cardwell. “The ideal would be two to three days after discharge, because then we could get them on the right track quickly.” At this point the system provides patient discharge data on a weekly basis; however, a project is in place to enhance those reports, she noted. At the outset of the patient phone call, Dr. Rief said, “we work very hard to engage the patient and make them comfortable. This is critical, because if you can’t engage the patient, the call might not be very successful.” Once they are successfully interacting with patients, she said, they begin the process of medication reconciliation by having patients gather all their medication to make sure that “what we think they’re taking is what they’re taking.” They then educate patients about each medication’s use and action, adverse effects, the timing of administration, drug-drug interactions, renal dosing and laboratory results. In addition to providing that education, the Novant pharmacists answer any questions patients may have and provide a toll-free phone number for a queue line on which the patient can leave a message if they have any follow-up questions. Pharmacists monitor the queue line every two hours during the week, so patients never have to wait long for a return call. The SafeMed pharmacists

Tips To Facilitate a Medication Reconciliation Program

long the way, Dr. Cardwell and her colleagues picked up some useful knowledge about the best ways to approach medication reconciliation:

• Identify high-risk populations to maximize the benefit of the program. • Target specific interventions to implement so the program can have immediate practical benefits. • Get support from key providers. • Build trust with providers as well as patients. • Budget for technicians so pharmacists can focus more on direct patient care.

also offer information about financial assistance programs in case patients are facing financial barriers preventing them from obtaining their medications. “It’s a lot easier than I thought initially to communicate with these patients on the phone,” said Dr. Cardwell, noting that an added benefit of a pharmacist conducting the medication reconciliation is that patients will “sometimes tell you things they wouldn’t or didn’t tell their physician. For example, ‘well, I don’t take that medication because it’s too expensive, but my doctor doesn’t know.’” After the encounter, the patient is entered into a clinic database that the pharmacists use to track trends and generate statistics. The database houses information on allergies and details of each encounter with the pharmacist— including an overall patient assessment, the specific patient education topics discussed, interventions and the recommended plan for the physician. The reconciled medication list, assessment and suggested plan is also detailed in a report sent to the physician, which includes information on potential drug– drug and adverse interactions, therapeutic duplications, renal dosing recommendations, suggestions to add or discontinue medications, and laboratory findings. The length of the reconciliation process varies, but Dr. Cardwell noted that while the process times varies from 20-90 minutes, on average it takes about 60 minutes to discuss the assessment and medications with the patient and enter the follow-up information into the database. Novant’s team found this time to be well spent and saw results right away. “At first,” Dr. Cardwell said, “we were calling the sickest of the sick,” so it was especially encouraging that ADEs also decreased in that population. When asked by Ms. Bobb whether the results were due to patient education, physician recommendations or both, Dr. Cardwell said, “The contact with the physician does help, but a lot of it is due to the education of the patient.” She said that although, in general, they interact with the patient just one time, “we try to empower the patient” to ask questions and follow up with their doctor, and she said that this has lasting effects. Ms. Bobb pointed out that preventing readmissions is “something the federal government is very interested in now,” and changes in reimbursement for readmissions that occur within 30 days are forthcoming. She predicted that a program such as SafeMed, which can prevent those readmissions, will become increasingly valuable to hospitals. Dr. Cardwell said Novant started out with a simple goal—“to make a difference one patient at a time,” but over time, the impact of that can become significant, both clinically and economically. —Sarah Tilyou

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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 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 should generally be avoided. Gastrointestinal Bleeding in Patients with Cirrhosis – Used only when the 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 Co-administration with Hypertonic Saline – Not recommended CYP 3A Inhibitors – Do not use with strong inhibitors of CYP 3A; avoid concomitant use with moderate CYP 3A inhibitors CYP 3A Inducers SAMSCA may need to be increased P-gp Inhibitors Hyperkalemia or Drugs that Increase Serum Potassium – Monitor serum potassium levels in patients 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 – (incidence ≥ and hyperglycemia (6% vs 1%)

Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on the following pages.

Reference: 1. Schrier RW, Gross P, Gheorghiade M, et al; SALT Investigators. Tolvaptan, a selective oral vasopressin V2 for hyponatremia. N Engl J Med

PRINTER-FRIENDLY VERSION AT PHARMACYPRACTICENEWS.COM

Antimicrobial Efficacy JARED L. CRANDON, PHARMD, BCPS Infectious Disease Pharmacotherapy Fellow Center for Anti-Infective Research and Development Hartford Hospital Hartford, Connecticut

JOSEPH L. KUTI, PHARMD Associate Director Center for Anti-Infective Research and Development Hartford Hospital Hartford, Connecticut

DAVID P. NICOLAU, PHARMD, FCCP, FIDSA Director Center for Anti-Infective Research and Development Hartford Hospital Hartford, Connecticut

his editorial review is intended

to be a reference to describe the potential in vivo activity of various

antimicrobial agents when the identity of the infecting organism is known. Because the early initiation of appropriate therapy has been noted to improve clinical outcomes, empiric therapy frequently demands powerful broad-spectrum antimicrobial agent(s) until the specific infecting bacteria has been identified.

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

Given the continuous evolution of infecting bacteria, the susceptibility profiles of many antimicrobial agents are in flux. Moreover, antimicrobial susceptibilities can be highly variable based on institution-specific and geographic factors (including various institutional sites—eg, outpatient vs inpatient, intensive care unit vs ward). Therefore, an awareness of local susceptibility data is essential to ensure the highest probability of successful clinical outcomes. While the use of various dosing techniques, especially for β-lactams, may potentiate in vivo activity, the information contained herein pertains only to standard dosing regimens. This editorial review reflects the opinions of the authors and is intended to be a general guide to antimicrobial applications with the appreciation that host factors (eg, site of infection, clinical picture, comorbid conditions) could greatly impact antimicrobial selection.

P H A R M AC Y P R AC T I C E N E WS • AU G U ST 2 0 0 9

Table 1. Penicillins & Related Antimicrobials

Nafcillin/Oxacillin

Ertapenem

Amoxicillin-Clavulanate

Cloxacillin/Dicloxacillin

Doripenem

Meropenem

Ampicillin-Sulbactam

Piperacillin-Tazobactam

Imipenem-Cilastatin

2 3

Aztreonam

Ticarcillin-Clavulanate

Penicillin V

Piperacillin

Cocci

Neisseria meningitidis

Others

Moraxella catarrhalis Neisseria gonorrhoeaea

Antistaphylococcal

Antipseudomonal

Ticarcillin

Penicillin G

Ampicillin

Amoxicillin

Nonantipseudomonal

Chlamydia pneumoniae (TWAR) Chlamydia

Chlamydia psittaci Chlamydia trachomatis

Coccobacilli

Bordetella pertussis Brucella spp.b Campylobacter jejuni

Helicobacter pylori c

Hemophilus ducreyi Hemophilus influenzaed Gram-Negative Aerobes

Francisella tularensis

2 3

Citrobacter spp.e

Enterobacter spp.e,f

Legionella pneumophila

Escherichia coli f,g

Enterobacteriaceae

Klebsiella pneumoniaef,g

Morganella morganii

Other Bacilli (Nonenterobacteriaceae)

Proteus vulgaris

Providencia stuartii

3 3

Acinetobacter spp.h

Burkholderia (Pseudomonas) cepaciah

Serratia spp.

Cocci

2 2

Shigella spp.

Gram-Positive Aerobes

2 2

Salmonella spp.

Pseudomonas aeruginosa

Stenotrophomonas (Xanthomonas) maltophilia

Enterococcus

2 2

Salmonella typhi

FermentPositive

2 2

Proteus mirabilis

FermentNegative

2 2

Pasteurella multocida

Vibrio cholerae

Enterococcus faecalis

3 2

Vancomycin-resistant Enterococcus faecalis Enterococcus faecium Vancomycin-resistant Enterococcus faecium

Key to Table 1

First-line agent based on clinical efficacy, susceptibility patterns, and consideration of the overall costs of therapy.

a drug with a low level of activity against this organism, and/or 3 Indicates limited clinical efficacy.

an alternative drug based on clinical efficacy, susceptibility 2 Indicates patterns, and consideration of the overall costs of therapy.

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

Either there is insufficient information to evaluate this drug against this organism at this time or this drug is not indicated for this organism.

Table 1. Penicillins & Related Antimicrobials

(continued) Antistaphylococcal

Meropenem

Doripenem

Cloxacillin/Dicloxacillin

Nafcillin/Oxacillin

Amoxicillin-Clavulanate

Ampicillin-Sulbactam

Ertapenem

Aztreonam

Ticarcillin-Clavulanate

Piperacillin-Tazobactam

Staphylococcus aureus

Others

Imipenem-Cilastatin

Antipseudomonal

Piperacillin

Penicillin V

Ticarcillin

Penicillin G

Ampicillin

Amoxicillin

Nonantipseudomonal

Methicillin-resistant Staphylococcus aureus Glycopeptide-intermediate susceptible Staphylococcus aureus Staphylococcus epidermidis

Cocci

Gram-Positive Aerobes

Methicillin-resistant Staphylococcus epidermidis

Actinomycetes

Streptococcus Group A (S. pyogenes)

Streptococcus Group B (S. agalactiae)

Streptococcus Group D (eg, S. bovis)

Streptococcus pneumoniaei

Penicillin-resistant Streptococcus pneumoniae j,k

Viridans streptococci

Actinomyces israelii

Bacilli

GramNegative GramPositive

2 2

Gardnerella vaginalis n

Anaerobes

3 2

Corynebacterium jeikeium

Bacteroides fragilis

Fusobacterium spp.

Prevotella melaninogenica

Clostridium difficile

Corynebacterium diphtheriaem

Listeria monocytogeneso

Nocardia spp. Bacillus anthracisl

Clostridium perfringens

Clostridium tetani

Peptostreptococcus spp.

Mycoplasma pneumoniae Mycoplasma

Ureaplasma urealyticum Borrelia burgdorferi (Lyme disease)q

Spiral Organisms

Borrelia recurrentis Leptospira spp. Treponema pallidum

2 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

Table 2. Cephalosporins Generations

2 2

Cefepime

Neisseria meningitidis

Ceftriaxone

Ceftizoxime

2 3

Ceftibuten

2 3

Ceftazidime

2 3

Cefpodoxime proxetil

3 3

4th

Cefotaxime

2 3

Cefditoren

Cefdinir

Cefuroxime

2 3

Cefprozil

Cefoxitin

Cefotetan

Cephapirin

3 3

Cefaclor

Cephalexin

3rd

Loracarbef

Cocci

Moraxella catarrhalis Neisseria gonorrhoeaea

2nd

Cefazolin

Cefadroxil

1st

Chlamydia pneumoniae (TWAR) Chlamydia

Chlamydia psittaci Chlamydia trachomatis

Coccobacilli

Bordetella pertussis Brucella spp.b

Campylobacter jejuni Francisella tularensis Helicobacter pylori c Hemophilus ducreyi

Gram-Negative Aerobes

Hemophilus influenzaed

2 1

Enterobacteriaceae

Legionella pneumophila Citrobacter spp.e

Enterobacter spp.e,f

Escherichia coli f,g

Klebsiella pneumoniae f,g

Morganella morganii Proteus mirabilis

3 2

1 2

Proteus vulgaris

Providencia stuartii

Salmonella spp.

Other Bacilli (Nonenterobacteriaceae)

Salmonella typhi

Serratia spp.

Shigella spp.

Acinetobacter spp.

Pseudomonas aeruginosa

Stenotrophomonas (Xanthomonas) maltophilia FermentPositive

Burkholderia (Pseudomonas) cepacia FermentNegative

Pasteurella multocida Vibrio cholerae

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 2

Table 2. Cephalosporins

(continued) Generations

Cefdinir

Cefepime

Loracarbef

Ceftriaxone

Cefuroxime

Ceftizoxime

Cefprozil

4th

Ceftibuten

Cefoxitin

Ceftazidime

Cefotetan

Cefpodoxime proxetil

Cefaclor

Cefotaxime

Cephapirin

Cefditoren

Cephalexin

3rd

Cefazolin

2nd

Cefadroxil

1st

Enterococcus faecalis

Enterococcus

Vancomycin-resistant Enterococcus faecalis Enterococcus faecium Vancomycin-resistant Enterococcus faecium Staphylococcus aureus

Glycopeptide-intermediate susceptible Staphylococcus aureus

Cocci

Gram-Positive Aerobes

Methicillin-resistant Staphylococcus aureus

Staphylococcus epidermidis Methicillin-resistant Staphylococcus epidermidis Streptococcus Group A (S. pyogenes)

Streptococcus Group B (S. agalactiae)

Streptococcus Group D (eg, S. bovis)

Streptococcus pneumoniae i

Penicillin-resistant Streptococcus pneumoniae j,k Viridans streptococci

Bacilli

2 2

Actinomyces israelii Actinomycetes

Nocardia spp.

2 3

Bacillus anthracis l Corynebacterium diphtheriae m Corynebacterium jeikeium Gardnerella vaginalis n

GramNegative

Bacteroides fragilis

Fusobacterium spp.

3 2

Prevotella melaninogenica

Clostridium difficile p GramPositive

Anaerobes

Listeria monocytogenes o

Clostridium perfringens

Clostridium tetani Peptostreptococcus spp.

3 2

Mycoplasma pneumoniae Mycoplasma

Ureaplasma urealyticum Borrelia burgdorferi (Lyme disease)q

Spiral Organisms

Borrelia recurrentis Leptospira spp. Treponema pallidum

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

Coccobacilli

Chlamydia

Neisseria meningitidis

3 2

Campylobacter jejuni Francisella tularensis

2 3

2 2

Enterobacter spp.e

Escherichia coli f

Klebsiella pneumoniaef

Morganella morganii

Proteus mirabilis

Proteus vulgaris

Acinetobacter spp.

1 2

2 2

Pasteurella multocida

Vibrio cholerae

Enterococcus faecalis

Vancomycin-resistant Enterococcus faecalis

Enterococcus faecium Vancomycin-resistant Enterococcus faecium 2

2 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

3 2

2 1

Stenotrophomonas (Xanthomonas) maltophilia

Staphylococcus aureus

2 2

Burkholderia (Pseudomonas) cepaciag Pseudomonas g aeruginosa

Salmonella spp.

Citrobacter spp.e

Providencia stuartii

2 1

1 2

Norfloxacin

Nitrofurantoin

Serratia spp.

FermentNegative

Shigella spp.

FermentPositive

Brucella spp.b

Enterococcus

Chlamydia psittaci

Bordetella pertussis

Enterobacteriaceae

Chlamydia trachomatis

Salmonella typhi

Other Bacilli (Nonenterobacteriaceae)

Legionella pneumophila

Cocci

Hemophilus influenzaed Gram-Negative Aerobes

Hemophilus ducreyi

Gram-Positive Aerobes

Chlamydia pneumoniae (TWAR)

Helicobacter pyloric

Fosfomycin

Colistin/Polymixin B

Vancomycin

Daptomycin u

Trimethoprim-Sulfamethoxazole

Tigecycline

Tetracyclines (eg, Doxycycline)v

Trovafloxacin t

Telithromycin

Moxifloxacin

Rifampin

Levofloxacin

Metronidazole

Gemifloxacin

UTI Agentsw

Other Antibiotics

Clindamycin

Ciprofloxacin

Streptogramin

Erythromycin

Chloramphenicol

Dirithromycin

Oxazolidinone

Clarithromycin

Gentamicin

Streptomycin

Amikacin Cocci

Moraxella catarrhalis Neisseria gonorrhoeaea

Quinoloness

Macrolides

Quinupristin-Dalfopristin

Lipopeptide

Azithromycin

Aminoglycosides

Linezolid

Glycylcycline

Tobramycin

Table 3. Aminoglycosides, Macrolides, Quinolones, & Other Antibiotics

2 3

Staphylococcus epidermidis

Methicillin-resistant Staphylococcus epidermidis

Streptococcus Group A (S. pyogenes)

Streptococcus Group B (S. agalactiae)

Trovafloxacin t

Moxifloxacin

Levofloxacin

Gemifloxacin

Ciprofloxacin 3

3 2

Bacilli GramNegative GramPositive

Spiral Organisms

2 3

Penicillin-resistant Streptococcus pneumoniaej,k

3 2

Corynebacterium jeikeium

Bacteroides fragilis

3 3

Fusobacterium spp. 2

Clostridium tetani

Peptostreptococcus spp.

Mycoplasma pneumoniae

Ureaplasma urealyticum

Borrelia burgdorferi (Lyme disease)q

Borrelia recurrentis

2 2

3 3

Corynebacterium diphtheriaem

3 1 2

Leptospira spp. Treponema pallidum

Bacillus anthracisl

Mycoâ&#x20AC;&#x201C; plasma

Clostridium difficile

Clostridium perfringens

Prevotella melaninogenica

Gardnerella vaginalis

Listeria monocytogenes o

Nocardia spp.

Actinomyces israelii

Streptococcus pneumoniaei

Viridans streptococci

2 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

Norfloxacin

Nitrofurantoin

Fosfomycin

Colistin/Polymixin B

Vancomycin

Trimethoprim-Sulfamethoxazole

Telithromycin

Rifampin

Streptogramin

Metronidazole

Oxazolidinone

Quinupristin-Dalfopristin

Clindamycin

Lipopeptide

Linezolid

UTI Agentsw

Other Antibiotics

Chloramphenicol

Glycylcycline

Streptococcus Group D (eg, S. bovis)

Actinomycetes

Anaerobes

Quinoloness

Tetracyclines (eg, Doxycycline)v

Gram-Positive Aerobes

Cocci

Glycopeptideintermediate susceptible Staphylococcus aureus

Daptomycin u

Erythromycin

Dirithromycin

Clarithromycin

Community-associated methicillin-resistant Staphylococcus aureusx Hospital-associated methicillin-resistant S taphylococcus aureusy

Macrolides

Azithromycin

Tobramycin

Streptomycin

Gentamicin

Amikacin

Aminoglycosides

Tigecycline

Table 3. Aminoglycosides, Macrolides, Quinolones, & Other Antibiotics (continued)

Notes to Chart

m Membranous pharyngitis treated with antitoxin and I.V. erythromycin (antimicrobials used to decrease toxin production and bacterial spread). n New classification: bacteria are gram-variable. o Aminoglycosides (gentamicin) may be synergistic with β-lactams. p Gastroenteritis is treated with only oral formulations of vancomycin. Vancomycin is recommended as first-line therapy for patients with severe illness, while metronidazole is recommended for patients with mild to moderate disease. q Stage of disease determines choice of treatment. Consult specifi c references. r Effective choice for meningeal infections if the ceftriaxone/cefotaxime MIC <0.5 mcg/mL. s Resistance rates can vary greatly against P. aeruginosa, Acinetobacter spp., and the Enterobacteriaceae. Use as empiric therapy against these organisms should be based on local susceptibilities. t Because of the risk for serious liver injury, trovafloxacin should be reserved for use in patients with serious life- or limb-threatening infections who receive their initial therapy in an inpatient health care facility. Trovafloxacin should not be used when alternative, safer antibiotic therapy will be effective. u Despite its potent in vitro activity against Streptococcus pneumoniae, daptomycin is not indicated for the treatment of pneumonia, due to extensive binding to pulmonary surfactant resulting in clinical failure. v The specific tetracycline recommended varies. For methicillin-resistant Staphylococcus aureus, minocycline is most active among class. Consult specific references. w These agents are generally recommended for urinary tract infections (UTIs) only. Use of the “1” to “3” scale refers to activity for treatment of UTI. x Vancomycin is considered first-line therapy when intravenous therapy is required. However, daptomycin, linezolid, and tigecycline may be suitable alternatives in specified patients. Tetracyclines, clindamycin, trimethoprim-sulfamethoxazole, macrolides, and linezolid are indicated when oral therapy can be used. In the face of erythromycin resistance, clindamycin should be considered only if the isolate is D-test–negative. y In recent years vancomycin MICs have gradually increased for S. aureus and have included an increased occurrence of heteroresistance. Clinical reports have associated this loss of in vitro potency with vancomycin clinical failures in a number of patients. Alternative therapies should be considered in this setting.

a Resistance to penicillin, tetracycline, and ciprofloxacin may be as high as 21.5%, 29.2%, and 47.7%, respectively, according to a 2006 report; 50% of patients have Chlamydia trachomatis. b Use a combination: for example, doxycycline with gentamicin or rifampin or doxycycline with trimethoprim-sulfamethoxazole and chloramphenicol. c Combination therapy with high eradication rates includes omeprazole + clarithromycin + amoxicillin; or bismuth sub salicylate + metronidazole + tetracycline. However, metro nidazole resistance has risen signifi cantly. d Up to 30% of Haemophilus influenzae strains are capable of producing β-lactamases. e Citrobacter spp. and Enterobacter spp. may differ in susceptibility patterns. Consult individual test results for appropriate choice. f Carbapenemase-producing Enterobacteriaceae are increasing, and are endemic in certain geographic regions. Viable treatment options are limited and should be based on susceptibilities. Generally, colistin/ polymixin B and tigecycline offer in vitro susceptibility, although clinical data are limited. g A significant number of strains are capable of producing extendedspectrum β-lactamases (ESBL). Consider this possibility according to antibiogram, patient’s history, and local resistance patterns. In suspected or proven cases, use carbapenems or proper non–β-lactam antibiotics based on susceptibility studies. h Combination therapy is suggested. i In 2005, the penicillin resistance rate in the United States was reported to be approximately 34%; 10% to 15% of isolates displayed high-level penicillin resistance (MIC [minimum inhibitory concentration] >1 mcg/ mL). The Centers for Disease Control and Prevention Drug-Resistant Streptococcus pneumoniae Therapeutic Working Group recommends MIC ≥4 mcg/mL for high-level resistance. The clinical significance of penicillin resistance in nonbacteremic patients is still uncertain when parenteral treatments are used. j PRSP (penicillin-resistant Streptococcus pneumoniae) being defined as nonsusceptible to penicillin (PCN [penicillin] MIC ≥2 mcg/mL). k Amoxicillin doses of 80 mg/kg/d may be effective against nonmeningeal PRSP infections. l For updates, see www.fda.gov/oc/opacom/hottopics/bioterrorism. html.

Suggested Reading Brook I. Management of anaerobic infection. Expert Rev Anti Infect Ther. 2004;2:153-158. Chow JW, Satishchandran V, Snyder TA, Harvey CM, Friedland IR, Dinubile MJ. In vitro susceptibilities of aerobic and facultative gram-negative bacilli isolated from patients with intra-abdominal infections worldwide: the 2002 Study for Monitoring Antimicrobial Resistance Trends (SMART). Surg Infect (Larchmt). 2005;6:439-448. Critchley IA, Blosser-Middleton RS, Jones ME, Thornsberry C, Sahm DF, Karlowsky JA. Baseline study to determine in vitro activities of daptomycin against gram-positive pathogens isolated in the United States in 20002001. Antimicrob Agents Chemother. 2003;47:1689-1693. Curran M, Simpson D, Perry C. Ertapenem: a review of its use in the management of bacterial infections. Drugs. 2003;63:1855-1878. Ferrara AM. Potentially multidrug-resistant nonfermentative gramnegative pathogens causing nosocomial pneumonia. Int J Antimicrob Agents. 2006;27:183-195. Gordon KA, Biedenbach DJ, Jones RN. Comparison of Streptococcus pneumoniae and Haemophilus influenzae susceptibilities from community-acquired respiratory tract infections and hospitalized patients with pneumonia: five-year results for the SENTRY Antimicrobial Surveillance Program. Diagn Microbiol Infect Dis. 2003;46:285-289. Hansen GT, Blondeau JM. Comparison of the minimum inhibitory, mutant prevention and minimum bactericidal concentrations of ciprofloxacin, levofloxacin and garenoxacin against enteric gram-negative urinary tract infection pathogens. J Chemother. 2005;17:484-492. Kuti JL, Florea NR, Nightingale CH, Nicolau DP. Pharmacodynamics of meropenem and imipenem against Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa. Pharmacotherapy. 2004;24:8-15. Livermore DM. Linezolid in vitro: mechanism and antibacterial spectrum. J Antimicrob Chemother. 2003;(suppl 2):ii9-ii16. Martin SI, Kaye KM. Beta-lactam antibiotics: newer formulations and newer agents. Infect Dis Clin North Am. 2004;18:603-619. Nicolau DP. Spotlight on Clostridium difficile infection: an educational resource for pharmacists. Pharmacy Times. 2009;2:91-99. Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase producing bacteria. Lancet Infect Dis. 2009;9:228-236.

Nguyen M, Chung EP. Telithromycin: the first ketolide antimicrobial. Clin Ther. 2005;27:1144-1163. Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microb Rev. 2005;18:657-686. Petersen PJ, Bradford PA, Weiss WJ, Murphy TM, Sum PE, Projan SJ. In vitro and in vivo activities of tigecycline (GAR-936), daptomycin, and comparative antimicrobial agents against glycopeptide-intermediate Staphylococcus aureus and other resistant gram-positive pathogens. Antimicrob Agents Chemother. 2002;46:2595-2601. Pfaller MA, Segreti J. Overview of the epidemiological profile and laboratory detection of extended-spectrum beta-lactamases. Clin Infect Dis. 2006;42(suppl 4):S153-S163. Rhomberg PR, Fritsche TR, Sader HS, Jones RN. Comparative antimicrobial potency of meropenem tested against gram-negative bacilli: report from the MYSTIC surveillance program in the United States (2004). J Chemother. 2005;17:459-469. Rice LB. Antimicrobial resistance in gram-positive bacteria. Am J Med. 2006;119(6 suppl 1):S11-S19; discussion S62-S70. Roberts S, Chambers S. Diagnosis and management of Staphylococcus aureus infections of the skin and soft tissue. Intern Med J. 2005;35(suppl 2):S97-S105. Torres-Viera C, Dembry LM. Approaches to vancomycin-resistant enterococci. Curr Opin Infect Dis. 2004;17:541-547. Trampuz A, Zimmerli W. Antimicrobial agents in orthopaedic surgery: prophylaxis and treatment. Drugs. 2006;66:1089-1105. Van Bambeke F, Michot JM, Van Eldere J, Tulkens PM. Quinolones in 2005: an update. Clin Microbiol Infect. 2005; 11:256-280. Erratum in: Clin Microbiol Infect. 2005;11:513. Yamaguchi T, Hashikita G, Takahashi S, Itabashi A, Yamazaki T, Maesaki S. In vitro activity of beta-lactams, macrolides, telithromycin, and fluoroquinolones against clinical isolates of Streptococcus pneumoniae: correlation between drug resistance and genetic characteristics. J Infect Chemother. 2005;11:262-264. Zhanel GG, Hisanaga TL, Laing NM, et al; NAUTICA Group. Antibiotic resistance in outpatient urinary isolates: final results from the North American Urinary Tract Infection Collaborative Alliance (NAUTICA). Int J Antimicrob Agents. 2005;26:380-388.

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In Focus

CLOSED SYSTEM continued from page 1

MS, assistant director of the Department of Pharmacy at Ohio State. But the cost of the devices may significantly exceed the manufacturers’ estimates, he said at the 5th annual conference of the Hematology/Oncology Pharmacy Association. “You really have to do your due diligence and figure out how you are going to use the CSTD ahead of time. Don’t just trust that the cost per dose that you have been quoted by the company is going to be accurate because it completely depends on how you choose to implement [these devices]. In our experience, we found that the CSTDs cost 75% more than the manufacturer said they would,” Dr. Forrey told Pharmacy Practice News. Dr. Forrey and his colleagues sought to determine how they could justify implementing the use of CSTDs in their comprehensive cancer center from clinical and operational perspectives, in addition to a financial one. “There is a lot of debate about using closed-system devices in chemotherapy preparation,” he said. “It’s not required, but it is recommended by several different organizations, and our hospital wanted to see just what kind of contamination we would have if we were to use these devices. We know that there is aerosolization of chemotherapy in the compounding process, and likewise during nursing; if there are leaks containing chemotherapy, these leaks can be released. While it is not so much of a problem for the patients, it can be dangerous for health care workers who are exposed to these substances over and over for years.” With the safety of their health care staff as their first point of justification, Dr. Forrey and colleagues conducted a six-month trial with a CSTD on all chemotherapy and biotherapy medications being used in their outpatient breast cancer clinic. They conducted wipe studies for cyclophosphamide and fluorouracil (5-FU) surface contamination before CSTD use, and then after CSTD use and documented significantly reduced surface contamination of both drugs after CSTD implementation (Figure). “We didn’t do anything differently as far as cleaning or decontamination. We just followed our normal processes and did wipe studies [pre- and post-procedure]. Clearly, the wipe studies pre and post show that there was a significant decrease in the amount of contamination in the environment. It didn’t eliminate it entirely, but there was a dramatic decrease,” Dr. Forrey said. Enlisting the support of nurses was crucial to achieving such good results, he added. “Getting their support is important when we try to justify it. Re-education did take some time with the nursing staff, but it was well worth it.”

Drug Level (ng/cm2)

Pre-Trial CP Level (ng/cm2)

Post-Trial CP Level (ng/cm2)

4 3 2 1 0 BSC surface

BSC airfoil

Floor in front of BSC

Checking counter

Chemotherapy bin

Floor next to bed

Figure. Surface contamination levels. BSC, biological safety cabinet; CP, cyclophosphamide

Dr. Forrey said the big “Aha!” moment for him was when he discovered that the correct use of the device was much more costly than the company said it would be. “Cost per dose is certainly an important factor, but what the companies don’t talk about is how you are going to use the device. That affects the cost per dose. The companies will say ‘our cost per dose is X dollars,’ but depending on how you choose to implement it in your institution, that cost can vary greatly.” “We went with the high road,” he continued. “We used the CSTD everywhere for everything to its fullest extent and found that our cost per dose was significantly higher than what was initially presented to us [by the vendor].” Paying such scrupulous attention to detail on usage meant that they used two vials instead of one per dose, and this meant that they used two pieces of equipment per dose. “That piece of equipment has a significant cost to it, and that’s what contributed to some of the difference in cost I found versus what was predicted.” Also adding to the cost was the nurses’ participation, he said. “There is the pharmacy side and the nursing side. If you used the CSTD only in pharmacy, that would minimize the cost quite a bit. There are many factors that impact your cost per dose, but we just didn’t feel right only using it in pharmacy and not having it in nursing.”

Where’s the Evidence? Unfortunately, there is no direct correlation between reducing health care worker exposure to cytotoxic agents via use of a CSTD and preventing adverse health outcomes in those workers, Dr. Forrey noted. If there was proof of a direct cause-and-effect relationship, it would probably make it easier to justify the use of CSTDs, and perhaps make them required by law, he noted. Nevertheless, he said, his institution is taking the benefits of reduced contamination on faith. “If it’s the right thing to do, you should be able to convince your institution that it’s the way you need to

go. We proved that point, and despite the cost, our institution saw that and supported [the initiative].” Thomas H. Connor, PhD, a research biologist at the National Institute for Occupational Safety and Health (NIOSH), in Cincinnati, agreed that “to some extent, it is often difficult to directly link a cytotoxic exposure to an adverse health effect. But it does not mean that exposures to known hazardous chemicals should go uncontrolled.” Dr. Connor explained that there are “dozens” of published reports in the literature showing that health care workers have sufficient exposures to cytotoxic agents such that the drugs can be measured in their urine, and that those workers have increased chromosomal and DNA damage. Furthermore, studies show that those genetic abnormalities place the workers at increased risk for developing cancers later in life.1,2 Indeed, “no other occupational setting has such a large number of known or suspected carcinogens and/or reproductive toxins placing workers at risk,” Dr. Connor said. “So there’s no need to simply ‘take it on faith’ that reducing exposure to cytotoxic agents can protect patients.” Debate over the data may continue, said Dr. Forrey. But he urged not to lose sight of the economic issue. “Do due diligence on the cost estimating and make sure you understand how you want to use [CSTD devices]. Understand how you are going to use them before you can know how much it is going to cost your facility.”

Manufacturer’s Comment Replying to Dr. Forrey’s comments a b o u t t h e c o s t o f C S T D, S t e v e Rammelsberg, Carmel Pharma’s director of sales for the Eastern region, said, “We agree with Dr. Forrey that each institution should look at all aspects of their intended usage before trying to determine the accurate cost of implementation of PhaSeal and the protection only it can provide to his staff and that of his institution. We welcome The Ohio State University on board as a PhaSeal user.” Carmel Pharma supplied the CSTDs and wipe

samples free of charge for this study. Luci A. Power, BS, MS, Pharmacy, a lecturer and consultant on pharmacy IV and hazardous drug systems, noted that CSTDs are recommended both in the NIOSH alert on hazardous drugs and in the 2008 revision of United States Pharmacopeia (USP) Chapter <797>, but the cost of the devices is not currently offset by any reimbursement. “Dr. Forrey brings up several important points about the actual cost of implementation of any of the CSTD systems,” said Ms. Power, the lead author of the 2006 ASHP Guidelines on Handling Hazardous Drugs (AJHP 2006;63:1172-1191). “The ability of the device to reduce contamination is partly the result of the vial cap being permanently affixed to the vial. This means that a dose requiring multiple vials results in multiple caps driving up the cost. As most of these devices allow repeated punctures to the vial and still maintain sterility of the drug and final product, a cost justification plan as well as an implementation plan should include inventory adjustments to utilize the appropriate number of vials to reduce the cost of the CSTD but not increase the inventory waste.” Ms. Power noted that the addition of a CSTD also includes the cost of purchasing and storage as well as the cost of disposal of hazardous drugs by adding to the weight of the waste. “There are finite financial considerations in implementing any new system that includes disposables,” she said. “But remember, the value of employee and environmental safety is priceless!” That point was echoed by the NIOSH’s Dr. Connor. “If there weren’t a concrete, documented risk here—one that you really should be heeding by adopting some type of protective system for your workers—then why would there be such a breadth of guidance on this issue?” he said. “Remember, NIOSH, OSHA [Occupational Safety and Health Administration], USP Chapter <797>, the American Society of Health-System Pharmacists, the Oncology Nursing Society and the International Society of Oncology Pharmacy Practitioners, along with numerous health care institutions around the world, have all adopted guidance for the safe handling of these drugs. So there’s a wealth of information out there that you can use to review your systems and procedures to make them safer for your workers.” —Fran Lowry

References 1. Connor TH. Hazardous anticancer drugs in healthcare: environmental exposure assessment. Ann N Y Acad Sci. 2006;1076:615-623. 2. Connor TH, McDiarmid MA. Preventing occupational exposure to antineoplastic drugs in health care settings. CA Cancer J Clin. 2006;56:354-365.

Hem/Onc Pharmacy 13

Pharmacy Practice News • August 2009

In Focus

Pharmacists Show Worth With Stem-Cell Transplants Discharge counseling program gains kudos from health care team Miami—One year after it was initiated, a pharmacist medication discharge counseling program (PMDCP), wherein pharmacists counsel departing hematopoietic stem cell transplantation (HSCT) patients on how to use their medications, has received a “two thumbs up” endorsement by the HSCT health care team, according to a poster presentation at the 5th annual conference of the Hematology/Oncology Pharmacy Association. “So far, the project has been very well received. We’ve had very positive comments from the nurse practitioners, the attending physicians, the physician assistants and the nurses, and also from inpatients and outpatients,” Anne McDonnell, PharmD, of Brigham and Women’s Hospital, Boston, told Pharmacy Practice News. “Our main goal is to make sure that the patients leave the hospital with their medications and with an understanding of how to use them. We don’t want a patient who gets a prescription for, say, an immune suppressant, and then is unable to get it filled at the local pharmacy because the pharmacy does not stock that particular drug.” The PMDCP includes the services of a care coordinator who makes sure that all of the patient’s medications are delivered to the hospital by the discharge date and a pharmacist who counsels the patient on their use, using a personalized medication grid that details each drug in a “show and tell” teaching session. “These sessions last anywhere from 30 minutes to an hour, depending on the type of patient and the number of medications. We go through them all and make sure that the things we needed from the pharmacy actually got delivered and that the patients understand how to take their medications, the frequency, side effects, duration, and so on,” Dr. McDonnell explained.

beneficial. The RNs and PAs also reported that they wanted the pharmacist counseling program to continue. Of the eight attending physicians who took the survey, 88% reported that their patients’ understanding of their medications improved. Overall, 67% of nurse practitioners, 95% of RNs, 80% of physicians and 100% of PAs rated the system as “excellent” or “good.” Having obtained such a good report

card, Dr. McDonnell said the program will continue at her hospital. But, she cautioned, hematology-oncology pharmacists who are thinking of setting up a similar program should be aware that it is very time-consuming. “You are looking at probably an hourand-a-half to a two-hour commitment for each patient, and that is on top of your regular daily work. A lot of people came by our poster and said they had

tried to do this but that it took up so much time,” she said. “For us, it is timeconsuming but it is definitely a worthwhile initiative. With the medical team and the administration behind it, I think that this is probably a direction that pharmacists will move in—discharge counseling and getting patients ready to go home.” —Fran Lowry

INTRODUCING A

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The Survey Said … Dr. McDonnell and her colleagues sent out electronic surveys to the various health care professionals who were involved in the management of HSCT patients to get their feedback and understand their perceptions about the counseling program. Of the 41 nurses who responded to the survey, 90% reported that the PMDCP improved the discharge process. The same number said they would like to see the PMDCP expanded to other services and that the program allowed them to spend more time with patients. Responses were similarly positive for the six physician assistants (PAs) surveyed; all said the program improved the discharge process and all said that expansion to other services would be

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Hem/Onc Pharmacy

Pharmacy Practice News • August 2009

In Focus

Cancer Burden Will Surge by 2030 O ‘This increase in cancer diagnosis is something that hem/onc ver the next 20 years, the number of new cancer cases diagnosed annually in the United States will increase by 45%, according to a study published in the Journal of Clinical Oncology (2009;17:2758-2765). The study predicts the number of cancer cases will jump from 1.6 million in 2010 to 2.3 million in 2030, with a dramatic spike in the elderly and minority populations. “In 2030, 70% of all cancers will be diagnosed in the elderly and 28%

pharmacists should be aware of, because it will dramatically affect the way we provide care to patients.’ —Cindy L. O’Bryant, PharmD in minorities, and the number of older adults diagnosed with cancer will be the same as the total number of Americans

diagnosed with cancer in 2010,” said Ben Smith, MD, senior author of the study and an adjunct assistant professor in the

Department of Radiation Oncology at The University of Texas M.D. Anderson Cancer Center, Houston. In the same 20-year span, cancer incidence is expected to increase by 31% in white Americans but will hit ethnic groups the hardest. Incidence is expected to increase by 64% in blacks, 76% in American Indian-Alaska Natives, 101% in multiracial individuals, 132% in AsianPacific Islanders and 142% in Hispanics. Investigators found that the leading

Hem/Onc Pharmacy 15

Pharmacy Practice News • August 2009

In Focus cancer sites—breast, prostate, colon and lung—are expected to remain constant. Cancers with the greatest increase in incidence expected are stomach (67%), liver (59%), myeloma (57%), pancreas (55%) and bladder (54%). “Also alarming is that a number of the types of cancers that are expected to increase, such as liver, stomach and pancreas, still have tremendously high mortality rates,” Dr. Smith said. The findings are even more troubling given the increasing cost of cancer care and the fact that minorities have been historically underrepresented in

clinical trials. For their analysis, investigators turned to U.S. Census Bureau statistics, updated in 2008 to project population growth through 2050, and the National Cancer Institute’s Surveillance, Epidemiology and End Results registry. Incidence rates for cancer were calculated by multiplying the age, sex, race and origin-specific population projections by the age, sex, race and origin-specific cancer incidence rates.

Implications for Hem/Onc Pharmacy “This increase in cancer diagnoses is something that hem/onc pharmacists should be aware of, because it will dramatically affect the way we provide care to patients,” said Cindy L. O’Bryant, PharmD, BCOP, outgoing president of the Hematology/Oncology Pharmacy Association (HOPA). “This increase will bring with it a greater need for oncology specialists in all medical disciplines— not just pharmacy.” However, from a pharmacy perspective, “there are a few things we as a profession need to think about,” said Dr. O’Bryant. “First, will there be enough hem/onc-trained pharmacists to deal with the day-to-day treatment aspect of a patient’s care? Today, many of us struggle to provide adequate services (i.e., dispensing, troubleshooting, patient care and patient education) with current pharmacy resources. So it is important that we increase the number of trained hem/onc pharmacists to meet the coming surge in cancer cases.” Dr. O’Bryant said that HOPA is embarking on the creation of a task force that will provide recommendations on how HOPA should approach this shortage. The increase in cancer cases “also underscores the need for us to do a better job documenting the value of hem/onc pharmacists,” she stressed. “We can help fill the coming treatment gap, but won’t have that opportunity if other health care disciplines and administrators don’t fully appreciate the contributions we make to exemplary patient care.” —Kate O’Rourke and David Bronstein

What’s Your View? =?6;A

@5.?2

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Are hem/onc pharmacists positioned to handle the coming surge in cancer diagnoses? What does the profession need to do, to prepare for the upsurge? Send replies to

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Hem/Onc Pharmacy

Pharmacy Practice News • August 2009

In Focus

The Case for—and Against—Vitamins in Cancer Miami—Supplementing one’s diet with certain vitamins and minerals does not appear to ward off cancer or to aid in the treatment of cancer, and may even be harmful, according to the results of several recent randomized trials, Jane Pruemer, PharmD, told delegates at the 5th annual conference of the Hematology/Oncology Pharmacy Association. Cancer chemoprevention is a concept that has been researched since the 1980s, when many clinical trials were launched based on epidemiologic observations. But, said Dr. Pruemer, quoting from an article that appeared in the April 1, 2009 issue of the Journal of the National Cancer Institute (101:446-451): “The dream of preventing cancer with a vitamin pill is rapidly evaporating. Over the past few months, results from clinical trials and observational studies report no benefit— and in a few cases, possible harm—from supplementation with several micronutrients, including vitamins C, D and E; selenium; calcium; and folate.” Pharmacists often find themselves on the front lines—explaining the role of vitamins in cancer prevention and treatment to the general public, to patients and even to physicians. This is why it is so important for them to be up-to-date with the latest findings when fielding questions, said Dr. Pruemer, professor of clinical pharmacy practice at the James L. Winkle College of Pharmacy at the University of Cincinnati, Ohio. In her talk, Dr. Pruemer reviewed data on calcium, vitamin D, beta-carotene and retinyl palmitate; vitamin E and selenium; and vitamin C and folic acid.

The Evidence for Calcium Currently, the only supplement that appears to be beneficial in reducing the risk for at least one cancer—colorectal cancer—is calcium. Dr. Pruemer presented results from two studies. The first, Dairy Food, Calcium, and Risk of Cancer in the NIH-AARP (National Institutes of Health– American Association of Retired Persons) Diet and Health Study (Arch Intern Med 2009;169:391-401), assessed the intake of dairy food and calcium from foods and supplements with a questionnaire sent to AARP members aged 50 to 71 years in 1995 and 1996. The 492,810 respondents were followed for seven years. With 3,383,377 person-years of follow-up, the study concluded that total calcium intake was associated with a lower risk for total cancer and cancers of the digestive system. The response in colorectal cancer was among the most pronounced in the study: the multivariate relative risk for the maligancy in men was 0.84 and for women it was 0.77; colerectal cancer risk was 16% lower in

men and 23% lower in women. The second study, Calcium Supplements for the Prevention of Colorectal Adenomas (N Engl J Med 1999:340;101107), randomly assigned 930 subjects (mean age 61 years; 72% men) with a recent history of colorectal adenomas to receive either calcium carbonate containing 1,200 mg of elemental calcium daily or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The results showed the adjusted risk ratio for any

women who were randomly assigned to 1,000 mg elemental calcium with 400 IU vitamin D3 daily or to placebo for a mean of seven years had no difference in their incidence of invasive breast cancer and concluded that calcium intake appeared to have no effect on its development.

The Evidence for Vitamin D There is a clear inverse relationship of vitamin D levels and the incidence and mortality of numerous malignancies, Dr. Pruemer said.

‘A summary of ... antioxidant vitamin [studies] is that they appear thus far to have very little effect on the prevention of cancers in either men or women.’ —Jane Pruemer, PharmD recurrence of adenoma with calcium versus placebo was 0.85 (95% confidence interval [CI], 0.74-0.98; P=0.3). One adenoma was diagnosed between the first and second follow-up exam in 127 patients (31%) in the calcium group and in 159 patients (38%) in the placebo group. The effect of calcium was independent of initial dietary fat and calcium intake. The results led the authors to conclude that calcium supplementation is associated with a significant, although moderate, reduction in the risk for recurrent colorectal adenomas. The mechanisms by which calcium suppresses colon cancer are not clear, but some researchers have proposed that calcium binds bile acids in the bowel lumen, thereby inhibiting their proliferative and carcinogenic effects. Animal studies have shown a protective effect of dietary calcium on bileinduced mucosal damage and experimental bowel carcinogenesis (N Engl J Med 1999;340:101-107). Another study, a secondary outcome measure of the Women’s Health Initiative (J Natl Cancer Inst 2007;100:158191), showed that 36,282 postmenopausal

Serum levels of vitamin D generally are higher among individuals living in sunnier latitudes, as vitamin D is produced in the skin through sunlight exposure and the incidence of colorectal cancer and breast cancer increases as one goes north, she added. Vitamin D deficiency is defined as serum levels less than 20 ng/mL; vitamin D insufficiency is defined as serum levels greater than 20 but less than 30 ng/mL; and vitamin D adequacy is defined as serum levels greater than 30 ng/mL. In a study by Garland CF et al (Am J Public Health 2006;96:252-261), patients with serum vitamin D levels of 52 ng/ mL had a 50% lower risk for breast cancer than those with levels less than 13 ng/mL. A study by Gorham E et al (Am J Prev Med 2007;32:210-216) found that individuals with a level of 34 ng/ mL developed colorectal malignancies half as frequently as those with a level of 6 ng/mL. A related study (J Natl Cancer Inst 2006;98:428-430) found a significant decrease in gastrointestinal and total cancer incidence and mortality as estimated vitamin D levels increased.

Specifically, an increment of 25 nmol/L in predicted vitamin D levels (as determined by serum 25[OH]D) was associated with a 17% reduction in total cancer incidence (multivariable relative risk [RR], 0.83; 95% CI, 0.74-0.92), a 29% reduction in total cancer mortality (RR, 0.71; 95% CI, 0.60-0.83), and a 45% reduction in digestive-system mortality (RR, 0.55; 95% CI, 0.41-0.74). There have been two randomized controlled trials that looked at vitamin D in cancer prevention, Dr. Pruemer said. The first (N Engl J Med 2006;354:684696) showed no effect on the incidence of colorectal cancer in postmenopausal women who had been randomized to 500 mg of calcium carbonate and 400 IU of vitamin D3 daily for seven years. However, the second trial, by Joan Lappe, PhD, and colleagues (Am J Clin Nutr 2007;85:1586-1589) found that postmenopausal women treated with 1,000 IU of vitamin D and calcium had a relative risk of 0.232 for developing a malignancy compared with women who were randomized to placebo. “Some say that 400 IU of vitamin D in the first study may not have been enough to show a positive effect, and the second trial offers some data to support the effect of higher doses of vitamin D as a cancer preventative,” Dr. Pruemer said. Vitamin D also may be of benefit for men with prostate cancer. One study (Nutr Cancer 2005;51:32-36) found that men with a prostate-specific antigen (PSA) relapse who received vitamin D supplements had a longer median PSA doubling time. Another study (J Urol 1998;160:840) found that vitamin D significantly decreased the rate of PSA rise in six of seven patients. “A lot of data are just beginning to come out with the use of vitamin D, but I don’t think we can have any firm conclusions. There are differences in the doses of vitamin D used in these trials, and we have to wait and see what future results show us,” Dr. Pruemer noted.

The Evidence For Beta-Carotene Here, however, the jury is very much in. Beta-carotene, once touted as being almost a miracle cancer preventative, is “not a good thing to try to prevent lung cancer in people who are at high risk,” she said. The multicenter CARET (Beta-Carotene and Retinol Efficacy Trial) study (J Natl Cancer Inst 2004;96:1743-1750) for the chemoprevention of lung cancer in 18,314 high-risk smokers and asbestosexposed workers had to be prematurely halted in 1996 because those who were receiving the active treatment had a 28%

Hem/Onc Pharmacy 17

Pharmacy Practice News • August 2009

In Focus increase in lung cancer, a 17% increase in the incidence of death and a higher rate of cardiovascular disease mortality. The deleterious effect was even greater in females than in males, and persisted even six years after the patients had stopped their therapy.

The Evidence for Selenium, Vitamin E and Vitamin C In the SELECT (Selenium and Vitamin E Cancer Prevention Trial) (JAMA 2009;301:39-51), researchers in the United States, Canada and Puerto Rico looked at combining selenium and vitamin E in an effort to decrease the incidence of prostate cancer as a primary end point, and of lung cancer, colorectal cancer and overall primary cancer as a secondary end point. But they found, after a median follow-up of almost five-and-a-half years, that the hazard ratio for prostate cancer was 1.04 for men randomized to selenium, 1.13 for men randomized to vitamin E, 1.05 for those who received selenium and vitamin E and 1.00 for those who received placebo. The researchers concluded there were no significant differences between the treatment arms with regard to prostate or any other cancer. “Basically, the SELECT trial shows us that there is no protective effect of selenium and that vitamin E has shown similar results,” Dr. Pruemer said. Similarly, the Physicians’ Health Study II (JAMA 2009;301:52-62) found a null effect of vitamin E on prostate cancer after a mean follow-up of eight years in 14,000 male physicians aged 50 years and older. The study also looked at the preventive effect of vitamin C, but again, found no significant effect on prostate or other cancers. “Critics of the trial have said that the dose of vitamin E was too low—they gave 400 IU every other day—and that there may also have been a ‘healthy enrollee effect’ because the subjects, who were all physicians and therefore likely to be in good health, were less likely to benefit from antioxidants to prevent disease,” Dr. Pruemer said. The WACS (Women’s Antioxidant Cardiovascular Study) is yet another negative trial, looking at the effects of vitamins C and E and beta-carotene on cancer risk. After 9.4 years of follow-up, the researchers concluded that neither micronutrient offered any overall benefit in the primary prevention of total cancer incidence or cancer mortality (J Natl Cancer Inst 2009;101:14-23). “A summary of our antioxidant vitamins is that they appear thus far to have very little effect on the prevention of cancers in either men or women,” Dr. Pruemer said.

tate cancer in two trials, Dr. Pruemer said. In one trial (JAMA 2007; 297:2351-2359), the rate of occurrence of at least one colorectal adenoma was 44.1% in subjects who were randomized to 1 mg per day of folic acid for three years, compared with 42.4% for those randomized to placebo (P=0.58). At almost seven years, the rate of adenoma occurrence was 41.9% for the folic acid group versus 37.2% for the placebo group (P=0.23). A more pronounced trend was noted in the Aspirin/Folate Polyp Prevention Study (J Natl Cancer Inst 2009;101:432435), which found that aspirin had no

effect on prostate cancer incidence but in subjects who were randomized to folic acid, the estimated probability of being diagnosed with prostate cancer over 10 years was 9.7% compared with 3.3% of those randomized to placebo (P=0.01).

Persistent Researchers Despite the mostly negative results, researchers are optimistic that smallscale intervention trials that focus on gene–nutrient and nutrient–nutrient interactions in the body will provide more answers than additional ques-

tions, she said. But for now, Dr. Pruemer left her audience with the following message: “If you are ever asked by patients or community pharmacists, what is the data, you will know and remember the positive effect of calcium on the prevention of colorectal cancer, the concerning effect of folic acid supplements in men, and that beta-carotene really can have a negative effect on those who continue to smoke. Those are probably the three most important points you want to remember about vitamins.” —Fran Lowry

VANCOCIN® is the only product indicated for

treatment of C. difficile infection1 Advantageous Pharmacokinetic Profile Oral vancomycin acts locally in the colon – where C. difficile produces toxin and treatment is needed1 Extremely high levels of vancomycin (often 500-1000 μg/mL) in colonic lumen – several hundred-fold more than the highest MIC for C. difficile1,2

vs. Undetectable to extremely low levels are seen in the colonic lumen with metronidazole, which is virtually 100% absorbed in the small bowel1,2

Outstanding Efficacy Significant head-to-head cure rates in severe C. difficile infection vs. metronidazole1,3

97% for vancomycin

vs.

76% for metronidazole

†3

* The product used in this study was vancomycin liquid. † Metronidazole is not approved for use in the treatment of Clostridium difﬁcile-associated diarrhea.

Plus – the advantageous pharmacokinetics of vancomycin may result in a lower probability of complications2

First-Line, First Choice for Severe Clostridium difﬁcile Infection

Please see brief summary of full Prescribing Information for VANCOCIN® HCl Capsules on following page. INDICATIONS AND USAGE VANCOCIN® (vancomycin hydrochloride, USP) Capsules may be administered orally for treatment of enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) and antibiotic-associated pseudomembranous colitis caused by Clostridium difﬁcile. Parenteral administration of vancomycin is not effective for the above indications; therefore, VANCOCIN HCl Capsules must be given orally for these indications. Orally administered VANCOCIN HCl Capsules are not effective for other types of infection. IMPORTANT SAFETY INFORMATION To reduce the development of drug-resistant bacteria and maintain the effectiveness of VANCOCIN HCl Capsules and other antibacterial drugs, VANCOCIN HCl Capsules should only be used to treat or prevent infections that are proven or strongly suspected to be caused by a susceptible bacterium. When culture and sensitivity are available, they should be considered in selecting or modifying antibacterial therapy.

The Evidence for Folic Acid Folic acid appears to be associated with an increased risk for colorectal and pros-

AA0076

Take control of C. difﬁcile

Adverse events include nephrotoxicity, ototoxicity, reversible neutropenia, thrombocytopenia, and “Red Man’s Syndrome.” In patients with renal dysfunction, or those receiving concomitant therapy with an aminoglycoside, serial renal function testing should be performed. In patients receiving concomitant therapy with another ototoxic agent, serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity. Infrequently, allergic reactions, including anaphylaxis and exfoliative dermatitis, have been reported. Clinically significant serum concentrations of vancomycin have been reported in some patients treated with VANCOCIN HCl Capsules for pseudomembranous colitis caused by Clostridium difficile. It is noteworthy that total systemic and renal clearance of vancomycin are reduced in the elderly. Monitoring of serum concentrations may be appropriate in patients with renal insufficiency and/or colitis. VANCOCIN HCl Capsules are contraindicated in patients with a known hypersensitivity to vancomycin.

REFERENCES: 1. Bartlett JG. The case for VANCOMYCIN as the preferred drug for treatment of Clostridium difficile infection. Clin Infect Dis. 2008;46:1489-1492. 2. Pépin J. Vancomycin for the treatment of Clostridium difficile Infection: for whom is this expensive bullet really magic? Clin Infect Dis. 2008;46:1493-1498. 3. Zar FA, Bakkanagari SR, Moorthi KMLST, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:302-307. ©2009 ViroPharma Incorporated. VANCOCIN and the VIROPHARMA INCORPORATED plus design logo are registered trademarks of ViroPharma Incorporated. The disintegrating upside-down triangle alone and in combination with VANCOCIN are trademarks of ViroPharma Incorporated.

05/2009

18 Operations & Management

Pharmacy Practice News • August 2009

Preparedness

ASHP Launches Flu Readiness Resource Center Rosemont, Ill.—With the World Health Organization’s pandemic declaration still fresh, the ASHP Research and Education Foundation unveiled its new Pandemic Readiness and Emergency Preparedness Resource Center at the American Society of Health-System Pharmacists’ Summer Meeting. The Web-based center features the foundation’s Pandemic Influenza Assessment Tool for Health-System Pharmacy Departments, along with other pandem-

ic information resources. Designed by a panel of experts, the pandemic assessment tool gives pharmacy directors and others worried about the resurgence of a more virulent flu strain the chance to test their departments’ readiness and to see how well their preparedness plans are plugged into those of their institutions and the community as a whole. “It’s fair to say that overall emergency preparedness planning, as well as plan-

VANCOCIN® HCl CAPSULES (vancomycin hydrochloride capsules, USP) INDICATIONS AND USAGE This preparation for the treatment of colitis is for oral use only and is not systemically absorbed. VANCOCIN HCl Capsules must be given orally for treatment of staphylococcal entero-colitis and antibiotic-associated pseudomembranous colitis caused by Clostridium difficile. Orally administered VANCOCIN HCl Capsules are not effective for other types of infection. Parenteral administration of vancomycin is not effective for treatment of staphylococcal enterocolitis and antibiotic-associated pseudomembranous colitis caused by C. difficile. If parenteral vancomycin therapy is desired, use an intravenous preparation of vancomycin and consult the package insert accompanying that preparation. VANCOCIN HCl Capsules may be administered orally for treatment of enterocolitis caused by Staphylococcus aureus (including methicillin-resistant strains) and antibiotic-associated pseudomembranous colitis caused by C. difficile. Parenteral administration of vancomycin is not effective for the above indications; therefore, VANCOCIN HCl Capsules must be given orally for these indications. Orally administered VANCOCIN HCl Capsules are not effective for other types of infection. To reduce the development of drug-resistant bacteria and maintain the effectiveness of VANCOCIN HCl Capsules and other antibacterial drugs, VANCOCIN HCl Capsules should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. CONTRAINDICATION VANCOCIN HCl Capsules are contraindicated in patients with known hypersensitivity to vancomycin. PRECAUTIONS General Prescribing VANCOCIN HCl Capsules in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Clinically significant serum concentrations have been reported in some patients who have taken multiple oral doses of vancomycin for active C. difficile-induced pseudomembranous colitis; therefore, monitoring of serum concentrations may be appropriate in some instances, e.g., in patients with renal insufficiency and/or colitis. Some patients with inflammatory disorders of the intestinal mucosa may have significant systemic absorption of vancomycin and, therefore, may be at risk for the development of adverse reactions associated with the parenteral administration of vancomycin (see package insert accompanying the intravenous preparation). The risk is greater if renal impairment is present. It should be noted that the total systemic and renal clearances of vancomycin are reduced in the elderly. Ototoxicity has occurred in patients receiving vancomycin. It may be transient or permanent. It has been reported mostly in patients who have been given excessive intravenous doses, who have an underlying hearing loss, or who are receiving concomitant therapy with another ototoxic agent, such as an aminoglycoside. Serial tests of auditory function may be helpful in order to minimize the risk of ototoxicity. When patients with underlying renal dysfunction or those receiving concomitant therapy with an aminoglycoside are being treated, serial monitoring of renal function should be performed. Use of vancomycin may result in the overgrowth of nonsusceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken. ADVERSE REACTIONS Nephrotoxicity — Rarely, renal failure, principally manifested by increased serum creatinine or BUN concentrations, especially in patients given large doses of intravenously administered vancomycin HCl has been reported. Rare cases of interstitial nephritis have been reported. Most of these have occurred in patients who were given aminoglycosides concomitantly or who had preexisting kidney dysfunction. When vancomycin HCl was discontinued, azotemia resolved in most patients. Ototoxicity — A few dozen cases of hearing loss associated with intravenously administered vancomycin HCl have been reported. Most of these patients had kidney dysfunction or a preexisting hearing loss or were receiving concomitant treatment with an ototoxic drug. Vertigo, dizziness, and tinnitus have been reported rarely. Hematopoietic — Reversible neutropenia, usually starting 1 week or more after onset of intravenous therapy with vancomycin HCl or after a total dose of more than 25 g, has been reported for several dozen patients. Neutropenia appears to be promptly reversible when vancomycin HCl is discontinued. Thrombocytopenia has rarely been reported. Miscellaneous — Infrequently, patients have been reported to have had anaphylaxis, drug fever, chills, nausea, eosinophilia, rashes (including exfoliative dermatitis), Stevens-Johnson syndrome, toxic epidermal necrolysis, and rare cases of vasculitis in association with the administration of vancomycin HCl. A condition has been reported that is similar to the IV–induced syndrome with symptoms consistent with anaphylactoid reactions, including hypotension, wheezing, dyspnea, urticaria, pruritus, flushing of the upper body (“Red Man Syndrome”), pain and muscle spasm of the chest and back. These reactions usually resolve within 20 minutes but may persist for several hours.

ning specifically for pandemic influenza, has been a challenge for departments of pharmacy and for hospitals and health systems in general,” said Daniel J. Cobaugh, PharmD, FAACT, DABAT, senior director for research and operations at the ASHP Foundation. With that in mind, Dr. Cobaugh said, the foundation’s aim was to give pharmacy leaders the resources to help “drive emergency planning and ultimately provide better care when an event occurs.”

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects — Pregnancy Category B — The highest doses of vancomycin tested were not teratogenic in rats given up to 200 mg/kg/day IV (1180 mg/m2 or 1 times the recommended maximum human dose based on mg/m2) or in rabbits given up to 120 mg/kg/day IV (1320 mg/m2 or 1.1 times the recommended maximum human dose based on mg/m2). No effects on fetal weight or development were seen in rats at the highest dose tested or in rabbits given 80 mg/kg/day (880 mg/m2 or 0.74 times the recommended maximum human dose based on mg/m2). In a controlled clinical study, the potential ototoxic and nephrotoxic effects of vancomycin HCl on infants were evaluated when the drug was administered intravenously to pregnant women for serious staphylococcal infections complicating intravenous drug abuse. Vancomycin was found in cord blood. No sensorineural hearing loss or nephrotoxicity attributable to vancomycin HCl was noted. One infant whose mother received vancomycin HCl in the third trimester experienced conductive hearing loss that was not attributed to the administration of vancomycin HCl. Because the number of patients treated in this study was limited and vancomycin HCl was administered only in the second and third trimesters, it is not known whether vancomycin HCl causes fetal harm. Because animal reproduction studies are not always predictive of human response, VANCOCIN HCl Capsules should be given to a pregnant woman only if clearly needed. Nursing Mothers Vancomycin is excreted in human milk based on information obtained with the intravenous administration of vancomycin HCl. However, systemic absorption of vancomycin is very low following oral administration of VANCOCIN HCl Capsules (see CLINICAL PHARMACOLOGY). It is not known whether oral vancomycin is excreted in human milk, as no studies of vancomycin concentration in human milk after oral administration have been done. Caution should be exercised when VANCOCIN HCl Capsules are administered to a nursing woman. Because of the potential for adverse events, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of vancomycin HCl for oral use 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. Clinically significant serum concentrations have been reported in some patients who have taken multiple oral doses of vancomycin HCl for active C. difficle-induced pseudomembranous colitis; therefore, monitoring of serum concentrations may be appropriate in some instances, e.g., in patients with renal insufficiency and/or colitis. Some patients with inflammatory disorders of the intestinal mucosa may have significant systemic absorption of vancomycin and, therefore, may be at risk for the development of adverse reactions associated with the parenteral administration of vancomycin. The risk is greater if renal impairment is present. It should be noted that the total systemic and renal clearances of vancomycin are reduced in the elderly (see PRECAUTIONS, General). OVERDOSAGE Supportive care is advised, with maintenance of glomerular filtration. Vancomycin is poorly removed by dialysis. Hemofiltration and hemoperfusion with polysulfone resin have been reported to result in increased vancomycin clearance. Treatment — To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term carcinogenesis studies in animals have been conducted. At concentrations up to 1000 μg/mL, vancomycin had no mutagenic effect in vitro in the mouse lymphoma forward mutation assay or the primary rat hepatocyte unscheduled DNA synthesis assay. The concentrations tested in vitro were above the peak plasma vancomycin concentrations of 20 to 40 μg/mL usually achieved in humans after slow infusion of the maximum recommended dose of 1 g. Vancomycin had no mutagenic effect in vivo in the Chinese hamster sister chromatid exchange assay (400 mg/kg IP) or the mouse micronucleus assay (800 mg/kg IP).

Residency Administration Project At Northwestern Memorial Hospital in Chicago, Elizabeth M. Gorski, PharmD, MBA, used the assessment tool during her residency administration rotation when she was asked to compare the hospital’s antiviral medication stockpile against what the needs might be in a future pandemic. “It was a large task,” Dr. Gorski said. “I was in communication with the Department of Public Health and with different suppliers. I used the tool to assess and plug in the various numbers relating to staff needs and those of any immediate family members, and, depending on the level of pandemic severity, the needs of different patient populations to help predict what an adequate supply would be for us. The tool was useful as a gauge.” The announcement of the foundation’s new pandemic resource center came on the heels of a recent report on the public response to the H1N1 outbreak,

•

see FLU READINESS, page 31

What’s Your View?

No definitive fertility studies have been conducted. PATIENT COUNSELING INFORMATION Patients should be counseled that antibacterial drugs including VANCOCIN HCl Capsules should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When VANCOCIN HCl Capsules are prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by VANCOCIN HCl Capsules or other antibacterial drugs in the future. Please see full prescribing information for additional information about VANCOCIN HCl Capsules

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Rx Only Date of issue: 04/2008 Manufactured for and distributed by ViroPharma Incorporated, Exton, PA 19341, USA www.viropharma.com www.vancocin.com AA0076

The 61 questions that make up the pandemic assessment tool are designed to drill down into a wide range of leadership, staffing, education and communication issues as well as concerns about accessibility and distribution of medications and supplies during a fullblown emergency. One member of the foundation’s expert panel, Victor Cohen, PharmD, BCPS, CGP, CMI-V, clinical pharmacy manager in the Department of Emergency Medicine and Pharmaceutical Services at Maimonides Medical Center in Brooklyn, N.Y., told Pharmacy Practice News that “the tool allows for a more coordinated, smart response. It allows pharmacy directors to make the most efficient use of their staffs and supplies.” Noting that departments of health and other agencies “have become much better in coordinating response to emergencies—at least in New York City,” Dr. Cohen said that “this tool allows you to start the process of opening lines of communication to local, state and federal agencies.”

05/2009

Special Advertising Section

Product/Service Profiles 2009 B. Braun Medical Inc. Bioniche Pharma Grifols Hospira Medi-Dose, Inc./EPS, Inc McMahon Publishing NuAire, Inc速 PharMEDium Services Sandoz Teva Health Systems

The profiles in this section have been reviewed and approved or were submitted by the advertisers

B. Braun Medical Inc. AT A GLANCE Address 824 Twelfth Avenue Bethlehem, PA 18018 Phone: (800) 227-2862 E-mail: info@bbmus.com Web site: www.bbraunusa.com

Products

B. Braun Medical Inc. (B. Braun) is a recognized health care manufacturing leader with an environmentally friendly focus, supporting today’s dynamic pharmacy environment—in hospital and outpatient settings—with advanced products and services that help improve safety and efficiency.

container that stores premeasured drug and diluent doses. It’s easy to stock because it can be stored ready to use wherever and whenever it is needed, which means fast, convenient and accurate administration of IV cephalosporins to patients. The DUPLEX system portfolio of products has a 17-month minimum dating and also fits in automated medication dispensing systems. Health care workers using the convenience of the DUPLEX system simply fold and squeeze the container and shake it to mix pharmaceuticals and diluent.

Making Infusion Therapy Easier and Safer B. Braun offers drug delivery, total parenteral nutrition (TPN) management B. Braun’s Outlook® Safety Infusion System automates IV pump and infusion systems that help pharmacy programming, reducing manual programming errors that could staffs protect patients and the environresult in medication errors and improving safety. It features an ment while improving workflow. B. Braun extensive drug library and bar-coding capabilities, enabling clialso works closely with clinicians to help nicians to improve patient safety while streamlining care. The them deliver the best patient care, comply simple, easy-to-use, flexible Outlook is with industry guidelines and achieve Surgidesigned to improve best practices as cal Care Improvement Project (SCIP), Joint it ensures the right patient is receiving Commission and USP Chapter <797> comthe right drug and the right dose by an pliance. Guided by the company’s “Sharing authorized clinician. The system’s open Expertise®” philosophy, B. Braun addresses architecture design allows it to interface with hospital or pharmacy inforthe critical issues of medication safety, infecmation management systems, making tion prevention and environmental responsiit adaptable to various health care envibility by promoting best practices that help ronments. Whether for large academic pharmacists and clinicians reduce medication institutions or smaller community hoserrors, prevent health care-acquired infecB. Braun’s Outlook® ES Safety Infusion System smart pump technology and data analysis services help institupitals, B. Braun offers a smart pump tions (HAIs) and also achieve sustainability tions evaluate the efficiency and efficacy of their infusion solution to meet every facility’s need. objectives. processes to improve best practices and patient care. Along with Outlook, B. Braun’s DoseMaking Drug Delivery Greener Trac™ Infusion Management Software, For More Than 30 Years which allows real-time monitoring of IV therapies, has the ability to monitor, trend, report B. Braun works to ensure that patients are safe and manage the IV administration process. during every stage of therapy, and that the enviDoseTrac provides both end users and hosronment is protected from unnecessary waste and chemicals. Efforts to reduce and eliminate pital information management systems with these chemicals from medical products, along real-time and retrospective information to with the environmental hazards they represent, help ensure patient safety. are an integral part of B. Braun’s commitment to Making TPN Compounding and Delivery improve patient care. For more than 30 years, More Streamlined B. Braun has offered a full line of PVC-free and DEHP-free basic IV solution containers. Medical B. Braun’s Pinnacle® TPN Management Sysdevices containing PVC and DEHP pose potentem also makes drug delivery safer and tial health hazards to humans exposed to them more streamlined. Pinnacle streamlines all during medication administration. They also functional areas of operation and manages create serious environmental consequences durall aspects of the TPN process for improved ing medical waste disposal. B. Braun’s IV solution efficiency, safety and patient care. The Pincontainers are nontoxic to the environment and nacle System automates all TPN calculations help protect patients. in a Windows® browser–based format. These ® include nutritional assessment, aluminum calDUPLEX Drug Delivery System can be stored, ready to use wherever and whenMaking Drug Delivery Safer and Easier culations/warnings, and Trissel’sTM calcium/ ever it is needed, which means fast, conphosphate (Ca/P) Check. A complete sysB. Braun developed the revolutionary DUPLEX® venient and accurate administration to tem, not solely a device, Pinnacle streamlines Drug Delivery System to help minimize the potenpatients. the TPN process by offering computerized tial for medication errors, eliminate the pharmacy physician order entry and pharlabor component of IV cephalosporin macist approval, IV solution delivery and reduce drug waste while compounding and bar-coded aiding compliance and advancing TPN containers that work with patient safety. B. Braun’s DUPLEX B. Braun bar code–compatible is a convenient, ready-to-use, twoinfusion devices. compartment, flexible, eco-friendly IV

Pinnacle ™ TPN Management System

B. Braun’s award-winning Pinnacle® TPN Management System represents a major advance in compounding technology.

Product/Service Profile 2009

Special Advertising Section Pharmacy Practice News

Bioniche Pharma Dedicated to Specialty Injectables

AT A GLANCE

Bioniche Pharma is a leading global developer and manufacturer of injectable pharmaceutical products. Fueled by an internal development pipeline and an aggressive acquisition strategy for products, Bioniche delivers a broad range of injectable products for specialty markets in the United States and abroad.

Address

Experience, Reliability and Stability Bioniche’s depth and breadth of experience enable the company to deliver a broad range and reliable supply of high-quality injectable products to specialty markets worldwide. This experience is paramount and comes from three sources: • A highly qualified management team made up of health care industry experts with firsthand knowledge of many areas within the injectables field. • The operational and financial strengths of the company’s owner, RoundTable Healthcare Partners, a private equity firm focused on the health care industry. Bioniche’s association with RoundTable has expanded its existing product portfolio by devoting additional resources to product development and product acquisitions. • Qualified and dedicated Bioniche Pharma employees around the world who are committed to enhancing the treatment options for physicians and patients alike. In February 2006, Bioniche Pharma was acquired by RoundTable Healthcare Partners, a private equity firm based in Lake Forest, Ill. RoundTable’s operating expertise, access to capital for product line extensions and acquisitions and industry contacts and relationships significantly enhance the company’s growth prospects.

ity is now at 5 million units per year, while syringe capacity is approximately 3.5 million units per year. Each of Bioniche’s manufacturing and packaging facilities are FDA- and Irish Medicines Board (IMB)–approved, as well as being ISO EN 13485 accredited by Amtac (manufacture and sale of medical devices), allowing for use of the CE mark.

Recent Product Launches Enlon® (edrophonium chloride injection, USP), Enlon-Plus® (edrophonium chloride, USP and atropine sulfate, USP) Injection

272 E. Deerpath Road, Suite 304 Lake Forest, IL 60045 Phone: (888) 258-4199 Fax: (877) 721-6348 E-mail: contactus@ bionichepharmausa.com Web site: www.bionichepharma.com

Products Bioniche offers a broad range of specialty injectable products spanning numerous therapeutic categories, including analgesics/ anesthetics, cardiovascular, dermatology, oncology, orthopedic and rheumatology, urology and vitamin/nutrition.

With the recent launch of Enlon and Enlon-Plus this past spring, Bioniche has put an important therapy back into the market and into the hands of health care professionals. Bioniche supplies Enlon in a 10 mg/mL, 15 mL vial; Enlon-Plus is available in a 10 mg/mL, 15 mL vial and a 5 mL ampul. Melphalan Hydrochloride for Injection

Manufacturing Facilities Poised for Growth To meet ever-increasing production demands and the prospect of even greater future growth, Bioniche opened a new, state-ofthe-art sterile filling facility located in Galway, Ireland. Its completion adds another 21,000 square feet of production space and almost doubles total manufacturing capability. The new facility meets all international standards for sterile injectables and substantially increases Bioniche’s overall vial and syringe production. Based on the current mix of vial sizes, vial capac-

The newest addition to the Bioniche product offering is Melphalan Hydrochloride for Injection—the generic equivalent of Alkeran® from GlaxoSmithKline. “The launch of Melphalan represents Bioniche’s introduction to the generic injectable oncology market and underscores our commitment to rapid and aggressive product line growth,” said George Zorich, president, U.S. Operations for Bioniche Pharma. Bioniche supplies cartons with one single-use vial containing melphalan hydrochloride equivalent to 50 mg melphalan and one 10 mL vial of sterile diluent.

With the recent launch of Enlon® and Enlon-Plus®, Bioniche has put an important therapy back into the market and into the hands of health care workers. The newest addition to the Bioniche line of products is Melphalan Hydrochloride for Injection, the generic equivalent of Alkeran® from GlaxoSmithKline..

Special Advertising Section Pharmacy Practice News

Product/Service Profile 2009

Grifols AT A GLANCE Address 2410 Lillyvale Avenue Los Angeles, CA 90032 Phone: (888) GRIFOLS (474-3657) Web site: www.grifols.com

Grifols, with a global presence in more than 90 countries, has established itself as a primary provider of plasma products, sterile IV preparation systems for specialty therapies such as pain management, oncology and pediatrics, and in vitro diagnostic products for the laboratory.

Divisions Bioscience – Specializes in the research, development, production and commercialization of high-quality plasma therapies.

IVIG Capacity Will Nearly Double With New Facility in the U.S.

rifols has broken ground on a stateof-the-art IVIG facility in Los Angeles, Hospital – Specializes in operawhich it expects to be fully operational by tional solutions for pharmacythe year 2013, to increase the company’s compounded IV solutions. manufacturing capacity for its new generation intravenous immune globulin (IVIG). Diagnostic – Specializes in The more than $50 million investment Immunology and Hematology will ensure ample supply into the foreseediagnostic solutions for the able future, and will add approximately clinical laboratory. 300 new jobs to the Los Angeles community. The new facility will further posiProducts tion Grifols as a proactive source of health Albumin (Human), marketed as innovation along with its corporate traits Albutein® 5% and 25% and Human of persistent growth, partnership, characAlbumin Grifols 25% ter and cultural diversity. Demand for IVIG has grown steadily Antihemophilic Factor/von Willeover the past decade in the U.S., European brand Factor Complex (Human), ® and other international markets. Noting marketed as Alphanate this trend, Marcia Boyle, president and Coagulation Factor IX (Human), founder of the Immune Deficiency Founmarketed as AlphaNine® SD dation (IDF), the national patient organization for persons with primary immune Factor IX Complex, marketed as diseases, commended Grifols’ increased Profilnine® SD commitment to the production of immune Immune Globulin Intravenous globulin therapy. “Assuring continued (Human) or IVIG, marketed as access to this lifesaving medicine means Flebogamma® 5% DIF countless people who live with primary immunodeficiencies, such as my son, can Gri-fill® System 3.0 for comlead healthy and productive lives.” pounding sterile preparations The new Los Angeles facility will utilize Misterium™ Mini Sterile Modular the same proprietary technologies and Room process flow designs employed at the Triturus® EIA Analyzer company’s existing IVIG production facility in Barcelona, Spain. It will serve as a In-vitro Diagnostic Reagents twin of the pioneering facility in Spain, which the FDA licensed in 2007. This new facility is a key component of Grifols’ multi-year global growth plan to meet demand for plasma therapies. Grifols obtained FDA approval for its state-of-the-art bulk processing and aseptic filling facility in Los Angeles in 2008.

Innovation and Transparency Inspire Confidence in Grifols’ Therapies What differentiates Grifols as much as its product integrity and customer service is its ongoing commitment to innovation and continuous improvement, as well as its high degree of transparency in sharing product quality and safety information about its plasma therapies. Since September 2008, Grifols has provided U.S. health care providers access to quality and safety information about the plasma used in its therapies, through the company’s proprietary PediGri® On Line system. Pharmacists, physicians and nurses registered on the site (www.pedigrionline.net) can view lot-specific information about the individual plasma sources that contributed to each product vial, as well as the complete certificate of analysis for the

Product/Service Profile 2009

The structure of the new IVIG plant has been completed with the installation of the suspended tanks, ranging from 5,000 to 25,000 liters capacity. The next phase is to finish the structure of the building and the doors and windows, before moving on to constructing the internal rooms and facilities.

lot, and the package insert. The system provides full traceability from donation to final product. “It is more important than ever that health care providers have confidence in the source of the medications they prescribe and administer,” says Bill Stopher, president of Grifols USA, which is the U.S. sales and marketing division of Grifols Inc., based in Los Angeles. “This level of transparency underscores Grifols’ commitment to quality and safety,” adds Laurence Logan, MD, medical director for Grifols USA. Indeed, Grifols’ PediGri® has been available in Europe for nearly a decade, and since autumn 2008 has been operational for all of the company’s plasma therapies marketed and sold in the United States.

Sustaining an International Legacy of Leadership The achievements of Grifols USA extend the parent company’s legacy of pioneering plasmapheresis more than half a century ago, which gave rise to today’s lifesaving plasma therapies that have benefited millions. As expressed by Victor Grifols Roura, president and chief executive officer of Grifols SA, based in Barcelona, “the company’s enduring values emphasize service, scientific excellence, technical proficiency and inventiveness, and a full awareness of the needs of the people who trust and depend on Grifols products.”

Los Angeles Mayor Antonio Villaraigosa, Cal State LA President James Rosser, and patient representative Marcia Boyle, president, IDF, and other dignitaries at the ceremonial dedication of Grifols’ new IVIG facility.

This corporate culture has driven Grifols to sustain a full and active research and development program. Grifols already has been granted more than 400 patents in the United States and other countries, 253 of which were for plasma therapies. The company also has obtained 1,242 official product registrations. Research and Development initiatives currently are focused on developing methods to obtain, purify and stabilize additional proteins from plasma, and to help identify new therapeutic uses for them. The company’s unwavering commitment to develop more effective and safer plasma-derived therapies and processing methods builds on an already impressive record of scientific contributions in the related fields of blood transfusion, blood banking, clinical analysis and plasma therapies. —Al Heller

Special Advertising Section Pharmacy Practice News

Hospira A global specialty pharmaceutical and medication delivery company dedicated to advancing wellness As the world leader in specialty generic injectable pharmaceuticals, Hospira offers one of the broadest portfolios of generic acute care and oncology injectables, as well as integrated infusion therapy and medication management solutions. Through its products, Hospira helps improve the safety, cost and productivity of patient care.

AT A GLANCE Address 275 North Field Drive Lake Forest, IL 60045 Phone: (877) 9HOSPIRA (877-946-7747) Web site: www.hospira.com

Products automatically initiating all drug delivery Generic acute care and oncology programs within the patient safety software system. Symbiq comes with built-in injectables, and infusion therapy Product Profiles • 2009 Hospira MedNet safety software and can and medication management Specialty Injectable Pharmaceuticals store data for up to 40 clinical care areas solutions. (CCAs) and 400 medications per CCA. Through its offering of high-quality, lower-cost alternatives to Plum A+® Infusion System. The Plum proprietary medications, Hospira continues to help reduce the overEmployees all costs of health care. The company offers one of the broadest general infusion system works with Hospi14,000 Worldwide portfolios of generic injectable products, many in multiple dosage ra MedNet software to enable hospitals to or delivery formats. Product areas apply include oncology, cardiovascular, best anesthesia, anti-infectives, analgeclinical practices consistently by sics, emergency and other therapeustoring medication information tic segments. Hospira also provides for up to 18 CCAs and 150 mediinfusion therapy products such as cations per CCA. The Plum A+ Voluven® (6% hydroxyethyl starch in features a unique positive valve mechanism that helps assure 0.9% sodium chloride injection) and delivery of secondary medicaPrecedex® (dexmedetomidine HCl tions, easily traps and removes air Injection). Many of Hospira’s injectfrom the system—without “breakable medications are available in ing” the system—and delivers two proprietary drug delivery platforms, medications concurrently through including: a single line. iSecure™ Syringe. iSecure is a LifeCare PCA® Infusion System. prefilled, ready-to-use, disposable syringe for injectable drug delivery, The LifeCare PCA infusion syswith a self-contained plunger rod tem is the only patient-controlled for easy administration and disposal. analgesia pump to incorporate It is needle-free and latex-free, with an integral bar-code reader that standardized dosing for accuracy. works with bar-coded medicaHospira’s injectable medications are available in a wide variety of proprietary drug delivery platforms. VisIV™ Container. VisIV is a flextion vials to identify and verify ible IV container that helps improve drug and dose concentrations caregiver safety and efficiency, and automatically. The LifeCare PCA increase environmental responsibildesign also allows hospitals to ity. VisIV was the first large-volassure the use of safety software ume plastic flexible IV container to in all medications delivered via require no overwrap and contain the pump. an advanced film, resulting in 40% GemStar® Infusion System. The to 70% less waste. VisIV also feaGemStar line of products offers tures a larger, sterile medication port three therapy-specific modthat helps offer greater protection els for parenteral infusion of IV against accidental needlesticks. fluid, medications, nutritional fluADD-Vantage® System. The ADDids and blood/blood products, and is used extensively for pain Vantage drug delivery system is a ® Most Hospira infusion pumps are compatible with Hospira MedNet management. Hospira recently two-part drug delivery system that Safety Software, which provides instant alerts to help prevent potential launched the enhanced GemStar does not require a needle and syringe medication errors. SP, which provides 25 flexible to mix the drug and the solution. It is drug protocols with hard limits to help prevent medication errors. designed to reduce waste and increase patient safety when giving GemStar infusion pumps provide single-channel administration of up medications that must be mixed just before administering. to seven different therapies in the hospital, home care environments Medication Management Systems and multiple ambulatory applications. EndoTool® Glucose Management System. EndoTool is a software Hospira MedNet® Safety Software. Hospira MedNet safety software platform links infusion devices with the pharmacy and hospital system that helps improve patient safety and quality of care in operinformation systems to help clinicians better manage IV medication ating rooms and acute/critical care settings by calculating the dose administration at the point of care. Hospira MedNet software is tiered of IV insulin needed to quickly control glycemic, or blood glucose, and scalable, to allow hospitals to migrate from a custom drug library, levels. EndoTool identifies individual patient responses to IV insulin which offers both hard- and soft-dosing limits, to a system that interto help manage current and predict future dosage levels. The softfaces with other clinical information systems (e.g., bar-code point-ofware also can produce a record of the patient’s blood glucose values care and electronic medication administration record systems). and insulin doses, and has the ability to interface with electronic Symbiq® Infusion System. Advanced, yet easy to use, the awardhealth records. Hospira recently announced the coming integration of EndoTool with the Symbiq infusion system. winning Symbiq infusion system makes patient safety easier by Special Advertising Section Pharmacy Practice News

Product/Service Profile 2009

Medi-Dose, Inc./EPS, Inc. AT A GLANCE Address 70 Industrial Drive Ivyland, PA 18974 Phone: (800) 523-8966 Fax: (800) 323-8966 E-mail: info@medi-dose.com Web site: www.medi-dose.com

Pioneers of unit-dose packaging, The Medi-Dose® Group constantly responds to pharmacy needs with innovative solid and liquid, oral unit-dose packaging products and a wide range of flexible, costeffective IV, filtration, pharmacy and nursing accessories.

customized work flow and comprehensive logs and reports; as well as laser, inkjet and thermal printer capabilities.

EPS, Inc.: A Focus on IV Medications

EPS® (Extemporaneous Packaging Systems), Inc., a companion company to Medi-Dose, Inc., was founded in 1977. Today, EPS manufactures and markets liquid unit-dose packaging supplies and IV additive disposables for the preparation and dispensing of IV mediThe Medi-Dose Group has always had cations. Other EPS products include deep roots—family roots. Medi-Dose began male/female Luer-lock closures, injecas a small family business in 1971, when Products tion ports, trays and totes, tapes and Milton Braverman, a former pharmaceutiMedi-Dose® (Solid) and labels, UV inhibitant bags and resealcal company territory manager, formed his TampAlerT® (Liquid) Oral Unitable bags, IV software and high-alert own company. He was acutely aware of the Dose Packaging medication identification bands. requirements of hospital pharmacy. His sons, Like Medi-Dose, the EPS TampAlerT® Medi-Cup® PLUS packaging for Robert and Mark, continue the tradition for system for liquids offers tamper eviThe Medi-Dose Group. extended beyond-use dating dence. “The premier advantage of The Bravermans carved a niche for the ® MILT by Medi-Dose unit-dose TampAlerT is its tamper-evident seal,” company—initially with solid oral unit-dose and bar-coding software Robert Braverman said. “Ten minutes packaging. Although the concept of unit LiquiDose® labeling, IV additive after you dispense your liquid and dose is familiar today, launching the idea MILT® by Medi-Dose program. and filtration products screw the TampAlerT cap on the vial, was one of the biggest problems the new the seal is in place. Heat tunnels and ® company faced. “We were one of the pioNultraviolet ultraviolet light accessory sealing equipment are not neers, the innovators inhibitant bags necessary. TampAlerT is tamper evipromoting unit dose Steri-Dropper sterile ophthalmic dence with a twist of the wrist!” in hospitals,” Robert dropper bottles The company’s IV accessories also Braverman recalled. are highly successful. “We see them High Alert and I.V. Line Tracing “Due in part to Medias natural advancements of the initial Labels Dose’s educational Medi-Dose system. In essence, IV disefforts, pharmacists Resealable bags, bottles and pensing is a highly specialized form and nurses accepted other pharmacy supplies and disof unit dose,” he added. “It’s the same the validity of unit posables idea—preparing and administering predose.” determined amounts of medication for Medi-Dose is conone regular dose or application.” stantly responding to Although all the products continue pharmacy packaging needs. Providing stability, Pharmacists’ input has made Medi-Dose the ideal manual, to meet with gratifying, widespread ultraviolet (UV) light inhibition, easy opening and solid oral unit-dose packaging system. acceptance, both Medi-Dose and tamper evidence have always been paramount EPS remain highly motivated. “We’re concerns regarding prepackaging. always looking for new products and Using Medi-Dose, a pharmacist can developing innovative, cost-effective package a medication and store it ways to help pharmacists, always with for up to one year without loss of an eye toward reducing the potenpotency due to UV light transmistial for medication error,” noted Mr. sion or moisture permeation. Braverman. “One of our newest prodHospitals can install the Mediucts meeting these criteria is our line Dose solid oral unit-dose system of IV and High Alert Line Tracing for about $700; this includes all the Labels which makes it easy to label supplies for 5,000 doses of mediand trace IV lines for any medication cation, as well as software for comin any setting (hospital, home or clinplete medication and bar-coding ic). Pharmacy simply places the entire identification. Total solid and liquid EPS’s innovative Line Tracing Label with a unique three-part piggyback label on an IV infusion container. When oral systems can be set up for less design provides safe and economical protection for IV lines. the medication is administered at the than $1,000. bedside, nursing applies one line label to each end of the tubing. This facilitates easy line traces, improves accuMILT® by Medi-Dose Software racy and helps minimize IV line confusion.” He added that 10 preprinted With bar coding increasingly important to pharmacy practice, Medilabels as well as customizable Line Tracing Labels (when used with the Dose designed its widely used MILT® by Medi-Dose software (Medi-Dose MILT 3.0 software) are immediately available. Information Labeling Technology, named for the company’s founder). “All our IV High Alert and Line Tracing Labels reduce the potential for “My father wanted bar coding on medication packaging early on, to error, minimize liability exposure and save lives—all for an extremely affordminimize the potential for medication error,” Robert Braverman said. able price,” Mr. Braverman said. “So, we’ve been constantly improving our programs to meet this vital Mark D. Braverman, director of operations, is responsible for the compapharmacy challenge and need.” ny’s extensive computer network. He coordinates all purchasing activities, MILT 3.0 by Medi-Dose not only has sophisticated one- and two-dimenboth domestic and international. Mark and Robert are aggressively bringing sional bar-coding technology to include lot numbers, beyond-use dates and an expanded line of economically priced, generic alternatives to expensive National Drug Codes (NDC) on one bar code; it also includes an upgradbrands of plastic products to the firm’s customers. able NDC database, directly from the FDA. Pharmacists can simply type or Robert Braverman noted, “We’ve come a long way from being a small scan in the NDC number, and MILT by Medi-Dose will supply the pertinent family business; we still have remained as attentive and responsive to information. The pharmacist can map this information to designated fields, pharmacy needs as we were more than 30 years ago. Now we have the reducing the risk for error. MILT by Medi-Dose also contains field-locking ability and the products to respond to pharmacists’ needs all over the capability for extra security; enhanced formatting for quick medication world—and we do.” identification; support for syringe, ampule and IV Line Tracing labeling;

Product/Service Profile 2009

Special Advertising Section Pharmacy Practice News

McMahon Publishing McMahon Publishing was founded in 1972 by Raymond E. McMahon. McMahon Publishing has grown to become one of the nation’s largest family-owned medical publishers, with a projected 2009 annual revenue of about $23 million across all product categories. Today, McMahon publishes a broad array of medical newsmagazines in various specialties, including anesthesiology, gastroenterology, general surgery, hospital pharmacy, infectious diseases, pain medicine and oncology. McMahon publications are at or near the top of their markets in independent readership scores. The combined circulation of McMahon Publishing publications approaches 330,000 doctors and pharmacists. Foremost among McMahon publications is Pharmacy Practice News. Launched more than 30 years ago, Pharmacy Practice News has grown to become the best-read publication in the field, according to Nielsen PERQ/HCI. Every month, 92% of the 45,000 U.S.-based health-system pharmacists read some or all of this publication. The mission of Pharmacy Practice News is twofold: to provide hospital pharmacists with the information they need to provide highquality patient care, and to help them demonstrate the value of that care to colleagues and administrators. To achieve these goals, the editorial staff of Pharmacy Practice News follows developments in both academic and hospital practice settings. The majority of Pharmacy Practice News’ coverage comes from attending meetings convened by the major pharmacy groups, such as the American Society of Health-System Pharmacists and the American College of Clinical Pharmacy. But we also attend smaller, more focused meetings in order to keep our readers abreast of specialty care. This year, for example, the magazine stepped up its coverage of the Hematology/Oncology Pharmacy Association’s annual meeting, with several “late breakers” posted on-site on the publication’s Web page (pharmacypracticenews.com) and additional articles featured in the July and August print issues. We also cover the Society of Critical Care Medicine (SCCM), with 2010 being a special year for the meeting and the magazine—editorial advisory board member Judi Jacobi, PharmD, will be installed as the first pharmacist-president of SCCM. McMahon Publishing also produces a wide variety of Special Editions—compendia of educational reviews written by thought leaders in various specialties. These include anesthesiology, gastroenterology and endoscopy, hospital pharmacy, general surgery, infectious

disease, oncology and pain medicine. The Special Projects division of McMahon Publishing produces educational reviews, wall charts and custom pocket guides and Special Reports and Literature Reviews. The educational reviews, written by authorities in a given treatment area, are comprehensive summaries of stateof-the-art thinking on a specific disease state. These often are published as wall charts and pocket guides that serve as on-the-spot educational tools for health care providers. Special Reports are custom-written monographs bound inside Pharmacy Practice News or other McMahon publications. Special Reports can be based on symposium coverage, interviews with experts, etc. Special Reports can be CME/CE accredited. Literature Reviews also are individual, custom-written monographs that are bound inside Pharmacy Practice News or other McMahon publications and distributed to the magazine’s full readership. We conduct a literature search for all peer-reviewed, published studies on a given subject and compile a detailed, scientifically sound review of these articles. Literature Reviews also can be CME/CE accredited. The McMahon Web site, McMahonMed. com, contains a wealth of medical information gleaned from the company’s print publications along with “Web only” content. CMEZone.com provides free continuing medical education and continuing education for pharmacists and nurses. At pharmacypracticenews.com, you can find articles from the print edition of the publication, as well as Web-exclusive content such as breaking news and expanded coverage of stories that appear in the magazine.

AT A GLANCE Address 545 W. 45th Street, 8th Floor New York, NY 10036 Phone: (212) 957-5300 Fax: (212) 957-7230 Web sites: www.mcmahonmed.com www.pharmacypracticenews.com www.cmezone.com

Products Medical newsmagazines, custom medical publications, educational reviews, educational and instructional pocket guides, special editions.

Employees 75

Publisher, CEO and Managing Partner Raymond E. McMahon

President, Partner Van Velle

Vice President, Medical Education Thomas Ciriacks

Pharmacy Practice News Publication Directors Dave Kaplan, Phil Redgate

Editorial Director David Bronstein

Senior Editor Sarah Tilyou

Production Manager Mark Neufeld

Art Director Frank Tagarello

Special Advertising Section Pharmacy Practice News

Product/Service Profile 2009

NuAire, Inc. ® AT A GLANCE Address 2100 Fernbrook Lane Plymouth, MN 55447 Phone: (800) 328-3352 E-mail: nuaire@nuaire.com Web site: www.nuaire.com

“Best Products, Best Performance, Best Protection” Founded in 1971, NuAire, Inc.® was started by Max D. Peters, “the entrepreneur,” in his home. He organized, operated and assumed the risk of the business venture.

Products

NuAire, Inc. was awarded the first contract to produce the first modern-day Biological Safety Cabinet per NIH-03-112c for the National Institutes of Health in PharmaGard™ Compounding Bethesda, Md. Aseptic Containment Isolators For more than 35 years, NuAire has LabGard® Class I, II, & III Biological been universally recognized as the leader Safety Cabinets in providing laboratory professionals with AireGard™ Laminar Airflow reliable products for the most demanding Equipment environments. With its state-of-the-art robotAireGard™ Clean Air Scrubber ic sheet metal facility, Aseptic Cleaning Supplies NuAire is able to delivErgonomic Accessories er standard as well as exceptional custom innovative products to its customers. The NuAire mission has always been and will continue to be to develop and deliver innovative products, to communicate the latest technologies and product improvements, to establish trust in both products and personnel, to see customer satisfaction and to continuously improve. PharmaGard™ Compounding Aseptic Isolators

filters increase filter life from eight years to an average of 10 to 12 years. NuAire’s proven HEPEX Zero Leak Airflow System guarantees uniform airflow and filter loading. With three control centers to choose from, LabGard guarantees maximized production for all laboratory needs. The exclusive TouchLink™ LCD control center features “night setback” to lower energy consumption when LabGard is not in use. The ergonomic design provides a wide range of motion in the work zone, increased vision, comfortable leg room, proper posture, easy accessible controls, and with multiple ergonomic accessories to choose from, LabGard is the true ergonomic BSC.

Class I Biological Safety Cabinets LabGard Class I Biological Safety Cabinets provide personnel protection for the handling of powders. The versatile designs can be configured to meet client specifications. Each enclosure provides a HEPA-filtered clean air environment. All Class I Biological Safety Cabinets are designed to be ergonomic, quiet, easy and efficient to operate while requiring less energy and maintenance.

Compounding Aseptic Isolators The PharmaGard™ Compounding Aseptic Isolator (CAI) and Compounding Aseptic Containment Isolator (CACI) are the single-source solution to ensure compliance with USP Chapter <797> for the proper preparation of compounding sterile products. PharmaGard uses the HEPEX™ Zero Leak Airflow System to ensure true unidirectional laminar airflow to minimize cross-contamination. The transfer chamber is under constant purge for less down time during transfer-chamber to work-zone transfers. PharmaGard comes standard with three IV bar locations, slanted oversized glove ports for increased vision and range of movement, vertical sliding transfer door and sliding work tray for easy movement of sterile product, cool-white lighting that is easy on the eyes, and spacesaving in-work-zone sharps and waste disposal. The optional automatic base stand lift guarantees that one size fits all. Order now and receive a free isolator cleaning kit from ITW Texwipe® with each PharmaGard.

Class II Biological Safety Cabinets

Laminar Airflow Equipment The AireGard™ series of laminar airflow equipment is specifically designed to provide the ideal particulate- and bacteria-free clean air environment for clinical applications. Products include horizontal and vertical flow clean benches, ceiling modules and vertical airflow work stations. All AireGard products use True Laminar Airflow, HEPEX Zero Leak Airflow System, HEPA filters, disposable prefilters, Attenumont™ Vibration Control and solid state electronics. All AireGard products are certified to exceed ISO Level 5 air quality of ISO 14644.

Portable Clean Air Scrubber LabGard NU-430 Class II, Type B2 Biological Safety Cabinet

NuAire’s AireGard NU-112 and NU-114 Clean Air Scrubber provides reliable protection against a wide range of airborne contaminants. This portable, self-contained unit is capable of filtering particulates where ISO Class 7 or 8 air quality is required. It is effective in controlling infectious bacteria and viruses ranging from “common cold” germs to more dangerous organisms such as those causing SARS and tuberculosis.

Helping To Change the Pharmacy Environment NuAire is dedicated to changing the pharmacy environment with a commitment to providing the best equipment available, and information on training, proper aseptic techniques, ergonomics and much more. For more information, please call (800) 328-3352 or visit www.nuaire.com.

Value

NuAire is recognized as the world leader in NuAire, Inc., family-owned and operated, Class II Biological Safety Cabinets (BSCs). Your offers a wide range of laboratory products and favorite BSC just got better. With the same systems to serve the needs of the world’s laboemphasis on ergonomics, LabGard® is now ratory community. NuAire’s prototype research PharmaGard NU-797NTE Compounding and development complements its In-House designed with energy saver (ES) technology for Aseptic Containment Isolator Training and Testing Center. NuAire’s sales low operational costs. A new DC/ECM motor lowers energy consumption while increasing representatives and service technicians are the performance. Engineered with optimally determined blower motor envy of the laboratory community. The unique features of NuAire’s fans for each product model, LabGard runs virtually silently with less products, at an overall lower cost, make those products an excelvibration. Standard oversized High Efficiency Particulate Air (HEPA) lent choice—“Quality and Dependability for the Future.”

Product/Service Profile 2009

Special Advertising Section Pharmacy Practice News

PharMEDium Services PharMEDium is the leading outsourced pharmacy provider, rigorously ensuring the accuracy and sterility of all your customized sterile compounded preparations. The company has grown into a nationwide network of state-licensed and federally registered compounding centers providing trusted solutions to more than 1,800 hospitals throughout the United States. Managed by licensed pharmacists and staffed by certified technicians, PharMEDium complies with all appropriate state laws and federal regulations, including requirements from the United States Pharmacopeia Chapter <797> and the Drug Enforcement Administration. Admixtures for All Areas Of Your Hospital PharMEDium can help. With proven admixture services for all areas of the hospital, PharMEDium can significantly reduce the time and effort required to produce high-quality compounded preparations. Your pharmacy will run smoothly, your admixtures will stay compliant with current and future regulations and you’ll have more time to focus on what you do best: taking care of your patients. Supported specialties include: • Pain management PCAs and epidurals; labor and delivery, nerve block and local anesthetics, OR anesthesia syringe preparations; electrolyte solutions; antibiotics; antiemetics, cardiovascular/cardioplegia; renal replacement solutions; total parenteral nutrition; intrathecal preparations. Rigorous sterility controls, accurate custom syringe preparations: PharMEDium anesthesia custom syringe preparations improve drug-name recognition in critical situations, thanks to labels with American Society of Anesthesiologists–endorsed ASTM color-coding by drug class. At PharMEDium, we understand that accuracy must begin long before a compounded preparation enters the operating room. That’s why we developed a process of 200% inspection along with a highly specialized system that uses automated bar-code verification to ensure that the right drug in the right concentration is present in each syringe and is labeled correctly, every time. Our tamper-evident packaging enhances patient care by reducing the potential for diversion and waste.

Special Advertising Section Pharmacy Practice News

PharMEDium OR anesthesia syringe preparations, in an array of requested concentrations, include: • Opioids: fentanyl, morphine PF, hydromorphone, • Vasopressors: phenylephrine, ephedrine • Sedatives: midazolam • Blockade agents: succinylcholine, rocuronium, vecuronium • Reversal agents: neostigmine • Anticholinergics: glycopyrrolate, atropine • Induction agents: ketamine • Local anesthetics: bupivacaine, ropivacaine, lidocaine • Antibiotics: cefazolin • β-blockers: labetolol, esmolol

Industry-Leading Label Design

AT A GLANCE Address Two Conway Park 150 N Field Drive, Suite 350 Lake Forest, IL 60045 Phone: (800) 523-7749 Web site: www.pharmedium.com

Services Pain management PCAs and epidurals; labor and delivery, nerve block and local anesthetics, OR anesthesia syringe preparations; electrolyte solutions; antibiotics; antiemetics, cardiovascular/cardioplegia; renal replacement solutions; total parenteral nutrition; intrathecal preparations.

The admixtures you receive from PharMEDium feature easy-to-read labels designed to help reduce errors and facilitate proper administration: • Easy-to-see “tall man” lettering allows for instant drug recognition • Drug concentration and total dose are listed, clearly indicating the precise amount of active drug contained in the admixture • Lot number and expiration date are prominent • Bar codes meet UCC.EAN standards and FDA regulations for drug identification • CII nomenclature indicates a scheduled substance • Enhanced safety messaging for correct infusion

e222: The Only Drug Order Form Officially Endorsed by Trees Paperless. Effortless. Costs less. Only from PharMEDium. Enjoy the benefits of PharMEDium even faster. An electronic version of DEA Form 222 for Schedule II Controlled Substances (e222) can now be filled out and submitted electronically at www.pharmedium.com. You can reduce the time you spend filling out orders from minutes to seconds! PharMEDium is the only outsourced compounder to offer this service! To learn more about PharMEDium, please visit our Web site at www.pharmedium.com or call us at (800) 523-7749.

Product/Service Profile 2009

Sandoz Sandoz is a leading global player in the generic pharmaceutical industry with a significant portfolio of approximately Address 1,000 high-quality, 506 Carnegie Center, Suite 400 affordable products Princeton, NJ 08540 Phone: (800) 525-8747 that are no longer Fax: (609) 627-8681 protected by patWeb site: www.us.sandoz.com ents. The employees of Sandoz are committed to delivering a full range of traditional generic medicines, as well as going a step further by constantly seeking new ways to improve patients’ quality of life.

AT A GLANCE

Global R&D

The global R&D centers of Sandoz work to ensure that the company continually brings opportunities to customers and patients. The eight major global development centers and a worldwide network of production sites and technology centers of excellence pursue not only tablets and capsules but injectables, creams, ointments and other dosage forms. These generic products include antibiotics, CNS disorder treatments, gastrointestinal medicines, cardiovascular treatments and hormone therapies. The introduction of the Omnitrope® Pen 5 with liquid cartridge for injection and the Omnitrope® Pen 10 with liquid cartridge for injection—new forms of the first follow-on version of a recombinant biotechnology drug—have further positioned Sandoz as a leader in the emerging field of follow-on biologics. The Sandoz pipeline is robust and, as the second largest generic supplier in the United States, the company is uniquely positioned to continue to expand its product portfolio offerings. Sandoz continues to differentiate itself through its ability to develop and produce difficult-to-make medicines. The company is well on its way to achieving its mission to be the main provider of high-quality, affordable medicines, helping to secure Christine Mundker, CEO of US Generics long-term access to healthcare for people Operations, Sandoz. around the world.

Sandoz’ decades of experience, combined with its global development and production network, enable the company to develop and manufacture the difficult-to-make generics that many other companies cannot or do not make. Sandoz produces far more than just traditional off-patent products. The company differentiates itself from other companies by developing and producing difficult-to-make-generics that require an exceptionally high degree of expertise and knowle dge and often involve complex high-tech delivery systems. These range from oral solids and inhalers through patch technologies to state-of-the-art biosimilars—follow-on versions of biopharmaceuticals following patent expiry.

As the second largest generic supplier in the United States, Sandoz is uniquely positioned to continue to expand its product portfolio offerings.

Sandoz excels at developing and manufacturing generic drugs that require an exceptionally high degree of expertise and knowledge.

Product/Service Profile 2009

Special Advertising Section Pharmacy Practice News

Teva Health Systems A Market Leader Teva Health Systems (THS), located in Irvine, Calif., is the division of Teva Pharmaceuticals focused on institutional markets. THS offers a single source for health systems products through a broad portfolio of generic oncology, hospital injectable, unit dose and oral products, as well as the most productive product pipeline. Teva Pharmaceuticals is among the top 20 pharmaceutical companies and among the largest generic pharmaceutical companies in the world. THS continues to introduce unit-dose versions of the company’s oral product line, and is the leading producer of oncology products in the United States. By any measure, Teva Pharmaceuticals (Teva) is the leader in the generic pharmaceutical market, ranking No. 1 in prescriptions filled, sales dollars, ANDA filings including first-to-files, product launches, breadth of product line, vertical integration, pedigree technology and many other criteria. Last year closed with the acquisition of Barr, effective Dec. 23, 2008. The combination of Teva and Barr creates an unrivaled management team and global product platform. Teva now has more than 38,000 employees and annual sales that totaled $11.1 billion in 2008. As a result of the acquisition, the combined company now markets the broadest product line in the United States, comprising more than 450 products and 1,500 SKUs. The acquisition also strengthens Teva’s development, manufacturing, legal, marketing and distribution capabilities, and significantly expands its portfolio and future product pipeline. Teva’s mission is to play a leading role in the continuing transformation of the U.S. health care system. With the integration of Barr, Teva will play an even greater part in expanding the public’s access to affordable medicines. Teva has a well-established and balanced portfolio of products that customers want, and a strong active pharmaceutical ingredient business to meet their needs. In addition, a vertically integrated structure ensures that as Teva continues to grow, the company can maintain its high standard of quality and its long-standing commitment to customer satisfaction.

A Biosimilars Strategy Teva also is making strides in the emerging biosimilars market, a major

AT A GLANCE Address 19 Hughes Irvine, CA 92618 Phone: (800) 729-9991 Web site: www.tevausa.com

Products growth driver in the company’s longterm strategy. Earlier this year, the comTeva Health Systems is focused pany announced an agreement with on the development and marketLonza Group Ltd., to establish a joint vening of multisource products in ture to develop, manufacture and market various fields including oncology, affordable, efficacious and safe generic antiemetics, cardiology and infecequivalents of a selected portfolio of tious disease. Products include biologic pharmaceuticals. The two orgasterile injectables in vials, syringes nizations complement each other. Lonza and bags and unit-dose products. brings a deep knowledge and experience in biopharmaceutical development, large-scale manufacturing and state-of-the-art manufacturing facilities. Combined with Teva’s global leadership and expertise in clinical development and marketing of generic pharmaceuticals, the joint venture generates significant opportunities and benefits for both companies. Teva launched 28 generic products in 2008, and had 197 ANDAs pending FDA approval as of April 27, 2009. Recently launched products include Mycophenolate Mofetil Tablets & Capsules, AB rated to Roche’s CellCept®; Topiramate Tablets and Capsules (Sprinkle), AB rated to Ortho McNeil’s Topamax®; Mixed Amphetamine Salt Extended-Release Capsules, same as Shire’s Adderall XR®; Sumatriptan Succinate Tablets and Injection, AB/ AP rated to GSK’s Imitrex®; Amiodarone Hydrochloride Injection in two new vial sizes, AP rated to SanofiAventis’ Cordarone ® ; Risperidone Tablets and Oral Solution, AB/AA rated to Janssen’s Risperdal®; Levetiracetam Tablets, AB rated to UCB Pharma’s Keppra ®; Fentanyl Transdermal System, AB rated to Janssen’s Duragesic ®; and Rocuronium Bromide Injection, AP rated to Organon’s Zemuron®. Teva is the leading provider of affordable generic medicines. Our robust pipeline of future products is a source of continuing value to American consumers.

Recent Teva product launches include Amiodarone Hydrochloride Injection in two new vial sizes, AP rated to Sanofi-Aventis’ Cordarone®; and Sumatriptan Succinate Tablets and Injection, AB/AP rated to GlaxoSmithKline’s Imitrex®. Also shown: Teva’s Fluconazole Portfolio.

Special Advertising Section Pharmacy Practice News

Product/Service Profile 2009

in Your Inbox Pharmacy Practice News is now available as an E-newsletter.

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

Operations & Management 31

Pharmacy Practice News • August 2009

Preparedness

FLU READINESS continued from page 18

which showed how much remained to be done to avoid a catastrophe if a virulent strain were to emerge. The report, titled “Pandemic Flu: Lessons from the Frontlines,” stated that although “U.S. officials executed strong coordination and communication and ability to adapt to changing circumstances,” the outbreak also suggested “how quickly the nation’s core public health capacity would be overwhelmed if an outbreak were more severe or widespread.” In addition to the assessment tool, the foundation’s new resource center contains links to other sources of timely information, including the Centers for Disease Control and Prevention and the World Health Organization as well as RSS feeds offering continually updated reports on pandemic developments. Since its original launch a year ago, approximately 250 individuals have accessed the assessment tool. Dr. Cobaugh said he was encouraged by the response so far. “As a percentage of the total number of hospitals, it’s a relatively small number,” he said, “but what we can say is that we’ve influenced preparedness practice in over 250 departments of pharmacy across the country.” Dr. Cobaugh said the H1N1 outbreak had served as a “wake-up call. Awareness is very heightened at this point, and departments of pharmacy and hospitals and health systems across the country are being much more vigilant about their preparedness. So it’s a good time to introduce the new resource center.” Dr. Cohen said pharmacies “really need to focus” on preparing their operations for a possible pandemic, including making sure that standard dosing charts are

Educational & Commercial Reprints Reprints of Pharmacy Practice News articles are available in minimum quantities of 500. Reprints can be ordered in black & white or 4-color versions and printed on 80-lb. glossy stock. Standard turnaround time is 4 weeks.

For specific price quotes, call Dave Kaplan at

(212) 957-5300 x912.

‘It’s fair to say that overall emergency preparedness planning, as well as planning specifically for pandemic influenza, has been a challenge for departments of pharmacy and for hospitals and health systems in general.’ —Daniel J. Cobaugh, PharmD, FAACT, DABAT available for children, adults, the elderly and patients with renal dysfunction. He said hospitals also need to determine who is going to dispense medica-

tions “when patients come to the hospital. Is the inpatient pharmacy going to fill or is the patient going to be referred to an outpatient pharmacy? Will the

patient be assured of getting Tamiflu [Roche] in the outpatient setting?” Additionally, Dr. Cohen said, vial labels need to be preprinted, especially for pediatric suspensions, and patient instructions need to be printed in all languages that patients are likely to understand. Finally, he added, providers should understand that flu can present atypically—“at Maimonides there was a lot of nausea and vomiting connected with the H1N1 outbreak”—and should expect the unexpected at all times. —Bruce Buckley

Gelfoam + Human Thrombin In one kit. ®

Gelfoam Plus...

• Provides cost savings compared to items purchased separately1 • Offers additional savings opportunities with inclusion in the Baxter Value Incentive Program • Allows easy management of thrombin use • Helps consolidate inventory of multiple products And FLOSEAL [Hemostatic Matrix] are part of a complete hemostasis product line from Baxter. For more information please contact your local Baxter BioSurgery Representative or call 1-800-423-2090.

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

FLOSEAL [Hemostatic Matrix] Indications FLOSEAL is indicated in surgical procedures (other than ophthalmic) as an adjunct to hemostasis when control of bleeding by ligature or conventional procedures is ineffective or impractical. Important Safety Information FLOSEAL must not be injected into blood vessels, or allowed to enter blood vessels. Do not apply in the absence of active bleeding. Extensive intravascular clotting and even death may result. Do not use FLOSEAL in the closure of skin incisions because it may interfere with the healing of the skin edges. Do not use FLOSEAL in patients with known allergies to materials of bovine origin. FLOSEAL is made from human plasma. It may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The maximum swell volume of approximately 20% is achieved within about 10 minutes. Excess FLOSEAL (material not incorporated in the hemostatic clot) should be removed from the site of application using gentle irrigation. RX only: For safe and proper use of these devices, please refer to full device Instructions For Use. 1. 2006 IMS Hemostat and Sealant Revenue, Unit, and ASP Sales Data. Baxter, FLOSEAL and ADVANCING SURGERY,ENHANCING LIFE are trademarks of Baxter International Inc. Gelfoam is a registered trademark of Pharmacia & Upjohn Company LLC., used under license. BS1889 4/2008

32 Clinical

Pharmacy Practice News • August 2009

Cardiology

IV Chemical Compound Linked to Impaired Heart Function F ‘[CHX] could be neurotoxic. It may affect the central nervous

or years, the chemical solvent cyclohexanone (CHX) has been an ideal component of medical plastic products. Not only does the bonding agent provide a strong, air- and water-tight seal with polyvinyl chloride (PVC) in IV bags and tubing, it also is inexpensive to manufacture. CHX has been an obvious choice for companies that make IV equipment … until now. Researchers in the Department of Biomedical Engineering in The Whitaker Biomedical Engineering Institute, Johns Hopkins University School of Medicine, Baltimore, have reported that CHX leaching into IV bags and tubing can significantly impair heart function in rats (Am J Physiol Heart Circ Physiol 2009;296:H1926-H1932). Additionally, the investigators speculated that CHX may cause some of the common side effects, such as edema, autonomic dysfunction and altered vasomotor function, that also occur with extracorporeal circulation used in medical procedures like extracorporeal membrane oxygenation (ECMO), bypass surgery and dialysis.

“The medical problems are not associated with PVC, per se,” said Artin A. Shoukas, PhD, senior author of the article, which was first published online May 1, 2009 (doi:10.1152/ajpheart.00184.2009). Noting that CHX is a wet welding agent that glues PVC to PVC or other plastic material, Dr. Shoukas said CHX alone appears to be the culprit in the adverse medical reactions they observed in their experiments. However, health care professionals should not expect to find CHX-free products available immediately, the Johns Hopkins researchers cautioned. “Changing over from CHX to a different manufacturing process, or even to a different wet welding agent, is going to take years, if not decades,” noted Caitlin Thompson-Torgerson, PhD, the study’s lead author. That’s why the Johns Hopkins team is now investigating a short-term fix, such as agents that protect against CHX or an alternative to CHX as the binding agent of choice. They plan further studies in rats and mice, as well as other mammals.

system, the peripheral nerves and receptors all over the body. We’re currently pursuing that.’

—Artin A. Shoukas, PhD

Previous and Current CHX Findings Although previous studies during the 1970s through the 1990s demonstrat-

ed that CHX found in plastic may be toxic to animals, no one determined the dosage that might harm people, Dr. Thompson-Torgerson said. Because of

the potential harm to human subjects, the researchers chose to conduct their studies in animal models. The researchers found CHX when they analyzed and quantified fluid samples from IV saline bags, lactated Ringer’s bags, cardiopulmonary bypass circuits, ECMO circuits and hemodialysis circuits. After determining an animal dosage that would be equivalent to that experienced by humans, the researchers injected rats with either a CHX-saline

DIVERSE PORTFOLIO

Clinical 33

Pharmacy Practice News • August 2009

Cardiology mixture or pure saline. Although the saline-treated animals had no adverse reactions, the CHX rats experienced significant adverse changes in all cardiovascular variables. Both stroke volume and heart rate values were significantly depressed after one hour of CHX versus saline, resulting in a 34% decline in cardiac output in rats injected with CHX. Also noted was an increase in systemic vascular resistance, an exaggerated increase in pulmonary vascular resistance and depressed ventricular contractility. After the CHX infusion, the baroreflex

The chemical solvent cyclohexanone (CHX) may someday trigger warnings similar to those that led to the removal of Bis(2-ethylhexyl)phthalate (DEHP) from most plastic tubing due to the risk for toxicity.

pressor response to bilateral carotid occlusion was less pronounced than at baseline values, and was totally abolished after a second infusion of CHX. Additionally, the researchers noted significant edema formation in the CHXinjected rats. Although not published in the new study, the researchers also have found preliminary evidence that CHX is affecting the neuronal system. “It could be neurotoxic,” Dr. Shoukas said. “It may affect the central nervous system, the peripheral nerves and receptors all over the body. We’re currently pursuing that.”

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Interestingly, one of the reasons that Dr. Shoukas became interested in investigating CHX was his own personal experience with coronary bypass surgery. He was curious as to the root cause for the loss of taste phenomenon. “I’m a chocoholic,” he said. “After my bypass surgery, everything tasted awful and chocolate tasted like charcoal for months.” The smell of CHX also is noticeable, he said, noting that it’s the basis of that “new car” smell with just-bought automobiles. Additionally, home plumbing products such as purple primer bought at the local hardware store contain CHX.

‘Changing over from CHX to a different manufacturing process, or even to a different wet welding agent, is going to take years, if not decades.’ —Caitlin ThompsonTorgerson, PhD

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“There are a number of animal studies looking at CHX exposure through the skin, inhaled or other routes of administration,” Dr. Thompson-Torgerson said. “There can be different levels of toxicity. Obviously, intravenous is the most direct route, with the greatest concentration. Inhaled is less direct, and transdermal even less so.” Whether any federal mandates regarding CHX come as a result of the Johns Hopkins study or others is still up in the air. Dr. Shoukas said the FDA is aware of the findings, but would not comment on the agency’s plans. One wonders, however, if CHX may be on the same road as Bis(2-ethylhexyl)phthalate, commonly abbreviated as DEHP. The agent was commonly used as a plasticizer in articles made of PVC until the FDA issued a public health warning on DEHP in 2002. Now, several companies manufacture DEHP-free IV products. —Sue Pondrom

Hem/Onc Pharmacy

Pharmacy Practice News • August 2009

In Focus

STOP SMOKING continued from page 1

only lung cancer but head and neck cancer and bladder cancer, and is related to many other tumors. If pharmacists have the opportunity to provide smoking cessation services or counseling to patients, family members and perhaps even employees at our place of work, we should be well trained and willing to provide those kinds of services.” That is exactly what she and colleagues did. After taking an intensive course at Mayo Clinic to become certified tobacco treatment specialists, they established the “Win by Quitting” Smoking Cessation Program at the Barrett Cancer Center, The University Hospital-Health Alliance of Greater Cincinnati, in August 2005. The program uses behavior modification and pharmacotherapeutic intervention for a total of six clinic visits over a 12-week period. The primary purpose of the current research was to evaluate the effectiveness of the program; a secondary objective was to see whether sex or race affects quit rates. The study population consisted of 224 patients (93 male, 131 female), who attended the clinic at least once between April 2006 and April 2008. Most (149; 67%) of the patients were white, 70 (31%) were African American and five (2%) were classified as “other.” Their average age (median) was 49.3 years; their average carbon monoxide level was 26.5 ppm, and their average Zung Self-rating Depression Scale score was 48 on a scale of 25 to 100. “Some were cancer patients. There were some family members of cancer patients, some employees from the health care institute, and some were people who basically had heard about the program from others. So we had a variety of patients besides those with cancer,” Dr. Pruemer explained. Patients received one of the following pharmacologic treatments—nicotine patch, bupropion, bupropion plus the nicotine patch, or varenicline (Chantix, Pfizer)—in addition to motivational counseling and behavioral modification therapy provided by the pharmacist. Quit rates were assessed by telephone interview to obtain self-reported cessation rates three months after the patient’s last visit to the clinic. The overall quit rate was 55.8%. There were no significant differences in quit rates by sex or race: 72 of 131 (55%) women and 52 of 93 (56%) men were able to quit smoking; and 82 of 149 (55%) whites, 38 of 70 (54%) African Americans, and four of five (80%) “others” were able to quit.

Study Limitations Dr. Pruemer noted that her study had the following limitations: a small,

non-randomized sample, reliance on patient selfreports to document quit rates, and a lack of any biologic verification such as carbon monoxide level to verify that patients had successfully quit. Also, the study did not factor in the possibility that adverse events from the pharmacologic agent the patient was taking might have caused the patient to stop taking the drug and perhaps fail at the quit attempt. Nevertheless, Dr. Pruemer said that the almost 56% quit rate obtained in this study has been very steady over the last four years that the program has been in place and that it compares favorably with quit rates reported in programs conducted elsewhere. “When you read the literature on some of the smoking cessation aids, the average quit rate for the nicotine patch is as low as 15%. When varenicline was coming out, its highest quit rate was 44%. For bupropion, it was in the 30% range,” she said. “We know that when we combine medication with a very intensive counseling program, we can practically double those quit rates. We’re never going to get a 100% quit rate with the first try.” In related research, Dr. Pruemer and her team evaluated the effectiveness of the various pharmacologic agents used in their clinic in 102 patients. They reported that there were no statistically significant differences between the results of the newest agent, varenicline, which was used in 15 patients, and the results of bupropion with or without the nicotine

Quit

Number of Patients

patch (57 patients and eight patients, respectively), or the nicotine p a t c h a l o n e, which was used in 22 patients. “ We f o u n d that varenicline was an effective therapy for smoking cessation, with at least a 50% success rate. However, there was no statistically significant difference between varenicline, bupropion, bupropion plus the nicotine patch, or the nicotine patch alone when used in combination with pharmacist support and a behavior modification program,” Dr. Pruemer concluded. “Medications plus counseling is the more effective strategy. Both are important, but it is not just due to one magic pill.” Again, she noted that the study was not randomized and the patient groups were mixed. “We had some patients in the varenicline group who had failed other therapies before. This was more of a real-world setting, where a pharmacist is counseling a patient and using pharmacologic means to assist in the quit attempt. So there doesn’t seem to be a significant difference between what you choose; it depends on the patients. If they have contraindications to a certain drug, or if they have failed on a previous medication, you could choose to try other things.” [The FDA recently announced that it will require manufacturers of varenicline and bupropion to add new boxed warnings to the labeling for both drugs. For details on how the warnings may impact smoking cessation interventions, see an expanded version of this article at pharmacypracticenews.com.]

Not Quit

50 23

40 30

34 6

20 10

7 8

4 4

Varenicline

Bupropion

Bupropion + NTP

NTP

Dr. Pruemer said she hoped that all pharmacists, not just those specializing in oncology, will recognize the importance of assisting their patients to stop smoking. “We can have a significant impact on the present and future lives of our patients. If we are going to spend a lot of time trying to control people’s blood sugars and keep their lipids under control, and yet do nothing about their smoking, we’re not doing our job.”

Pharmacists Comment Alan J. Zillich, PharmD, from Roudebush VA Medical Center and Purdue University, West Lafayette, Ind., said that being involved in smoking cessation is rewarding, “even if we get just one patient to quit.” But, he said, it is also challenging. For example, “you do need to market your services,” noted Dr. Zillich, who has published a study documenting the positive impact of a pharmacist-run smoking cessation program (Pharmacotherapy 2002;22:759-765). “You have to get people to know about it, and to sign up for it, and some people just aren’t ready to attend, or don’t want to even if they want to quit smoking. This can be difficult for pharmacists; we’re not marketing people.” Larry Dent, PharmD, from the University of Montana, Missoula, agreed that counseling patients to quit smoking is a very worthwhile activity. As a clinical pharmacy specialist, Dr. Dent works with many different types of patients, including those who are on anticoagulants, people with diabetes and people with lipid disorders. However, helping patients quit smoking is the most rewarding. “Individuals who are able to maintain abstinence get a powerful sense of empowerment. When you see them again after quitting, they are overflowing with gratitude. It’s a great feeling.” he said. Pharmacists are perfect for the role of smoking cessation counselor, he added, because they have the medication expertise, as well as the counseling skills, to mount a successful program. As for Dr. Pruemer’s findings, Dr. Dent said: “Although this study doesn’t use gold-standard methods such as a randomized controlled design with biochemical verification, it does demonstrate that pharmacists can provide tobacco cessation and have the potential for being very effective.” Also, quit rates at three months are not quite as dependable an indication of long-term abstinence as six months or greater, Dr. Dent said. “Still, observational studies are good examples of how well pharmacists can deliver tobacco cessation.” —Fran Lowry

Figure. Quit results for therapeutic modality. NTP, nicotine transdermal patch

The “Win by Quitting” Program is supported by a grant from the Ohio Tobacco Prevention Foundation.

36 Pharmacy Heritage

Pharmacy Practice News • August 2009

How Hot Is Hot? Scoville’s test for heat of peppers marked an early success for pharmacist research apsicum fastigiatum Blume, or cayenne pepper, was an important product in the materia medica of the late 19th and early 20th centuries. Noted as a drug of choice for delirium tremens, it also found use in chronic renal congestion, debility of both the young and old and as an aphrodisiac in cases of “diminished vital action.” External uses included toothache, chilblains and ulceration of the cornea. It also was a condiment: Edmund McIlhenny began nationally marketing his famous Tabasco sauce in the early post–Civil War years. The challenge that faced pharmacist and chef alike was the level of heat produced by the pepper. Color, fat content and shape provided few clues as to just how hot the pepper might be. Chemical tests of the period could detect and measure the level of capsaicin, the crystalline principle of capsicum; however, the heat level could not be determined until pharmacist Wilbur Lincoln Scoville developed a test for heat that still is seen in grocery store pepper displays today.

At the 1912 annual meeting of the American Pharmaceutical Association (APhA), Scoville reported on his work with capsicum (JAPhA 1912;1:454-455). His short introductory comment noted the variance of heat in different species of capsicum, ranging from the paprika, a non-peppery pepper, to Tabasco. He measured relative heat through a physiologic, or organoleptic, test involving the perception of pungency or heat in the mouth. The test, a series of dilutions of capsicum in an aqueous sugar solution, was more useful than most organoleptic tests because the standard was pungency rather than taste. The lowest level of heat perceived provided the baseline for comparing one lot of pepper to another. Dilutions of one part capsicum to increasing parts aqueous solution were repeated until the tester could no longer perceive pungency.

In the Scoville Organoleptic test, bell peppers had a value of zero; the pepper has no perceivable heat. The heat of the jalapeño, largely dependent on cultivation and processing, ranges from 2,500 to 10,000 Scoville units. Habañero peppers, on the other hand,

register at 300,000 Scoville units and higher, indicating that the pepper would have to be diluted in a sweetened aqueous solution in a ratio of 1:300,000 units before the sensation of heat was imperceptible. Many pepper sprays used for self-defense contain capsaicin registering at least 5 million Scoville units.

College of Pharmacy. Earning the highest grade in his class, Scoville joined the faculty upon graduation in 1889. Fascinated with journalism, Scoville served simultaneously as the editor of both the New England Druggist and the Spatula for 10 years. He taught applied and theoretical pharmacy; his métier

Dennis B. Worthen, PhD Dennis B. Worthen, PhD, the author of “Pharmacy Heritage,” is the Lloyd Scholar at the Lloyd Library and Museum in Cincinnati. He can be reached at dbworthen@lloydlibrary.org

was pharmaceutical compounding. His text, the Art of Compounding, first published in 1895, went through six editions in his lifetime; further editions were published after his death in 1942. Generations of pharmacists were introduced to the pharmaceutical art through Scoville because U.S.

CREDIT:American Pharmacists Association Foundation Archives

Capsicum meets the debility of young and old. Capsicum is the very best agent that can be used in delirium tremens. —Kings American Dispensatory, 19th edition, 1909 colleges of pharmacy commonly used his text. In 1905, as secretary of the American Conference of Pharmaceutical Faculties (now the American Association of Colleges of Pharmacy), Scoville conducted the first survey of U.S. pharmacy schools and colleges. His findings of a lack of standardization of degrees, content and length of courses became a significant tool in the ongoing efforts to strengthen pharmacy education and regulations.

Scoville Influenced Generations of Pharmacists So, who was Scoville? His involvement with pharmacy began in 1881 when, at the of 14, he went to work at a drug store owned by E. Toucey in Bridgeport, Conn. In 1887, he moved to Boston to attend the Massachusetts

A Staunch Advocate Of Pharmacy Standards In 1907, Scoville moved to Detroit to join Parke-Davis & Company. He was a lifelong advocate of pharmaceutical standards through his work with the National Formulary and the United States Pharmacopoeia. In 1922, Scoville’s work on cinchona extraction garnered him the Ebert Prize, established by Chicago pharmacist Albert Ebert as the first national prize to recognize practi-

Wilbur Lincoln Scoville as a young man.

cal pharmacy research and publication. In acknowledging the honor, Scoville remarked that Ebert certainly would have been pleased because his research was of practical use to pharmacists. In 1924, he was nominated for presidency of APhA but requested to have his name withdrawn, explaining that his work as chairman of the National Formulary Revision Committee left no time for extra outside work. In 1929, Scoville received the Remington Honor Medal, pharmacy’s highest honor, for his distinguished service to pharmacy. Although heat is now more often measured using high-performance liquid chromatography, the pepper bins in grocery stores still are likely to show the relative heat of chili peppers by posting Scoville units—a measure of heat, as we now see, named in honor of Wilbur Lincoln Scoville, pharmacist.

More Pharmacy Heritage To Come Here are a few topics slated for future columns: • “Lest We Forget.” Documenting the lives of pharmacists and pharmacy students who were killed in action during World War II. • “Pinkhams, Puruna, and Swamp-Root.” These were three of the most popular home remedies at the beginning of the 20th century and had enough alcohol to guarantee a happy happy hour. • “Mutual Insurance for the Pharmacy.” The story of the birth of pharmacists’ insurance when other companies refused to provide such coverage. • “From Mustard Plasters to Band-aids.” The genesis of pharmaceutical plasters of old to today’s bandages, with a look at the beginnings of Johnson & Johnson.

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Policy 39

Pharmacy Practice News • August 2009

Medication safety

FDA To Study Anesthesia Risks in Pediatrics C

oncerned about the potential risk to young children of exposure to general anesthesia, the FDA has launched an initiative, called SAFEKIDS, to study the effects of these agents on the developing brain. The agency has partnered with five anesthesiology groups and universities on the project, known formally as Safety of Key Inhaled and Intravenous Drugs in Pediatrics: the International Anesthesia Research Society (IARS), Children’s Hospital Boston of Harvard University, Mayo Clinic, Columbia University and the Arkansas Children’s Hospital Research Institute. Investigators at these sites will lead studies—from epidemiologic analyses to randomized controlled trials in humans—of the effects of anesthetic agents on young children. Although the FDA will provide some money for the studies, officials hope to enlist the help of private foundations and other wealthy donors to come up with most of what they estimate will be hundreds of millions of dollars needed to pay for the research. “This is such a critical international public health issue, I can’t imagine we won’t find the funds we need from private sources,” said Bob Rappaport, MD, director of the Division of Anesthesia, Analgesia and Rheumatology Products at the FDA Center for Drug Evaluation and Research, in Rockville, Md., who is overseeing the program for the agency. Depending on what information emerges from SAFEKIDS, regulators could ask drug companies to modify the labels on certain anesthetics—such as volatile compounds—to warn about the cognitive risk to young patients, Dr. Rappaport said. The findings also could spur pharmaceutical firms to develop “better products,” or agents that counteract the brain effects of anesthetics, should such effects be proven to exist, he said. Studies in animals have suggested that volatile anesthetics may be harmful to neurons in the brain. No data in humans have directly demonstrated such a link. However, several recent studies have hinted at a connection between exposure to anesthesia in early childhood and cognitive and behavioral problems in later life. In a retrospective study published in the April issue of Anesthesiology, for example, Mayo Clinic researchers reported an association between repeated, although not single, exposures to anesthesia before age 4 and subsequent development of learning disabilities. The researchers found that two exposures to anesthetics before age 4 raised by 50% the likelihood of being identified as having learning disabilities—in reading, writing and math—by age 19.

Three or more exposures raised the risk for learning problems 2.6-fold. Exposure times under two hours did not appear to be linked to learning difficulties, the researchers said. That makes sense in light of new evidence in animals, particularly primates, said Randall Flick, MD, chair of pediatric anesthesia at Mayo Clinic in Rochester, Minn., and a co-author of the study. “The increasing animal data suggests that the exposure times have to be longer than

we thought before, and that the children have to be younger,” Dr. Flick said. “The more data we gather, the more refined the question becomes.” Until more data become available, however, anesthesiologists will have to deal with a groundswell of public anxiety about the risks of anesthesia in children— fueled by coverage of the issue in the popular press, said Gregory Crosby, MD, president-elect of the Society of Neurosurgical Anesthesia and Critical Care.

“I think studying outcomes is the right thing to do, but I’m amazed, frankly, at how quickly this thing caught on fire. It’s consuming people,” said Dr. Crosby, associate professor of anesthesia at Brigham and Women’s Hospital and Harvard Medical School, in Boston. “After all, what we have is a smoking gun but no victim. In the setting of surgical illness, clinical outcome studies will be hard-pressed to assign any adverse effect to anesthesia itself. Also, given the incredible plasticity and capacity for recovery of the developing brain, I’m a little concerned that

•

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40 Policy

Pharmacy Practice News • August 2009

Reimbursement

DRUG PRICING continued from page 1

“If the payment rates are set artificially low—which they may be if too many hospitals fail to maintain their charge master—everyone suffers,” Ms. Pierce told Pharmacy Practice News. “So there are compelling reasons why hospitals should scrutinize and update their hospital pharmacy charge masters at frequent intervals—especially when you consider the growth of high-cost drug products such as biologics.” The study was based on a self-reporting questionnaire that was sent to the directors of pharmacy and chief financial officers at 4,000 U.S. hospitals. A total of 48 states were included in the survey (rural 72%, urban 28%; beds: <100 52%, 100-300 30%, >300 18%). Participation was voluntary and no payments were offered for completing the survey.

Wide Variation Seen The frequency of reviewing and changing line-item drug products varied considerably, noted Ms. Pierce, a partner in The Resource Group, a reimbursement consulting firm based in Richfield, Ohio. Some of the respondents reported updating the products continually, in “real time,” when manufacturers and distributors announce drug price changes. In contrast, “some of the respondents said they only looked at pricing information in their hospital charge master data once a year,” she said. “And in more than 15% of cases, the respondents said the methodology used to develop the charge master had not been reviewed or changed in more than five years.” Ms. Pierce acknowledged several limitations to the study, which was included in a poster session at the ASHP Summer Meeting. The findings, for example, were based on only 356 returned surveys. “So from a power calculation standpoint, the sample size is too low for these results to be generalizable,” she said. Additionally, the survey is a self-reporting instrument, “so there’s always the potential for bias—that people’s perceptions come through, rather than objective data.” But Ms. Pierce stressed that the results “do provide a snapshot of what’s happening in hospitals of varying sizes across the United States, and what it suggests is that many facilities may not be paying enough attention to keeping their charge masters up to date.”

Why the Oversight? Asked to explain the lax updating, Ms. Pierce replied, “I don’t think it’s a lack of awareness.” Instead, she cited several factors, particularly the challenge of managing today’s business

‘There are compelling reasons why hospitals should scrutinize and update their hospital pharmacy charge masters at frequent intervals—especially when you consider the growth of high-cost drug products such as biologics.’ —Christine A. Pierce

A Master Class in Charge Masters Rob Adamson, PharmD, recently began a review of the hospital charge master at Saint Barnabas Health Care System and offers the following lessons learned thus far: Get focused. Trying to analyze the charge master for the hospital’s entire lineup of drugs can be overwhelming. Instead, Dr. Adamson suggested focusing on the top 20 to 50 drugs, ranked by dollars. “We looked at our top 50, and it told us what we needed to know about our pricing problems and where efforts to fix them could yield the maximum savings,” he said. Develop talent internally. In some cases, it may be costeffective to hire an outside consultant to review the charge master. But having a full-time equivalent (FTE) pharmacist take ownership of the process could be a better alternative, especially for larger health systems. “Our FTE now works with our systems business office, and we’ve found that we can solve rejected claims and pricing problems much faster now that we have someone with both clinical and reimbursement acumen reviewing the process,” Dr. Adamson said.

Don’t forget about overbilling. Ceftriaxone (Rocephin; Roche) is a case in point: when the drug went generic, the price per gram fell from approximately $20 to $4-$5. “Do you know if you went back into your charge master to change the price when that happened?” Dr. Adamson asked. “If you didn’t, you’re overcharging patients nearly 10-fold.” Aside from being an unnecessary cost burden on patients and insurers, “it’s also potentially fraudulent,” he said. “Some contracts state that you can only charge two to three times your drug acquisition cost. If you go beyond that, you are in violation of that contract, and there could be legal ramifications.” Remember to use multipliers. Although the right code might be listed for a drug, and even the right per-unit cost, the hospital still might be underpaid. For example, darbepoetin alfa (Aranesp; Amgen) is billed in 1-mcg increments, but often is administered in 100-mcg doses. “To get full reimbursement, you need to put in 100 of those charge codes,” Dr. Adamson said. “If you don’t multiply it, you will only get paid 1/100th of what you are owed. At about $500 AWP per treatment cycle, that adds up very quickly.” —David Bronstein

while balancing the long-term implications of untimely pricing updates. “Hospitals are scampering to deal with what’s immediately in front of them, especially in this ongoing economic downturn,” she said. As a result, “it just may be too much” to expect hospitals to constantly be thinking about what they do today impacting their reimbursement in the future. Under CMS rate-setting methodology, Ms. Pierce noted, cost reports from today will be used to determine reimbursement rates two years later. “In hospital-think,” she said, “that two-year time frame is infinity—it’s too far away from what they have to deal with today to survive, whether it be crushing loads of charity care, lost endowments, regulatory and accreditation reviews, a tough new technology rollout, and so on.”

Understanding the Problem Ms. Pierce listed several steps hospitals can take to ensure that their pharmacy charge master is updated consistently. The first step is to have all stakeholders understand why that process is such an important undertaking for maintaining fiscal health. “Hospital finance, pharmacy and clinical departments must work synergistically so that updates are not missed,” she said. “If your charges are understated on the charge master, that flows to your cost report into a category called drugs charged to patients, which provides an aggregate snapshot of hospital drug charges. So when Medicare goes to set [national] reimbursement rates and it looks at your data, it is starting with a flawed baseline. Coupled with other hospitals that don’t update regularly, over time, that is going to give Medicare the impression that the products and services you rendered cost you less than they actually did.” Hospitals already are under intense financial pressure, she added, “but you don’t need to add to that with flawed charging practices.”

Fixing the Problem Hospitals that want to improve their charge master updating should follow the lead of facilities that excel at the process, Ms. Pierce noted; one common strategy “is the wisdom to get someone at a very senior level to take ownership of this [process].” Increasingly, Ms. Pierce said, positions such as vice president or senior vice president of the revenue cycle are being created to tackle the hospital charge master as an essential aspect of reimbursement accuracy. Such an approach is important, she added, because the charge master “is just one cog in the wheel of the entire revenue cycle. So

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42 Policy

Pharmacy Practice News • August 2009

Reimbursement

DRUG PRICING continued from page 40

appointing someone in a leadership position in finance is crucial to pulling this off.” The next step is to team up the finance person with a colleague in pharmacy who can take ownership of the pharmacy-specific aspects of the charge master. This commonly, she said, is the pharmacy director, who typically has both the clinical and business acumen to understand the spectrum of drug costs, handling and what needs to be done to

‘The charge master is where the rubber meets the road. I can get a great contract price for a drug, but if I’m not tracking price updates and entering them into the charge master on a regular basis, those savings can go out the window.’ —Rob Adamson, PharmD ensure adequate payment rates. “When new drug payment rates and coding are released,” Ms. Pierce explained, “the pharmacy director is

usually in an ideal position to bring that new information to the attention of the vice president of revenue cycle or a similar position within finance,

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.

and then have the team determine how the information will impact charging strategy going forward.”

A Not Uncommon Failing Rob Adamson, PharmD, corporate vice president of clinical services, Saint Barnabas Health Care System, West Orange, N.J., said he was not surprised that 15% of respondents to Ms. Pierce’s survey failed to upgrade their hospital charge masters. “Most pharmacy departments do a great job negotiating contracts with

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see DRUG PRICING, page 45

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.

Technology 43

Pharmacy Practice News • August 2009

E-Prescribing

CPOE in Ambulatory Setting Comes With Growing Pains Miami–Pharmacists thinking of starting computerized physician order entry (CPOE)—a system that allows direct entry of medical orders by a physician, pharmacist, nurse or any person with the licensure and privileges to do so—in an ambulatory oncology infusion setting should know that although it is definitely doable, it also can be a challenge to implement. “As with anything new, there is a learning curve associated with setting up a

computerized physician order entry system in the outpatient oncology department,” Joseph Barletti, PharmD, told Pharmacy Practice News at his poster at the 5th annual conference of the Hematology/Oncology Pharmacy Association. Dr. Barletti is the ambulatory oncology manager at Montefiore Medical Center, Einstein Division, in New York City. The medical center has had a CPOE system in place for approximately 10 years; the only part of the hospital that was not

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

using the system was ambulatory oncology, he explained. Deciding that the time was right to implement CPOE in their outpatient clinic, Montefiore pharmacists, nurses, physicians and information technology staff got together to build the system, which went live in May 2008. The purpose of the poster presentation, Dr. Barletti said, was to share some of their experiences with fellow pharmacists who may be contemplating doing some-

thing similar at their institutions. Dr. Barletti and his colleagues did a retrospective chart review of 67 patients to determine if the CPOE process duplicated the efficiency of the former paper process. “In the past, we would get paper orders from the physicians and we would then enter the orders ourselves into the electronic system. That doesn’t take a lot of time, but still you can shave off that time. Plus you don’t have to worry about

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)

figuring out a physician’s handwriting. That could be a problem even with our regular prescriptions. The next time you get a prescription from your doctor, take a look at it and see if you can make out what it says,” Dr. Barletti said.

A Host of Problems Uncovered The review, which covered the first three months of experience with the CPOE system after all users had become familiar with it, identified several overall problems that could reduce the effectiveness of the e-prescribing tool: • incorrect/omitted demographic information • incorrect/omitted dosing information • nonadherence to institutional cosignature policy • orders entered under wrong patient accounts

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see CPOE, page 44

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Want to share your own lessons learned from CPOE rollouts? Send comments to

ppneditor@mcmahonmed.com

44 Technology

Pharmacy Practice News • August 2009

Informatics

Anticoagulation Made Easier Via Tracking Software A nticoagulation therapy is risky business. Just how risky became common knowledge in November 2007, amidst widespread media reports that the newborn twins of actor Dennis Quaid had accidentally been given 1,000-fold overdoses of heparin at a Los Angeles hospital. (They survived.) But blood clots, uncontrolled bleeding and other potentially lethal problems associated with blood thinners may become largely things of the past if computerized patient-safety surveillance tools live up to their early promise. “Anticoagulation therapy has a narrow therapeutic window,” said John Poikonen, PharmD, clinical informatics director at UMass Memorial Medical Center in Worcester. “Getting it right requires initial and ongoing expertise and close monitoring, and information tools to alert and guide the dosing and monitoring of anticoagulants can be extremely valuable.” Numerous studies have demonstrated the benefits of such tools, which automate the tracking of patients on blood thinners and warn hospital workers of impending hazards while there is still time to prevent them. (See “Electronic Alerts to Prevent Venous Thromboembolism among Hospitalized Patients,” N Engl J Med 2005;352:969-977.) In light of this research—and in an effort to meet stringent anticoagulation safety guidelines put into effect last Jan. 1 by the Joint Commission—a growing number of hospitals have begun implementing these tools. Among the first to do so is the University of Pittsburgh Medical Center (UPMC), which started using TheraDoc Anticoagulation Alerts last May. This software

package compares patient laboratory values and pharmacy records to data streams from radiology, microbiology and other hospital departments and then sends anticoagulation-related updates and alerts to hospital staff. It was developed by the Salt Lake City–based medical informatics company TheraDoc (www.theradoc. com) and piggybacks on the firm’s existing expert system platform. (UPMC is an investor in the company as well as an early adopter of its products.)

UPMC pharmacists say the TheraDoc software has generated hundreds of alerts about potential bleeding events and other problems that required patient interventions. “TheraDoc has become the backbone of our anticoagulation program to help us quickly catch and document potential adverse events, tests that need to be ordered, or lab values that are too high or too low,” said Susan Skledar, RPh, MPH, director of UPMC’s Drug Use and Disease State Management Program. “It’s quick and efficient, and it lets you know in real time when something needs to be looked at. Rather than looking through five or six paper reports, it provides a single integrated system for alerting us when a patient’s medication may need to be adjusted.” The software comes preprogrammed with 34 different anticoagulation alerts, including ones that point out out-ofrange international normalized ratio values, potential drug interactions and patients who are new to anticoagulant therapy (and who are thus candidates

for the patient education mandated by the Joint Commission goals). Hospitals can customize the system to meet their needs, activating some alerts and turning off others. Additionally, the system can be configured to work smoothly with a variety of workflow patterns—for example, firing off real-time pager or e-mail alerts in hospitals with rounding pharmacists or sending out once-daily reports in hospitals where pharmacists play a more centralized clinical role. According to Ms. Skledar, the system’s key benefit is its adaptability. “You can

match it to whatever pharmacy practice model you have,” she said. By the end of the year, TheraDoc will begin selling a more robust anticoagulation alert product, Anticoagulation Assistant Module. The company said it will incorporate an expanded set of alerts, clinical care dashboards and intervention documentation and compliance reporting tools designed to streamline communication among caregivers, improve clinical workflow and enhance clinical decision making and patient safety. —David W. Freeman

CPOE

“We found out that some of the attending physicians weren’t co-signing their orders electronically in a timely fashion, so we could not go ahead [with administering the chemotherapy] until that was done. This would mean that the patient would have to wait longer in the chair, so a one-hour infusion would turn into a two-hour infusion because we had to wait for the attending to co-sign the order,” Dr. Barletti said. Another issue was the failure to enter dosage ranges. “Most drugs are dosed by body surface area, which includes height and weight. We would get the order and we would just see the total dose of drug for the patient but we wouldn’t see the dosage range. So it would take us longer to figure out the dose that the physician actually wanted and what he or she was basing it on,” he said. There also were instances where the nurses were not charting certain drugs, or did not document that they had completed the infusion. “For instance, a patient came in on June 1 for infusion.

The nurse would chart that but would forget to document that it had finished, so when you go back on July 14, you look in the computer and the drug is still infusing,” Dr. Barletti said. At least one success became apparent during the chart review process—the use of pharmacist-created drug “order sets” for the most common chemotherapy regimens. “When chemotherapy is given, it’s never usually just one drug; it’s typically two, three or four drugs, and these are all given at specific times, so we made up these order sets to make it as easy as possible for the physicians to enter the drugs,” Dr. Barletti said. “We had regimens under various icons for breast, lung, colon and so on,” he explained. “This development had a positive impact on CPOE implementation.” He concluded that implementation and maintenance of CPOE is an ongoing process and it is imperative that the institution allow enough time and resources— both financial and human—for training.

“In our poster, we just wanted to share our experience. These are issues that other pharmacists who are considering a similar entry system will come up against,” Dr. Barletti said. Royston Browne, PharmD, and Pragna Patel, PharmD, were co-authors of the CPOE poster. Asked to comment on the findings, Valerie Moussou, PharmD, an oncology pharmacist at Kaiser Permanente—Ventura, Calif., said that adding CPOE in oncology care areas “is definitely the way to go. If the process is user-friendly, it can greatly help in reducing dosing errors, alerting practitioners of things that should be followed or checked on before ordering chemotherapy and providing a template for treatment. It increases patient safety and can be more efficient.” Dr. Moussou said Kaiser is in the process of rolling out CPOE in the oncology departments of several sites in southern and northern Califormia.

continued from page 43

• incorrect/incomplete electronic nursing documentation Additionally, several problems were uncovered that were specific to the 67 patient charts reviewed: • 2% of the charts had no orders entered • 20% had incorrectly entered orders • 8% omitted entry of demographic information • 19% had incorrect dosing information • 15% had the wrong dose calculated • 4% had incorrect diluents or quantity of diluents • 10% had incorrect or omitted dose rate of infusion • 12% had orders not co-signed by a physician • 2% had orders that were entered in the incorrect account • 2% had incorrect documentation by the RN • 6% had no documentation of dose administration by RN

Hundreds of Alerts Generated TheraDoc software analyzes patient laboratory values and pharmacy records to send anticoagulation-related alerts to hospital staff.

‘Getting [anticoagulation] right requires initial and ongoing expertise and close monitoring, and information tools to [guide practitioners] can be extremely invaluable.’ —John Poikonen, PharmD

—Fran Lowry

Policy 45

Pharmacy Practice News • August 2009

Reimbursement

DRUG PRICING continued from page 42

manufacturers and insurers and in general holding drug costs down as much as possible,” Dr. Adamson said. “But the charge master is where the rubber meets the road. I can get a great contract price for a drug, but if I’m not tracking price updates and entering them into the charge master on a regular basis, those savings can go out the window.” Saint Barnabas is certainly not immune to the oversight. After more than a year of not tracking its hospital charge mas-

“The lesson we learned,” he said, “is that it’s not just about the charge master—there are other pieces to the reimbursement puzzle that have to be in place.” Accurate charging is all the more

ter on a regular basis, Dr. Adamson said, the institution found several problems, including wrong reimbursement codes for drugs, out-of-date drug prices and a lack of dose “multipliers” that result in underbilling (sidebar, page 42).

important because of the growth of high-ticket pharmaceuticals. “Very few drugs come to market at anywhere near the pricing structure of five to eight years ago,” Dr. Adamson said. “Biologics are a case in point; these treatments can cost hundreds of thousands of dollars per patient per year, and they’re the fastest growing line of the business. You can’t afford to not get this right.” —David Bronstein Ms. Pierce’s poster study was funded by Centocor Ortho Biotech Services, LLC.

Medication safety

ANESTHESIA RISKS continued from page 39

the hype is overblown and that patients, parents and physicians will get scared unnecessarily.”

N O W A VA I L A B L E F

Hearing Triggered Program The possible tie between general anesthesia and cognitive damage has been suggested for more than a decade, starting with a seminal 1999 study in Science showing that rat pups exposed to N-methyl-d-aspartate (NMDA) antagonists produced neuronal cell death through apoptosis. Those findings prompted the FDA to form an expert working group and to sponsor studies to evaluate the potential neurotoxic effects of NMDA antagonists, such as ketamine, on the developing brain. In March 2007, the FDA’s Anesthesia and Life-Support Drugs advisory committee held the first official and public inquiry into the relationship, which, if proved, has enormous consequences for patients and clinicians alike. SAFEKIDS, which grew out of that hearing, initially was supported by $1.5 million from unspent Congressional appropriations, Dr. Rappaport said. Because the government cannot solicit funding, the FDA will leave that step to other members of the group. Fundraising should begin in earnest over the next six to 12 months, he said. In the meantime, the search is on for members of both scientific and governance committees, as well as for a prominent figurehead who can assist in attracting large donations to the effort. The FDA last August notified anesthesia researchers that it would be organizing four projects related to SAFEKIDS. These included finding an administrative partner for the initiative, which turned out to be IARS; and funding several studies, with grants of up to $308,000, on the long-term neurotoxicity of anesthetics, the pharmacodynamics and pharmacokinetics of these drugs and animal research into the issue. Michael K. Cahalan, MD, chair of anesthesiology at the University of Utah

•

Enlon

(edrophonium chloride injection, USP)

Enlon-Plus

(edrophonium chloride, USP & atropine sulfate, USP) Injection

PLAC E AN OR DER TO DAY. Enlon

NDC Number

Description

AmerisourceBergen

Cardinal

McKesson

67457-190 -15

10 mg/mL, 15 mL Vial

368878

4119566

1853506

67457-191-15

10 mg/mL edrophonium Cl, 0.14 mg/mL atropine sulfate 15 mL Vial

367797

4119582

1878313

67457-192- 05

10 mg/mL edrophonium Cl, 0.14 mg/mL atropine sulfate 5 mL Ampul

367342

4119590

1860527

Enlon-Plus

see ANESTHESIA RISKS, page 46

46 Policy

Pharmacy Practice News • August 2009

Pediatrics

ANESTHESIA RISKS continued from page 45

School of Medicine, in Salt Lake City, and the IARS liaison to SAFEKIDS, said the FDA chose his society as a partner for its international membership and its “apolitical” nature. IARS will be primarily responsible for raising the money for SAFEKIDS and for distributing the funds “based on the priorities of the [project’s] scientific advisory board,” Dr. Cahalan said. The society is not planning to raise the dues of its 15,000 members to pay for the research, he added. Tom Cooper, executive director of IARS, said the group has received $99,000 from FDA and has committed $50,000 of its own resources for the first 18 months of the project. The research group does not have a total budget in mind, however. “IARS is making a longterm commitment to the success of the SAFEKIDS initiative,” Mr. Cooper said. Given the shaky economy, Dr. Cahalan acknowledged, SAFEKIDS may be forced to do more with less. “It’s a tough time to raise money. There are lots of other good causes.” The FDA has been working with Mayo Clinic investigators on a follow-up to the recently published research. Dr. Flick said the second Minnesota study will be a matched-cohort design in which each child exposed to anesthesia before his or her second birthday will be matched with two others who did not undergo surgery. The study will be completed by mid-summer, he said, with data ready for publication in the fall. Compounding the issue, Dr. Flick said, will be trying to tease apart the effects of anesthesia from those of surgery itself. “We never do surgery without anesthesia and we rarely do anesthesia without surgery. To be able to differentiate those two things is likely to be very difficult.” In an attempt to address that problem, the FDA is collaborating with Harvard researchers on the GAS trial, a randomized controlled comparison of the effects on cognitive development of general and regional anesthesia. Investigators in the multicenter GAS study, which aims to enroll 660 healthy newborns undergoing inguinal hernia repair (some with circumcision), will test participants for neurodevelopment at age 2 and for intelligence at age 5. Mary Ellen McCann, MD, MPH, assistant professor of anesthesia at Harvard Medical School and at Children’s Hospital Boston, said the prospective nature of GAS makes it stronger than previous efforts to assess the effects of anesthesia on early childhood development. A weakness, however, is the relatively short duration of anesthesia—no more than two hours. “It won’t answer the question of how prolonged anesthesia affects young

The researchers found that two exposures to anesthetics before age 4 raised by 50% the likelihood of being identified as having learning disabilities—in reading, writing and math—by age 19. children,” Dr. McCann said. Although several other hospitals in the United States have expressed interest in joining the study, so far only Children’s Hospital Boston has begun enrolling patients in this country, as have institutions in Australia, Italy, Canada and the United Kingdom. Every child in GAS will receive a standardized anesthetic. For general, the protocol is sevoflurane, air and oxygen, with the possible addition of a caudal anesthetic or field block. Patients may be given a neuromuscular blocker but do not receive opioids during the case, although they may receive them or other drugs in the PACU. For regional, the protocol is caudal or spinal anesthetic or both, continuous bupivacaine, or a regional block with bupivacaine. Whatever the choice, the total dose administered should not exceed 2.5 mg/kg. Researchers already have begun the developmental testing on the first cohort of children enrolled in GAS. “The study will continue unless it is determined partway through the trial that one anesthetic is preferable to another,” Dr. McCann said. “Our hypothesis is that both types lead to equivalent outcomes.” Dr. McCann said she would be “surprised” to find a difference between anesthetic regimens and developmental outcomes. “It’s a remote possibility, and that is why we are doing the study,” she said. “If both types of anesthesia prove to be the same in terms of development, then we can reassure parents that short general anesthetics are safe for even very young children.” Dr. Cahalan said even a randomized trial comparing general with regional anesthesia was unlikely to control adequately for all the variables in the surgical experience. “Imagine that it’s not just an effect of anesthesia but a combination of certain amounts of stress and agents” that leads to brain damage, he said. “Just testing regional versus gen-

eral will not be able to show that.” What’s more, regional anesthesia typically is not used by itself for the surgical procedures that are most common in neonates and young children, Dr. Cahalan said. “It’s pretty hard to give a child just a regional anesthetic alone for the kinds of surgery infants receive.”

A Decade Later, More Questions Than Answers Even before the announcement of SAFEKIDS and the release of the latest data on learning disabilities, many anesthesiologists had been advising parents to postpone elective surgeries in very young children. But that precaution is not necessarily the safest step. Although delaying some surgeries might make sense, Dr. Flick said, for others, such as myringotomy to open ear tubes, waiting even a few months could be more harmful to the acquisition of language skills than any possible damage anesthesia might cause. “We have to be careful of the unintended consequences,” he said. Experts generally agree that the populations considered to be at highest risk for anesthesia-related cognitive problems are developing neonates and elderly patients. In addition to the latest Mayo Clinic data, recent observational studies presented at the 2008 annual meeting of the American Society of Anesthesiologists found hints of a problem. One study found that children undergoing hernia repair were twice as likely as those who had no surgeries to end up with diagnoses of developmental and behavioral disorders. In another, Dutch children who underwent urologic procedures showed a trend linking anesthesia exposure to cognitive problems. Animal data indicate that anesthetics may affect brain cells in three ways, said Dr. Crosby, who has studied the issue extensively in the elderly. The drugs may disrupt the proper formation of synapses in developing neurons, which could

explain the learning problems observed in young rodents exposed to general anesthesia. Anesthetic agents also have been shown to induce programmed cell death in neurons, another possible driver of stunted learning. The studies to date confirm that NMDA antagonists and GABAergic agents induce neuroapoptosis in developing rodent and primate brains. Some evidence also has linked exposure to general anesthesia with potentially deleterious changes in the brain protein amyloid-β, thus implicating anesthetics in either the development or acceleration of Alzheimer’s disease. These studies, performed mainly in cell culture, have found that certain general anesthetics promote particularly “sticky” amyloid-β molecules and increase production of the substance. To Dr. Crosby, the studies make a fairly compelling case. “In my heart, I believe that general anesthetics can harm the brain if you are very young or old; but if this effect exists, it’s going to be quite subtle,” he said. “It’s quite possible that it could have been missed for decades or a century, and that unless you go looking for it, you’re not going to see it. But we shouldn’t be too quick to take the blame—illness and surgery aren’t nontoxic either.” —Adam Marcus

Suggested Reading Culley DJ, Baxter M, Yukhananov R, Crosby G. The memory effects of general anesthesia persist for weeks in young and aged rats. Anesth Analg. 2003;96:1004-1009. Culley DJ, Yukhananov RY, Baxter MG, Crosby G. Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats. Anesthesiology. 2004;100:309-314. Eckenhoff RG, Johansson JS, Wei H, et al. Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. Anesthesiology. 2004;101:703-709. Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science. 1999;283:70-74. Jevtovic-Todorovic V et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876-882. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg. 2007;104:509-520. Planel E, Richter KE, Nolan CE, et al. Anesthesia leads to tau hyperphosphorylation through inhibition of phosphatase activity by hypothermia. J Neurosci. 2007;27:3090-3097. Wilder R, Flick R, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a populationbased cohort. Anesthesiology. 2009;110. E-pub ahead of print. Xie Z, Dong Y, Maeda U, et al. The common inhalation anesthetic isoflurane induces apoptosis and increases amyloid beta protein levels. Anesthesiology. 2006;104:988-994. Xie Z, Dong Y, Maeda U, et al. The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and Aβ accumulation. J Neurosci. 2007;27:1247-1254.

Midazolam Hydrochloride Injection CIV Brief Summary See package insert for full prescribing information Adult and Pediatric Intravenous midazolam HCl has been associated with respiratory depression and respiratory arrest, especially when used for sedation in noncritical care settings. In some cases, where this was not recognized promptly and treated effectively, death or hypoxic encephalopathy has resulted. Intravenous midazolam HCl should be used only in hospital or ambulatory care settings, including physicians’ and dental offices, that provide for continuous monitoring of respiratory and cardiac function, i.e., pulse oximetry. Immediate availability of resuscitative drugs and age- and sizeappropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured. (See WARNINGS.) For deeply sedated pediatric patients, a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. The initial intravenous dose for sedation in adult patients may be as little as 1 mg, but should not exceed 2.5 mg in a normal healthy adult. Lower doses are necessary for older (over 60 years) or debilitated patients and in patients receiving concomitant narcotics or other central nervous system (CNS) depressants. The initial dose and all subsequent doses should always be titrated slowly; administer over at least 2 minutes and allow an additional 2 or more minutes to fully evaluate the sedative effect. The use of the 1 mg/mL formulation or dilution of the 1 mg/mL or 5 mg/mL formulation is recommended to facilitate slower injection. Doses of sedative medications in pediatric patients must be calculated on a mg/kg basis, and initial doses and all subsequent doses should always be titrated slowly. The initial pediatric dose of midazolam for sedation/anxiolysis/amnesia is age, procedure and route dependent (see DOSAGE AND ADMINISTRATION in full prescribing information). Neonates Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid IV administration, particularly with concomitant use of fentanyl (see DOSAGE AND ADMINISTRATION in full prescribing information). INDICATIONS AND USAGE Midazolam HCl Injection is indicated: intramuscularly or intravenously for preoperative sedation/anxiolysis/amnesia; intravenously as an agent for sedation/anxiolysis/amnesia prior to or during diagnostic, therapeutic or endoscopic procedures, such as bronchoscopy, gastroscopy, cystoscopy, coronary angiography, cardiac catheterization, oncology procedures, radiologic procedures, suture of lacerations and other procedures either alone or in combination with other CNS depressants; intravenously for induction of general anesthesia, before administration of other anesthetic agents. With the use of narcotic premedication, induction of anesthesia can be attained within a relatively narrow dose range and in a short period of time. Intravenous midazolam can also be used as a component of intravenous supplementation of nitrous oxide and oxygen (balanced anesthesia); continuous intravenous infusion for sedation of intubated and mechanically ventilated patients as a component of anesthesia or during treatment in a critical care setting. Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours (see CLINICAL PHARMACOLOGY in full prescribing information). CONTRAINDICATIONS Injectable midazolam is contraindicated in patients with a known hypersensitivity to the drug. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with openangle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction with midazolam; patients with glaucoma have not been studied. Midazolam HCl Injection is not intended for intrathecal or epidural administration due to the presence of the preservative benzyl alcohol in the dosage form. WARNINGS Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression. Prior to the intravenous administration of midazolam in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured. Patients should be continuously monitored with some means of detection for early signs of hypoventilation, airway obstruction, or apnea, i.e., pulse oximetry. Hypoventilation, airway obstruction and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. Because intravenous midazolam depresses respiration (see CLINICAL PHARMACOLOGY in full prescribing information) and because opioid agonists and other sedatives can add to this depression, midazolam should be administered as an induction agent only by a person trained in general anesthesia and should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway and supporting ventilation. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population. See DOSAGE AND ADMINISTRATION in full prescribing information. Serious cardiorespiratory adverse events have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations particularly in adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with a narcotic. Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. These reactions may be due to inadequate or excessive dosing or improper administration of midazolam; however, consideration should be given to the possibility of cerebral hypoxia or true paradoxical reactions. Should such reactions occur, the response to each dose of midazolam and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric patients. Concomitant use of barbiturates, alcohol or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation or apnea and may contribute to profound and/or prolonged drug effect. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation. Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. Adult or pediatric patients with COPD are unusually sensitive to the respiratory depressant effect of midazolam. Pediatric and adult patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Adult and pediatric patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly (see CLINICAL PHARMACOLOGY in full prescribing information). Because elderly patients frequently have inefficient function of one or more organ systems, and because dosage requirements have been shown to decrease with age, reduced initial dosage of midazolam is recommended, and the possibility of profound and/or prolonged effect should be considered. Injectable midazolam should not be administered to adult or pediatric patients in shock or coma, or in acute alcohol intoxication with depression of vital signs. Particular care should be exercised in the use of intravenous midazolam in adult or pediatric patients with uncompensated acute illnesses, such as severe fluid or electrolyte disturbances. There have been limited reports of intra-arterial injection of midazolam hydrochloride. Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. Precautions against unintended intra-arterial injection should be taken. Extravasation should also be avoided. The safety and efficacy of midazolam following nonintravenous and nonintramuscular routes of administration have not been established. Midazolam should only be administered intramuscularly or intravenously. The decision as to when patients who have received injectable midazolam, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam (see CLINICAL PHARMACOLOGY in full prescribing information) cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. For pediatric patients, particular care should be taken to assure safe ambulation. Usage in Pregnancy An increased risk of congenital malformations associated with the use of benzodiazepine drugs (diazepam and chlordiazepoxide) has been suggested in several studies. If this drug is used during pregnancy, the patient should be apprised of the potential hazard to the fetus. Withdrawal symptoms of the barbiturate type have occurred after the discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE section).

Usage in Preterm Infants and Neonates Rapid injection should be avoided in the neonatal population. Midazolam administered rapidly as an intravenous injection (less than 2 minutes) has been associated with severe hypotension in neonates, particularly when the patient has also received fentanyl. Likewise, severe hypotension has been observed in neonates receiving a continuous infusion of midazolam who then receive a rapid intravenous injection of fentanyl. Seizures have been reported in several neonates following rapid intravenous administration. The neonate also has reduced and/or immature organ function and is also vulnerable to profound and/or prolonged respiratory effects of midazolam. Exposure to excessive amounts of benzyl alcohol has been associated with toxicity (hypotension, metabolic acidosis), particularly in neonates, and an increased incidence of kernicterus, particularly in small preterm infants. There have been rare reports of deaths, primarily in preterm infants, associated with exposure to excessive amounts of benzyl alcohol. The amount of benzyl alcohol from medications is usually considered negligible compared to that received in flush solutions containing benzyl alcohol. Administration of high dosages of medications (including midazolam hydrochloride) containing this preservative must take into account the total amount of benzyl alcohol administered. The recommended dosage range of midazolam for preterm and term infants includes amounts of benzyl alcohol well below that associated with toxicity; however, the amount of benzyl alcohol at which toxicity may occur is not known. If the patient requires more than the recommended dosages or other medications containing this preservative, the practitioner must consider the daily metabolic load of benzyl alcohol from these combined sources. PRECAUTIONS General Intravenous doses of midazolam should be decreased for elderly and for debilitated patients (see WARNINGS above and DOSAGE AND ADMINISTRATION in full prescribing information). These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Midazolam does not protect against the increase in intracranial pressure or against the heart rate rise and/or blood pressure rise associated with endotracheal intubation under light general anesthesia. Use with Other CNS Depressants The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient and the use of concomitant medications capable of depressing the CNS. Anticipated effects range from mild sedation to deep levels of sedation virtually equivalent to a state of general anesthesia where the patient may require external support of vital functions. Care must be taken to individualize and carefully titrate the dose of midazolam to the patient’s underlying medical/surgical conditions, administer to the desired effect being certain to wait an adequate time for peak CNS effects of both midazolam and concomitant medications, and have the personnel and size-appropriate equipment and facilities available for monitoring and intervention (see BOX WARNING, WARNINGS above and DOSAGE AND ADMINISTRATION section in full prescribing information.) Practitioners administering midazolam must have the skills necessary to manage reasonably foreseeable adverse effects, particularly skills in airway management. For information regarding withdrawal, see DRUG ABUSE AND DEPENDENCE section. Drug Interactions The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly narcotics (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION in full prescribing information). Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole. These drug interactions may result in prolonged sedation due to a decrease in plasma clearance of midazolam. For additional drug interaction information, refer to full prescribing information. Pregnancy Teratogenic Effects – Pregnancy Category D (see WARNINGS) Labor and Delivery In humans, measurable levels of midazolam were found in maternal venous serum, umbilical venous and arterial serum and amniotic fluid, indicating placental transfer of the drug. Following intramuscular administration of 0.05 mg/kg of midazolam, both the venous and the umbilical arterial serum concentrations were lower than maternal concentrations. The use of injectable midazolam in obstetrics has not been evaluated in clinical studies. Because midazolam is transferred transplacentally and because other benzodiazepines given in the last weeks of pregnancy have resulted in neonatal CNS depression, midazolam is not recommended for obstetrical use. Nursing Mothers Midazolam is excreted in human milk. Caution should be exercised when midazolam is administered to a nursing woman. ADVERSE REACTIONS See WARNINGS concerning serious cardiorespiratory events and possible paradoxical reactions. Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following IV and 10.8% of patients following IM administration) and apnea (15.4% of patients following IV administration), as well as variations in blood pressure and pulse rate. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube, e.g., upper endoscopy and dental procedures. Adults: The following additional adverse reactions were reported after intramuscular administration: headache (1.3%); Local effects at IM injection site included: pain (3.7%), induration (0.5%), redness (0.5%), muscle stiffness (0.3%). Administration of IM midazolam hydrochloride to elderly and/or higher risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially narcotics (see DOSAGE AND ADMINISTRATION in full prescribing information). The following additional adverse reactions were reported subsequent to intravenous administration as a single sedative/anxiolytic/amnestic agent in adult patients: hiccoughs (3.9%), nausea (2.8%), vomiting (2.6%), coughing (1.3%), “oversedation” (1.6%), headache (1.5%), drowsiness (1.2%); Local effects at the IV site included: tenderness (5.6%), pain during injection (5.0%), redness (2.6%), induration (1.7%), phlebitis (0.4%). Pediatric Patients The following adverse events related to the use of IV midazolam in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2.0%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%. The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent. Neonates For information concerning hypotensive episodes and seizures following the administration of midazolam to neonates, see BOX WARNING, CONTRAINDICATIONS, WARNINGS and PRECAUTIONS sections. DRUG ABUSE AND DEPENDENCE Midazolam is subject to Schedule IV control under the Controlled Substances Act of 1970. Midazolam was actively self-administered in primate models used to assess the positive reinforcing effects of psychoactive drugs. Midazolam produced physical dependence of a mild to moderate intensity in cynomolgus monkeys after 5 to 10 weeks of administration. Available data concerning the drug abuse and dependence potential of midazolam suggest that its abuse potential is at least equivalent to that of diazepam. Withdrawal symptoms similar in character to those noted with barbiturates and alcohol (convulsions, hallucinations, tremor, abdominal and muscle cramps, vomiting and sweating), have occurred following abrupt discontinuation of benzodiazepines, including midazolam. Abdominal distention, nausea, vomiting and tachycardia are prominent symptoms of withdrawal in infants. The more severe withdrawal symptoms have usually been limited to those patients who had received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. There is no consensus in the medical literature regarding tapering schedules; therefore, practitioners are advised to individualize therapy to meet patient’s needs. In some case reports, patients who have had severe withdrawal reactions due to abrupt discontinuation of high-dose long-term midazolam, have been successfully weaned off of midazolam over a period of several days. Baxter Healthcare Corporation Deerfield, IL 60015 USA For Product Inquiry 1 800 ANA DRUG (1-800-262-3784) BAXTER is a trademark of Baxter International Inc. 462-051-06 4/2009