July 2013 by McMahon Group

The Pharmacist’s News Source

pharmacypracticenews.com

Volume 40 • Number 7 • July 2013

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in this issue UP FRONT

Without an MD degree, are pharmacists qualified to deliver patient care?

CLINICAL

14 28

ISMP: unsafe injection practices all too common.

Posaconazole, sirolimus PI contraindication not a deal killer.

Flood of oral chemotherapy drugs challenges clinicians and d patients.

OPERATIONS & MGMT

Improving CAD adherence boosts clinical outcomes and health care savings.

Billion-Dollar Savings Projected From Biosimilars

Tips for Solving the Puzzle Of Difficult Drugs and Devices

Orlando, Fla.—National drug spending could be cut by $250 billion between 2014 and 2024 if only 11 biosimilar versions of current best-selling biologics are approved during those 10 years, Express Scripts has forecasted (www.lab.express-scripts.com). The company’s vice president of research and analysis, Sharon Frazee, said the projection is based on an “uber-conservative” model and suggested the savings could even be higher. “There are 92 patent expiries coming up,” Ms. Frazee said. “We only included the 11 that we believe are certainly going to have competitor biosimilars come to market.” The analysis, which was presented at the Express Scripts Outcomes Symposium, compared a scenario in which 11 generic versions of current best-selling biologics would be available between 2014 and 2024 with one in which only the branded biologics would be available (Table). In the biologics-only scenario, spending on

Minneapolis—In 200 07, Fairview Health Services in Minneapolis ceased administering insulin with vialls and syringes to patients with diabetes and began using insulin pens exclusivelyy at all six of its hospitals. Ovver the next five years, thee number of wrong-dosee errors reported annuallly dropped by half, from 43 to 21. Steven Meisel, PharmD, CPPS, the direector of patient safety at Fairview, can’t claim definittively that the decline resulted from the conversion to penss, but he said he believes that t the correlation is theree. “I just can’t prove causee and effect,” Dr. Meisel said during a session on medicatiion safety at the American Society ty of Health HealthSystem Pharmacists 2013 Summer Meeting. What Dr. Meisel can point to is the reason why Fairview decided to make the switch to pens. It was done, he noted, in an effort to reduce a variety of dosing errors that have been

see BIOSIMILARS, page 45

see DIFFICULT DRUGS, page 16

•

TECHNOLOGY

Real-time clinical data makes all the difference.

POLICY

Regulatory hurdles still remain for generic biologics.

EDUCATIONAL REVIEW

Perioperative Approach to Patients With Opioid Abuse and Tolerance Visit pharmacy practicenews.com

Hi-Tech Tools Boost Savings As Well as Safety Minneapolis—Many of the advances in hospital pharmacy practice have resulted from medication therapy–related automation, such as computerized prescriber order entry (CPOE) and bar-code scanning. At the 2013 Summer Meeting of the American Society of HealthSystem Pharmacists, a number of posters described innovative ways that these technologies are being applied to improve medication safety

•

see HI-TECH TOOLS, page 40

What’s Inside Patent Medicines?

ld apothecary jars, from as far back as the 1880s, fill a back room at the Henry Ford Museum in Dearborn, Mich. Although the museum has an inventory of these patent medicines and old newspaper ads showing the costs of the various items, no one knew what the jars actually contained. Concerned that they might be preserving dangerous substances, museum staff approached Mark Benvenuto, PhD, a chemist at nearby University of Detroit Mercy, to perform the pharmacologic equivalent of a

crime scene investigation. Dr. Benvenuto, a professor and the chair of the university’s Chemistry and Biochemistry Department, was curious enough to recruit a team of undergraduates to provide chemical analysis of the ingredients in the old patent medicines. For the unfunded research project, he asked the Henry Ford Museum to choose 25 items it would most want analyzed. Dr. Benvenuto suspects product names were major criteria: Selections

New Product

•

see PATENT MEDICINES, page 9

The Book Page

Amneal Institutional launches Haloperidol Decoanate Injection.

Pharmacotherapy Self-Assessment Program, Seventh Edition: 2013 Book 1 Cardiology/Endocrinology

See page 39.

Go to McMAHONMEDICALBOOKS.COM

ACCP

N NOW APPROVED APP Kcentra

DURING WARFARINRELATED BLEEDS…

bin m o r h t al ro s P r e r v o t e c R arin t 4-Fa f s r r a i F W e t ™—th rgen U a r r t o n f e ) g Kc -PCC n F i c 4 ( u e d t o Intr entra c n o C x Comple Important Safety Information Kcentra is indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA—eg, warfarin) therapy in adult patients with acute major bleeding. Kcentra is not indicated for urgent reversal of VKA anticoagulation in patients without acute major bleeding. Kcentra is for intravenous use only. Warning: Patients being treated with Vitamin K antagonist therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing VKA should be weighed against the risk of thromboembolic events, especially in patients with history of such events. Resumption of anticoagulation therapy should be carefully considered once the risk of thromboembolic events outweighs the risk of acute bleeding. Both fatal and nonfatal arterial and venous thromboembolic complications have been reported in clinical trials and postmarketing surveillance. Monitor patients receiving Kcentra, and inform them of signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation (DIC), cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra might not be suitable for patients with thromboembolic events in the prior 3 months. Kcentra is contraindicated in patients with known anaphylactic or severe systemic reactions to Kcentra or any of its components (including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin). Kcentra is also contraindicated in patients with DIC. Because Kcentra contains heparin, it is contraindicated in patients with heparin-induced thrombocytopenia (HIT). Hypersensitivity reactions to Kcentra may occur. If patient experiences severe allergic or anaphylactic type reactions, discontinue administration and institute appropriate treatment. In clinical trials, the most frequent (≥2.8%) adverse reactions observed in subjects receiving Kcentra were headache, nausea/vomiting, arthralgia, and hypotension. The most serious adverse reactions were thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis. Kcentra is derived from human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated. The safety and efficacy of Kcentra in pediatric use have not been studied, and Kcentra should be used in women who are pregnant or nursing only if clearly needed. Please see brief summary of full prescribing information on reverse.

Approved by the FDA for the urgent reversal of Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with acute major bleeding Non-activated 4F-PCC containing Vitamin K– dependent coagulation Factors II, VII, IX, and X, and antithrombotic Proteins C and S

Kcentra has over 15 years of clinical experience as Beriplex® in 25 countries.

For more information, please visit www.Kcentra.com or call the toll-free Kcentra Hotline: 1-855-4KCENTRA (1-855-452-3687)

Urgent Warfarin Reversal Kcentra is manufactured by CSL Behring GmbH and is distributed by CSL Behring LLC. Kcentra is a trademark of CSL Behring and Beriplex is a registered trademark of CSL Behring GmbH. ©2013 CSL Behring LLC 1020 First Avenue, PO Box 61501, King of Prussia, PA 19406-0901 USA www.CSLBehring-us.com www.Kcentra.com KCT11-12-0003 7/2013

Up Front 3

Pharmacy Practice News • July 2013

Infectious Disease

FDA Reconsiders Stance on Fecal Transplants

fter indicating that it would seek to strengthen the regulation of fecal microbiota for transplantation (FMT) for Clostridium difficile infection, the FDA has reversed course and announced that it will leave such treatment up to the discretion of physicians. The FDA’s initial stance was to require that physicians get agency approval before using FMT to treat the potentially life-threatening gastrointestinal

infection. That position was prompted, the agency stated, by its view that FMT is a biological product and drug. Thus, an Investigational New Drug application (IND) would have to be submitted prior to use, “to assure that subjects are not exposed to unreasonable risks,” noted FDA spokesperson Curtis Allen. The original policy did make exceptions for clinical emergencies. In such cases, “the request to use [FMT] may

be made via telephone or other rapid means of communication, and authorization may be given by the FDA official over the telephone,” Mr. Allen pointed out. “In these situations … treatment may begin prior to FDA’s receipt of the written IND submission that is to follow the initial emergency request.” Criticism of the initial FDA decision was swift and forceful. According to Mr. Allen, some participants at an FDA public

‘FMT represents a potentially valuable therapy with a cure rate of 92%.’ —Lawrence J. Brandt, MD

KCENTRA™ (Prothrombin Complex Concentrate [Human]) For Intravenous Use, Lyophilized Powder for Reconstitution Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use KCENTRA safely and effectively. See full prescribing information for KCENTRA. WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS Patients being treated with Vitamin K antagonists (VKA) therapy have underlying disease states that predispose them to thromboembolic events. Potential beneﬁts of reversing VKA should be weighed against the potential risks of thromboembolic events, especially in patients with the history of a thromboembolic event. Resumption of anticoagulation should be carefully considered as soon as the risk of thromboembolic events outweighs the risk of acute bleeding. s Both fatal and non-fatal arterial and venous thromboembolic complications have been reported with Kcentra in clinical trials and post marketing surveillance. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. s Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. ---------------------------------INDICATIONS AND USAGE-----------------------------------Kcentra, Prothrombin Complex Concentrate (Human), is indicated for the urgent reversal of acquired coagulation factor deﬁciency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with acute major bleeding. Kcentra is not indicated for urgent reversal of VKA anticoagulation in patients without acute major bleeding. -----------------------------DOSAGE AND ADMINISTRATION--------------------------------For intravenous use only s Kcentra dosing should be individualized based on the patient’s baseline International Normalized Ratio (INR) value, and body weight. s Administer Vitamin K concurrently to patients receiving Kcentra to maintain factor levels once the effects of Kcentra have diminished. s Repeat dosing with Kcentra is not supported by clinical data and is not recommended. s Administer reconstituted Kcentra at a rate of 0.12 mL/kg/min (~3 units/kg/min) up to a maximum rate of 8.4 mL/min (~210 units/min.).

Pre-treatment INR

2–<4

4–6

Dose* of Kcentra (units† of Factor IX) / kg body weight

Maximum dose‡ (units of Factor IX)

Not to exceed 2500

Not to exceed 3500

Not to exceed 5000

* Base dosing on actual potency, which is stated on the carton and will vary from 20-31 Factor IX units/mL. Nominal potency is 500 units per vial, approximately 25 units per mL after reconstitution. † Units refer to International Units. ‡ Dose is based on body weight up to but not exceeding 100 kg. Do not exceed stated maximum dose for patients weighing more than 100 kg.

--------------------------------DOSAGE FORMS AND STRENGTHS-------------------------s Kcentra is available as a single-use vial containing coagulation Factors II, VII, IX and X, and antithrombotic Proteins C and S as a lyophilized concentrate. -------------------------------------CONTRAINDICATIONS ------------------------------------Kcentra is contraindicated in patients with: s Known anaphylactic or severe systemic reactions to Kcentra or any components in Kcentra including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and Human albumin. sDisseminated intravascular coagulation. sKnown heparin-induced thrombocytopenia. Kcentra contains heparin. --------------------------------WARNINGS AND PRECAUTIONS-----------------------------sHypersensitivity reactions may occur. If necessary, discontinue administration and institute appropriate treatment. s Arterial and venous thromboembolic complications have been reported in patients receiving Kcentra. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thrombotic or thromboembolic (TE) event within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. sKcentra is made from human blood and may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. ------------------------------------ADVERSE REACTIONS--------------------------------------s The most common adverse reactions (ARs) (frequency *2.8%) observed in subjects receiving Kcentra were headache, nausea/vomiting, arthralgia, and hypotension. s The most serious ARs were thromboembolic events including stroke, pulmonary embolism, and deep vein thrombosis. To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-9156958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------------USE IN SPECIFIC POPULATIONS---------------------------------Pregnancy: No human or animal data. Use only if clearly needed. Based on April 2013 version.

workshop in early May “expressed concerns about the administrative aspects of submitting an IND” and “expressed the concern that FDA involvement in the process would deprive ill patients of curative or palliative therapy.” In an interview, Lawrence J. Brandt, MD, a professor of medicine and surgery at Albert Einstein College of Medicine, in New York City, said, “I have the greatest respect for the FDA and for the responsibility it has to protect the population against injury from inappropriate and unsafe products. I do think, however, that the restrictions placed on FMT in the treatment of recurrent Clostridium difficile infection are unduly restrictive.” Dr. Brandt, who is also the emeritus chief of the Division of Gastroenterology at Montefiore Medical Center, in New York City, noted that thousands of FMT cases have been presented in various formats, with “an acknowledged serious adverse event frequency of close to zero.” The main point of a study presented at Digestive Disease Week in May (abstract 998), of which he was an author, “was that in a patient who has severe or complicated Clostridium difficile infection not responding to antibiotics, FMT represents a potentially valuable therapy with a cure rate of 92%.” Against such findings, he suggested, concerns about long-term risks have to be put into perspective. “About 25,000 patients per year die of Clostridium difficile infection in the United States. If you went over to each of them and said, ‘You can die from the Clostridium difficile or you might die 20 years from now from a disease you might contract from the fecal transplant,’ what would most of them answer?” In June, the FDA responded to these concerns by stating that it will “exercise enforcement discretion” and no longer require prior approval of FMT for C. difficile treatment. —George Ochoa Dr. Brandt and Mr. Allen reported no relevant ﬁnancial conﬂicts of interest.

4 Up Front

Pharmacy Practice News • July 2013

Medication Safety

Tennessee Pharmacy the Latest Compounding Culprit T

he FDA found “bacterial and fungal growth” in two vials of preservative-free methylprednisolone acetate (PF MPA) provided by a Tennessee pharmacy but has no knowledge of any cases of meningitis or “life-threatening infections” stemming from use of the product, according to a June 13 announcement. The testing of the vials comes as part of an ongoing investigation of Main Street Family Pharmacy, in Newbern, Tenn. The microbial growth was seen in samples from two separate (80 mg/mL, 10 mL) lots, and the FDA is continuing to evaluate other lots of PF MPA from Main Street Family Pharmacy, the agency said in a press statement. “Although bacteria and fungi have been isolated from unopened vials of MPA from [Main Street Family Pharmacy], it is not possible to determine which infections are due to this contamination event versus other factors, including improper handling and/or administration at the injection facility,” the agency stated. Main Street Family Pharmacy began a voluntary recall in late May of all compounded products from the pharmacy with a “use by” date of on or before Nov. 30, 2013. In a May 31 conference call, Tennessee Health Commissioner John Dreyzehner stated that although the investigation was still in its very early stages, the situation was not as dire as the 2012 meningitis scare related to contaminated steroid injections from New England Compounding Center in Framingham, Mass. That outbreak ultimately resulted in 745 meningitis cases and 58 deaths across 20 states. “Based

heard here

‘I traded one lifethreatening disease for another.’

first

—Evelyn McKnight, AuD, a cancer patient who contracted hepatitis C as a result of unsafe injection practices.

See article, page 14

on everything we know right now, this situation does not approach the severity of the fungal infections in 2012,” he said. As of June 13, there were 25 confirmed cases in four states (Arkansas, Florida, Illinois and North Carolina), all linked with use of PF MPA products received from Main Street Family Pharmacy since Dec. 1, 2012. The FDA reported that bacteria or fungi were found in wounds in four of the patients, with Enterobacter cloacae and Klebsiella identified in two individuals, possible Aspergillus species found in one and as-yet-to-be-identified bacteria seen in a fourth. “At this point in [the] FDA’s investigation, the sterility of all sterile products produced by Main Street is of significant concern and the products should not be used,” the FDA said in a press statement. The most common reports were of skin and soft tissue infections following intramuscular injections with the compounded products. The FDA stated that it “is not aware” of any meningitis cases linked to Main Street Family Pharmacy’s PF MPA products. In addition to the four states with confirmed cases, Main Street Family Pharmacy PF MPA products were shipped to facilities and administered to patients in 11 states, including Alabama, Kansas, Kentucky, Louisiana, Mississippi, New Mexico, New York, Oklahoma, South Carolina, Tennessee and Texas, since Dec. 1, 2012. The product was shipped to facilities in California and Montana as well, but it was not administered to patients in those states. Information regarding suspected infections can be found by state at the Centers for Disease Control and Prevention’s website, www.cdc.gov/hai/outbreaks/TN-pharmacy/index.html. The FDA stated in its release that clinics or customers looking to return vials of the PF MPA product should contact Main Street Family Pharmacy by phone at (731) 627-2221 or (888) 658-6200. The FDA urged health care providers and consumers to report any adverse events or quality problems with the use of any Main Street Family Pharmacy products to the FDA’s MedWatch Adverse Event Reporting program (www.fda.gov/medwatch/report.htm or by fax [800] FDA-0178). Health care providers and patients also may call the FDA’s Drug Information Line at (855) 543-DRUG (3784) and press * to get the most recent information regarding the recall, or to speak directly with a pharmacist. Foxnews.com reported in early June that Main Street Family Pharmacy, which was licensed in 1985 and became a manufacturer and distributor of compounded products in 2010, was found to have out-of-date medications on its shelves during a 2011 inspection, and that a follow-up inspection in late 2012 uncovered 109 such violations. The pharmacy was placed on a three-year probation on March 31 and fined $25,600 for the inspection violations, according to the Foxnews.com report. —Donald Pizzi

EDITORIAL BOARD

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

ADMINISTRATION Robert Adamson, PharmD, Livingston, NJ

James O’Neill, Senior Systems Manager

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

Dan Radebaugh, Director of Production and Technical Operations

Volume 40 • Number 7 • July 2013 • pharmacypracticenews.com

ANESTHESIOLOGY/PAIN

Marty Barbieri, Production Manager

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

INTERNAL MEDICINE

EDITORIAL STAFF

Brandy Wilson, Circulation Coordinator

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

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

David Bronstein, Editorial Director davidb@mcmahonmed.com

McMAHON PUBLISHING

Robert L. Barkin, MBA, PharmD, Chicago, IL

NUCLEAR PHARMACY Jeffrey Norenberg, PharmD, Albuquerque, NM

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

CARDIOLOGY

ONCOLOGY

C. Michael White, PharmD, Storrs, s CT

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

Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Contributing Editors

CNS/PSYCHIATRY

Robert Ignoffo, PharmD, San Francisco, CA

Charles F. Caley, PharmD, Storrs, CT

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

BIOTECHNOLOGY Indu Lew, PharmD, Livingston, NJ

James Prudden, Group Editorial Director

Lawrence Cohen, PharmD, FASHP, FCCP, Fort Worth, Texas

Robin B. Weisberg, Manager, r Editorial Services

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

MCMAHON PUBLISHING MCMAHONMED.COM Sales, Production and Editorial Offices: 545 West 45th Street, 8th Floor, New York, NY 10036. Telephone: (212) 957-5300. Corporate Office: 83 Peaceable Street, Redding CT 06896

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

SALES

Cathy Rosenbaum, PharmD, Cincinnati, OH

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

David Kaplan, Group Publication Director dkaplan@mcmahonmed.com

CRITICAL CARE

PEDIATRICS

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Gretchen Brummel, PharmD, BCPS, Hudson, OH

COMPLEMENTARY AND ALTERNATIVE MEDICINE

Van Velle, President, Partner

Elizabeth Zhong, Associate Copy Chief

Cindy O’Bryant, PharmD, Aurora, CO

Larry Ereshefsky, PharmD, San Antonio, TX

Raymond E. McMahon, Publisher and CEO, Managing Partner

Matt Spoto, Senior Account Manager mspoto@mcmahonmed.com

David P. Nicolau, PharmD, Hartford, CT

TECHNOLOGY

ART/PRODUCTION STAFF

Robert P. Rapp, PharmD, Lexington, KY

Thomas Van Hassel, RPh, Yuma, AZ

Michele McMahon Velle, MAX Graphics/Creative Director

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6 Up Front

Pharmacy Practice News • July 2013

Forum

Pharmacists Not Qualified To Improve Medication Use? Online comment to “FIP Panel: Pharmacists Are an Untapped Resource” (May 2013)

lease advise as to how a person with no diagnostic training, having not done an examination, not having evaluated a possibly very complex p e batbat tery of simple or complex llaboratory tests, not having sorteed through the complex inter-play of physical, physiologic and psychosocial factors and potential comorbidities, could improve upon the decision-making process of someone who has, at least in theory, met these qualifications? Gimme a break. Is the pharmacist going to spend an hour, often with models and diagrams, explaining to the patient what his or her medical problem appears to be and what the most appropriate potential treatments, pharmacologic or otherwise, might be? If that is what is proposed, then the pharmacist is really a physician and should simply be reclassified as such. How the pharmacy profession pre-

sumes to rectify the very real problems of overprescribing and woeful patient compliance in the face of the above, demands de a explanation. One cannott help but be reminded of tthe dangers of the combining of arrogance and ignorance. Generating broadsides at the medical profession, simplistically painting all physicians with the same paintbrush, and then proposing themselves as a solution, appears disingenuous at the very d least. Or, cynic that I am, do I smell the careful, under-the-radar hand of the sophisticated, well-funded pharmaceutical industry exploiting the age-old guild-like motivations of pitting one profession vs. another? Efforts to somehow validate this proposal with vague commentary about the cost of pharmaceutical waste in this country are equally hollow. The incredi-

If pharmacists really want to treat patients, why not simply go to medical school? ble waste, overpricing and pathetic level of medication compliance detailed in the article are certainly real. But this proposal smacks of exploitation rather than an effective solution. We really do appreciate pharmacists’ help where they have expertise. But this effort to tread into waters where they are unqualified is not helpful— except, perhaps, to commercial interests who have no ethical commitment to, or professional responsibility for, the individual patient’s best interests, and who instead only focus on their limitless obligation to their stockholders and performance bonus.

If pharmacists really want to treat patients, why not simply go to medical school? After all, they say there is a shortage of physicians. Shouldn’t be that hard to get into medical school. And if it is, does that not underscore the concept that maybe making all these complex decisions does demand more awareness than is obtainable by pharmacy training alone? —wch74... Editor’s note: This reply was posted on the website of our sister publication, Pain Medicine News, which shares some content with PPN and is sent to U.S. physicians specializing in pain medicine.

Why No ‘Angry Pharmacist’ in Blogging Article? Online comment to “Why Pharmacists Blog” (web exclusive)

hat a shame The Angry Pharmacist (TAP) was not included on the list of blogs to follow ((www.theangrypharmacist.com). Although he may be categorized as “ranting” and “promoting a negative impression of pharmacy,” his blog presents the good, the bad and the ugly of the profession from the front lines. Let’s be real, all professions have the ugly, and if you can’t find the humor in it (as TAP astutely does), you will have a great deal of difficulty maintaining a balance throughout your career. Pharmacy schools have long promoted a Pollyanna view of pharmacy and don’t include training on real-world issues such as how to deal

Kudos to Ignoffo (and PPN) Online comment to “A Career of Excellence” (March 2013)

his Q&A with Bob Ignoffo, PharmD, was an excellent—both interesting and informative—discussion of the valuable role clinical pharmacists play in the area of cancer chemotherapy. In addition, it highlighted the need for clinical and hem/onc pharmacists to play an increasingly important role in this crucial area of

with difficult people who are struggling with addiction. This is a disservice to the profession as a whole. It’s time these issues were discussed openly and pharmacy students were given the training and skills they deserve to deal with it. —robbi… Editor’s note: Judging by a recent tweet by TAP—“Mouth-breathing woman planting her big jugs on the counter; I think she’s looking to eat one of my clerks”—I’d say this wasn’t a glaring omission.

practice. The interviewer is to be commended on the generation and use of wellthought-out questions and “Bob,” in his understated manner, has enlightened the reader about this important area of pharmacy practice. He is an exemplar role model for our profession!! —louis… Editor’s note: The writer identiﬁed himself in his posted comments as Louis Pagliaro, PharmD, MS, PhD, a professor emeritus at the University of Alberta, in Edmonton.

Underwhelmed by Med Rec App Online comment to “Medication Reconciliation In a Snap” (February 2013)

irst let me acknowledge that medication reconciliation is sometimes cunningly difficult, but it seems to me that this app will be useful mainly for those patients who bring in unmarked pill bottles or bags full of pills. Even if the medication name and strength can be identified, what about the directions for use? If a patient brings in a bag full of pills, someone will ultimately have to determine a dose and frequency for each medication and assess compliance. There’s no easy tech fix for that. —theke...

can identify pills all day long. It’s how patients take them that is the challenge. There’s no app for that unless all physician offices were on the same electronic system that we can tap into. Until then, this technology is a good movement in the right direction, but honestly, you can just Google the tablet shape, the color and the inscription; usually it’ll pop right up for you without spending extra money. —bethl...

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IMPORTANT SAFETY INFORMATION Tranexamic acid injection is ccon ontr trai aind ndic icat ated ed:: 1. In patients wiith acq cqu uireed de defe fect ctiv ivee co colo lorr vi visi s on, since this prohibits measuring one endpoint that should be followed as a measure of toxicity. 2. In patients witth suba barach hno noid id h hem emor orrh rhag age. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by tranexamic acid injection in such patients. 3. In patients wiith aact ctiv ivee in intr trav avas ascu cula larr cl clot otti ting n . 4. In patients with th hyperseens nsit itivvit ityy to traane nexamic acid or any of the ingredients. Focal areas of retinal degeneration have developed in cats, dogs and rats following oral or intravenous tranexamic acid at doses between 250 to 1600 mg/kg/day (6 to 40 times the recommended usual human dose) from 6 days to 1 year. The incidence of such lesions has varied from 25% to 100% of animals treated and was dose-related. At lower doses some lesions have appeared to be reversible. Limited data in cats and rabbits showed retinal changes in some animals with doses as low as 126 mg/kg/day (only about 3 times the recommended human dose) administered for several days to two weeks. No retinal changes have been reported or noted in eye examinations in patients treated with tranexamic acid for weeks to months in clinical trials. However, visual abnormalities, often poorly characterized, represent the most frequently reported postmarketing adverse reaction in Sweden. For patients who are to be treated continually for longer than several days, an ophthalmological examination, including visual acuity, color vision, eye-ground and visual fields, is advised, before commencing and at regular intervals during the course of treatment. Tranexamic acid should be discontinued if changes in examination results are found. Convulsions have been reported in association with tranexamic acid treatment. The dose of tranexamic acid injection should be reduced in patients with renal insufficiency because of the risk of accumulation. Ureteral obstruction due to clot formation in patients with upper urinary tract bleeding has been reported in patients treated with tranexamic acid. Venous and arterial thrombosis or thromboembolism has been reported in patients treated with tranexamic acid injection. Central retinal artery and central retinal vein obstruction have been reported. Patients with a previous history of thromboembolic disease may be at increased risk for venous or arterial thrombosis. Tranexamic acid injection should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates, as the risk of thrombosis may be increased. Patients with disseminated intravascular coagulation (DIC), who require treatment with tranexamic acid, must be under strict supervision of a physician experienced in treating this disorder. Tranexamic acid may cause dizziness and therefore may influence the ability to drive or use machines. Pregnancy Category B: Reproduction studies performed in mice, rats, and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to tranexamic acid. There are no adequate and well-controlled studies in pregnant women. However tranexamic acid is known to pass the placenta and appears in cord blood at concentrations approximately equal to maternal concentration. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur but disappear when the dosage is reduced. Allergic dermatitis, giddiness, and hypotension have been reported occasionally. Hypotension has been observed when intravenous injection is too rapid. To avoid this response, the solution should not be injected more rapidly than 1 mL per minute. Worldwide Postmarketing Reports: Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in patients with hemophilia. Convulsion, chromatopsia, and visual impairment have also been reported. However, due to the spontaneous nature of the reporting of medical events and the lack of controls, the actual incidence and causal relationship of drug and event cannot be determined.

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TRANEXAMIC ACID INJECTION

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DRUG DESCRIPTION Tranexamic acid is an antifibrinolytic agent. Each mL of the sterile solution for intravenous injection contains Tranexamic Acid 100 mg and Water for Injection to 1 mL. INDICATIONS Tranexamic acid injection is indicated in patients with hemophilia for short-term use (two to eight days) to reduce or prevent hemorrhage and reduce the need for replacement therapy during and following tooth extraction. CONTRAINDICATIONS Tranexamic acid injection is contraindicated in patients with acquired defective color vision, since this prohibits measuring one endpoint that should be followed as a measure of toxicity (see WARNINGS); in patients with subarachnoid hemorrhage. Anecdotal experience indicates that cerebral edema and cerebral infarction may be caused by tranexamic acid injection in such patients; in patients with active intravascular clotting; and in patients with hypersensitivity to tranexamic acid or any of its ingredients. WARNINGS Focal areas of retinal degeneration have developed in cats, dogs and rats following oral or intravenous tranexamic acid at doses between 250 to 1600 mg/kg/day (6 to 40 times the recommended usual human dose) from 6 days to 1 year. The incidence of such lesions has varied from 25% to 100% of animals treated and was dose-related. At lower doses, some lesions have appeared to be reversible. Limited data in cats and rabbits showed retinal changes in some animals with doses as low as 126 mg/kg/day (only about 3 times the recommended human dose) administered for several days to two weeks. No retinal changes have been reported or noted in eye examinations in patients treated with tranexamic acid for weeks to months in clinical trials. However, visual abnormalities, often poorly characterized, represent the most frequently reported postmarketing adverse reaction in Sweden. For patients who are to be treated continually for longer than several days, an ophthalmological examination, including visual acuity, color vision, eye-ground and visual fields, is advised, before commencing and at regular intervals during the course of treatment. Tranexamic acid should be discontinued if changes in examination results are found. Convulsions have been reported in association with tranexamic acid treatment. PRECAUTIONS General: The dose of tranexamic acid injection should be reduced in patients with renal insufficiency because of the risk of accumulation. Ureteral obstruction due to clot formation in patients with upper urinary tract bleeding has been reported in patients treated with tranexamic acid injection. Venous and arterial thrombosis or thromboembolism has been reported in patients treated with tranexamic acid injection. In addition, cases of central retinal artery and central retinal vein obstruction have been reported. Patients with a previous history of thromboembolic disease may be at increased risk for venous or arterial thrombosis. Tranexamic acid injection should not be administered concomitantly with Factor IX Complex concentrates or Anti-inhibitor Coagulant concentrates, as the risk of thrombosis may be increased. Patients with disseminated intravascular coagulation (DIC), who require treatment with tranexamic acid injection, must be under strict supervision of a physician experienced in treating this disorder. Tranexamic acid may cause dizziness and therefore may influence the ability to drive or use machines. DRUG INTERACTIONS No studies of interactions between tranexamic acid and other drugs have been conducted. CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY An increased incidence of leukemia in male mice receiving tranexamic acid in food at a concentration of 4.8% (equivalent to doses as high as 5 g/kg/day) may have been related to treatment. Female mice were not included in this experiment. Hyperplasia of the biliary tract and cholangioma and adenocarcinoma of the intrahepatic biliary system have been reported in one strain of rats after dietary administration of doses exceeding the maximum tolerated dose for 22 months. Hyperplastic, but not neoplastic, lesions were reported at lower doses. Subsequent long-term dietary administration studies in a different strain of rat, each with an exposure level equal to the maximum level employed in the earlier experiment, have failed to show such hyperplastic/neoplastic changes in the liver. No mutagenic activity has been demonstrated in several in vitroo and in vivo test systems. There are no clinical or nonclinical data to assess the effects of tranexamic acid on fertility.

Pregnancy (Category B) Reproduction studies performed in mice, rats, and rabbits have not revealed any evidence of impaired fertility or adverse effects on the fetus due to tranexamic acid. There are no adequate and well-controlled studies in pregnant women. However, tranexamic acid is known to pass the placenta and appears in cord blood at concentrations approximately equal to maternal concentration. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery (See above under Pregnancy) Nursing Mothers: Tranexamic acid is present in the mother’s milk at a concentration of about a hundredth of the corresponding serum levels. Caution should be exercised when tranexamic acid injection is administered to a nursing woman. Pediatric Use: The drug has had limited use in pediatric patients, principally in connection with tooth extraction. The limited data suggest that dosing instructions for adults can be used for pediatric patients needing tranexamic acid injection therapy. Geriatric Use: Clinical studies of tranexamic acid injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In 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. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. ADVERSE REACTIONS Gastrointestinal disturbances (nausea, vomiting, diarrhea) may occur but disappear when the dosage is reduced. Allergic dermatitis, giddiness, and hypotension have been reported occasionally. Hypotension has been observed when intravenous injection is too rapid. To avoid this response, the solution should not be injected more rapidly than 1 mL per minute. Worldwide Postmarketing Reports: Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, cerebral thrombosis, acute renal cortical necrosis, and central retinal artery and vein obstruction) have been rarely reported in patients receiving tranexamic acid for indications other than hemorrhage prevention in patients with hemophilia. Convulsion, chromatopsia, and visual impairment have also been reported. However, due to the spontaneous nature of the reporting of medical events and the lack of controls, the actual incidence and causal relationship of drug and event cannot be determined. OVERDOSAGE Cases of overdosage of tranexamic acid injection have been reported. Based on these reports, symptoms of overdosage may be gastrointestinal, e.g., nausea, vomiting, diarrhea; hypotensive, e.g., orthostatic symptoms; thromboembolic, e.g., arterial, venous, embolic; visual impairment; convulsions, mental status changes; myoclonus, and rash. DOSAGE AND ADMINISTRATION Immediately before tooth extraction in patients with hemophilia, administer 10 mg per kg body weight of tranexamic acid injection intravenously together with replacement therapy (see PRECAUTIONS). Following tooth extraction, intravenous therapy, at a dose of 10 mg per kg body weight three to four times daily, may be used for 2 to 8 days. For dosing in patients with moderate to severe impaired renal function, see Full Prescribing Information. For intravenous infusion, tranexamic acid injection may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions and Dextran solutions. The mixture should be prepared the same day the solution is to be used. Heparin may be added to tranexamic acid injection. Tranexamic acid injection should NOT be mixed with blood. The drug is a synthetic amino acid, and should NOT be mixed with solutions containing penicillin. HOW SUPPLIED Tranexamic Acid Injection, 100 mg/mL, is a clear, colorless solution STORAGE Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Discard unused portion. AR117 Iss. Date 9/2011

Pharmacy Practice News • July 2013

Clinical 9

History of Pharmacy

PATENT MEDICINES continued from page 1

included Dr. J.J. Gallop’s Vegetable Family Pills, Parson’s Purgative Pills and Dr. F. G. Johnson’s French Female Pills.

What’s in a Patent Medicine? The contents of the museum’s jars “were often unlisted so competitors wouldn’t steal them,” Dr. Benvenuto learned. Some of the ingredients his team found, including an assortment of minerals, are considered helpful today. Diamond Dinner Pills, for instance, were a benign combination of iron, potassium, copper, zinc and calcium. Small amounts of silver often were included, perhaps because colloidal silver was believed to help digestion. “If you crank the clock back 120 years, mercury was often used to treat diseases, including syphilis. It would almost kill you, but it actually did kill the spirochete bacteria,” Dr. Benvenuto said. “If you took a controlled mercury dose, it would probably make you vomit, which may have been the way Parson’s Purgative Pills worked.” He attributes the significant amounts of iron in Dr. F. G. Johnson’s French Female Pills to “an old wives’ tale that said you need more iron when you’re pregnant.” The high mercury and lead content surprised fourth-year mechanical engineering student Andrew Diefenbach, who presented the results of the investigation at the recent annual meeting of the American Chemical Society, in New Orleans. “I knew lots of these [elements] had been in medicine, but didn’t realize how much had been used,” he said. “Lead compounds made things taste sweet—the Romans used it to sweeten food and wine.” Despite often having names that evoked the medical profession—such as Dr. Sawen’s Magic Nervine Pills, Dr. Comfort’s Candy-Covered Cathartic Compills and Dr. Tutt’s Liver Pills—patent medicines were not

—Mark Benvenuto, PhD

see PATENT MEDICINES, page 10

Photo courtesy of Mark Benvenuto, PhD

•

‘If you crank the clock back 120 years, mercury was often used to treat diseases, including syphilis. It would almost kill you, but it actually did kill the spirochete bacteria.’

All photos unless otherwise noted courtesy of the University of Kansas School of Pharmacy, Lawrence.

10 Clinical

Pharmacy Practice News • July 2013

PATENT MEDICINES continued from page 9

necessarily created by doctors. They sometimes made outlandish claims (like Rhodes’ Fever & Ague Cure or Antidote to Malaria) and misled people about their contents. Whoever produced them, physicians or not, had at least the elementary equipment to make a capsule, Dr. Benvenuto discovered. “They look professional, with gaudy labels we wouldn’t use anymore. But they don’t look like, say, homemade rock candy, either.”

Modern-Day Detective Techniques To figure out the amount of each toxic compound in the patent medicines, “we took each sample and bombarded it with x-rays. Different ingredients give off a different radiation, and then you can try to figure out the approximate percentage of each,” Dr. Benvenuto explained. “We ran [tests looking for] 1,000 parts per million of lead, and checked peak intensity. Mercury, arsenic and lead content all seemed to be in that range. Intriguingly, we found the same percentages of calcium and iron.” The next phase of their research will look at inactive or inert ingredients. “We now think of what these people were doing as primitive,” Dr. Benvenuto said. “The inactive ingredients were probably inert, like talc or sugar—things that are not harmful. The cellulose fillings are still used today, and so is titanium dioxide, the whitener in gum. You don’t need that in your body, though.” Because the inert materials made a pill manageable for holding in one’s fingers, he suspects that “even 120 years ago, people didn’t want a giant capsule.” Phase 2 of the research project will use nuclear magnetic resonance imaging. “We’ll dissolve a [product] sample in a solvent, then spin it at 24 times per minute. It’s kind of a CSI effect,” said Dr. Benvenuto, referring to the popular TV series that uses forensic science to solve crimes. Organic ingredients such as cocaine don’t show up on x-rays, but may be detectable in phase 2. However, “after 100 years, codeine, laudanum, cocaine and opium would break down, so we may not find them,” Dr. Benvenuto conceded.

A Viagra Precursor? Kenneth L. Audus, PhD, dean of the University of Kansas School of Pharmacy, in Lawrence, said these patent medicines existed in a sort of regulatory time warp. “These ingredients were accepted at the time, although today’s laws would block them,” he said. “Products were put together based on experience, not analysis. Some ingredients we now consider

poisons were commonly used. But most drugs are poisonous at some dose.” The University of Kansas has a small pharmacy museum. Its contents, including several hundred bottles, come mainly from local pharmacies that were going out of business and donated long-stored, very old products. Many were sold well into the 20th century. Dr. Audus’ favorites include Blosser’s Cigarettes for Bronchial Asthma, DeWitt’s Toilet Cream (possibly for diaper rash) and Cocaine Drops for Toothaches. The museum has acquired print advertisements for several of the products. In one ad, for a mineral/ vitamin combination, a woman laments, “He didn’t even kiss me goodnight last night!” Dr. Audus suspects Vitasafe was a probable Viagra (sildenafil) precursor.

Patent medicines required a prescription; some were made by legitimate drug companies. The majority of items at the Kansas museum were mass-produced, according to labels on old bottles. For example, Harrower Lab in California produced Thyro-Pancreas with Ovaries (dose: one sani-tablet before meals), which may have been a hormone replacement therapy–like preparation. The Merrill Company in Cincinnati, which later became Merrill-Dow, made red sugarcoated strychnine sulfate tablets (dose: one tablet). Some of the museum’s mercury tablets are coffinshaped. Years ago, “for poisons, the coffin shape was a warning that it’s dangerous,” Dr. Audus said. Although some products listed their active ingredients, he believes the lists often were incomplete. Strychnine, a popular additive, was used as a stimulant or tonic, “like a high caffeine dose, but more dangerous,” he noted. A hundred years ago, sophisticated controlled clinical trials did not exist. The common practice was to simply combine into a patent medicine all the ingre-

Photo courtesy of Mark Benvenuto, PhD

History of Pharmacy

dients currently considered to be the safest and best cure for a particular ailment. Dr. Benvenuto said he is convinced that their prevalence actually contributed to medical progress. “Nowadays, we start by seeing if a drug can kill certain kinds of cells, then we try it in mice, then dogs, then humans,” he said. “Obviously, we have a better system now, but I think [patent] medicine [put us] on the road to where we are now. Compared to folk cures, it was a first step at being logical.” However, one famous “ingredient” probably did very little to advance the science. Although neither museum acquired any snake oil products, they’re not a myth: During his popular performances at Chicago’s 1893 Columbian Exposition, Clark Stanley killed rattlesnakes, allegedly for use in his patent medicine. Stanley had production facilities in Massachusetts and Rhode Island for the product he marketed as Clark Stanley Snake Oil Liniment, “a wonderful pain-destroying compound,” product claims stated. In 1917, tests by the U.S. government determined that his product contained mineral oil, red pepper, turpentine and camphor (none extracted from snakes). The Rhode Island Supreme Court fined him $20 for “misbranding.” —Carol Milano

Interested in More Pharmacy History? To access “The Jake Leg Blues–A Story of Adulteration,” by Dennis B. Worthen, PhD, scan the barcode at right or enter the following URL into your web browser: http://tinyurl.com/ lguh4eq

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ABELCET saves. With invasive fungal infections (IFIs) being a leading cause of morbidity and mortality in the most vulnerable immunocompromised patients, polyenes offer effective fungicidal therapy.1,2,3 Abelcet is a key treatment for patients with IFIs who are refractory to, or intolerant of conventional amphotericin B (CAB) therapy. With its single-use vial,4 Abelcet is the only amphotericin B product5,6,7 that does not require reconstitution, saving preparation time and resources. And Abelcet is a cost-effective treatment option that may save you money based on 2012 versus 2013 price offerings. Contact your Abelcet national account manager to learn about the new

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Fridkin SK. The changing face of fungal infections in health care settings. Clin Infect Dis. 2005;41:1455-1460. Manavathu EK, Ramesh MS, Baskaran I, Ganesan LT, Chandrasekar PH. A comparative study of the postantifungal effect (PAFE) of amphotericin B, triazoles and echinocandins on Aspergillus fumigatus and Candida albicans. J Antimicrob Chemother. 2004; 53:386-389. 3 Moosa MYS, Alangaden GJ, Manavathu E, Chandrasekar PH. Resistance to amphotericin B does not emerge during treatment for invasive aspergillosis. J Antimicrob Chemother. 2002;49:209-213. 4 Abelcet® Prescribing Information. Gaithersburg, MD: Sigma-Tau Pharmaceuticals, Inc; 2010. 5 Amphocin® Prescribing Information. New York, NY: Pﬁzer, Inc. 6 AmBisome® Prescribing Information. Deerﬁeld, IL: Astellas Pharma US. 7 Amphotec® Prescribing Information. Warrendale, PA: Three Rivers Pharmaceuticals, LLC. US.

Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs (<0.1% incidence rate with Abelcet). Despite generally less nephrotoxicity of Abelcet observed at a dose of 5 mg/kg/d compared with CAB therapy at a dose range of 0.6 mg/kg/d to 1 mg/kg/d, dose-limiting renal toxicity may still be observed with Abelcet. Renal toxicity of doses greater than 5 mg/kg/d of Abelcet has not been formally studied. The adverse events most commonly reported with Abelcet are transient chills and/or fever during infusion of the drug.

ABL-164-0413

12 Clinical

Pharmacy Practice News • July 2013

Critical Care

Researchers Probe Causes of Opioid Infusion Errors in Peds Study highlights importance of standards, particularly for transfers, in pain care

lthough potentially critical incidents occur regularly during opioid infusions in children, such events typically involve minor errors in the administration of the drugs and the overwhelming majority of incidents occurr in children being treated by clinicians not in the acute pain service, Canadian researchers have found.

“When I took over as director of the acute pain service here, I realized we needed to make changes, partly in response to some incidents that had occurred and partly through wanting to understand if patients not being managed by the pain service were having adequate analgesia,” said Gillian Lauder, MD, a clinical associate professor of

I-101-41-US-N ABELCETT® (Amphotericin B Lipid Complex Injection) BRIEF SUMMARY (SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION) INDICATIONS AND USAGE ABELCETT® is indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy. This is based on open-label treatment of patients judged by their physicians to be intolerant to or failing conventional amphotericin B therapy (See DESCRIPTION OF CLINICAL STUDIES IN FULL P.I.). Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug’s functional properrties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipidcomplexed products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect functional properties of these drug products. DOSAGE AND ADMINISTRATION The recommended daily dosage for adults and children is 5 mg/kg given as a single infusion. ABELCETT® should be administered by intravenous infusion at a rate of 2.5 mg/kg/h. If the infusion time exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours. Renal toxicity of ABELCETT®, as measured by serum creatinine levels, has been shown to be dose dependent. Decisions about dose adjustments should be made only after taking into account the overall clinical condition of the patient. Preparation of Admixture for Infusion: Shake the vial gently until there is no evidence of any yellow sediment at the bottom. Withdraw the appropriate dose of ABELCETT® from the required number of vials into one or more sterile syringes using an 18-gauge needle. Remove the needle from each syringe filled with ABELCET® and replace with the 5-micron filter needle supplied with each vial. Each filter needle may be used to filter the contents of up to four 100 mg vials. Insert the filter needle of the syringe into an IV bag containing 5% Dextrose Injection USP, and empty the contents of the syringe into the bag. The final infusion concentration should be 1 mg/mL. For pediatric patients and patients with cardiovascular disease the drug may be diluted with 5% Dextrose Injection to a final infusion concentration of 2 mg/mL. Before infusion, shake the bag until the contents are thoroughly mixed. Do not use the admixture after dilution with 5% Dextrose Injection if there is any evidence of foreign matter. Vials are for single use. Unused material should be discarded. Aseptic technique must be strictly observed throughout handling of ABELCETT®, since no bacteriostatic agent or preservative is present. DO NOT DILUTE WITH SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR ELECTROLYTES as the compatibility of ABELCET® with these materials has not been established. An existing intravenous line should be flushed with 5% Dextrose Injection before infusion of ABELCETT®, or a separate infusion line should be used. DO NOT USE AN IN-LINE FILTER. The diluted ready-for-use admixture is stable for up to 48 hours at 2$ to 8$C (36$ to 46$F) and an additional 6 hours at room temperature. CONTRAINDICATIONS ABELCETT® is contraindicated in patients who have shown hypersensitivity to amphotericin B or any other component in the formulation. WARNINGS Anaphylaxis has been reported with amphotericin B desoxycholate and other amphotericin B-containing drugs. Anaphylaxis has been reported with ABELCETT® with an incidence rate of <0.1%. If severe respiratory distress occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of ABELCETT®. PRECAUTIONS General: As with any amphotericin B-containing product, during the initial dosing of ABELCETT®, the drug should be administered under close clinical observation by medically trained personnel. Acute reactions including fever and chills may occur 1 to 2 hours after starting an intravenous infusion of ABELCETT®. These reactions are usually more common with the first few doses of ABELCETT® and generally diminish with subsequent doses. Infusion has been rarely associated with hypotension, bronchospasm, arrhythmias, and shock. Laboratory Tests: Serum creatinine should be monitored frequently during ABELCETT® therapy (see ADVERSE REACTIONS). It is also advisable to regularly monitor liver function, serum electrolytes (particularly magnesium and potassium), and complete blood counts. Drug Interactions: No formal clinical studies of drug interactions have been conducted with ABELCET®. However, when administered concomitantly, the following drugs are known to interact with amphotericin B; therefore, the following drugs may interact with ABELCETT®: Antineoplastic agents: Concurrent use of antineoplastic agents and amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with ABELCET® with great caution. Corticosteroids and corticotropin (ACTH): Concurrent use of corticosteroids and corticotropin (ACTH) with amphotericin B may potentiate hypokalemia which could predispose the patient to cardiac dysfunction. If used concomitantly with ABELCETT®, serum electrolytes and cardiac function should be closely monitored. Cyclosporin A: Data from a prospective study of prophylactic ABELCETT® in 22 patients undergoing bone marrow transplantation suggested that concurrent initiation of cyclosporin A and ABELCETT® within several days of bone marrow ablation may be associated with increased nephrotoxicity. Digitalis glycosides: Concurrent use of amphotericin B may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly with ABELCETT®, serum potassium levels should be closely monitored. Flucytosine: Concurrent use of flucytosine with amphotericin B-containing preparations may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Flucytosine should be given concomitantly with ABELCETT® with caution. Imidazoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.): Antagonism between amphotericin B and imidazole derivatives such as miconazole and ketoconazole, which inhibit ergosterol synthesis, has been reported in both in vitroo and in vivoo animal studies. The clinical significance of these findings has not been determined. Leukocyte transfusions: Acute pulmonary toxicity has been reported in patients receiving intravenous amphotericin B and leukocyte transfusions. Leukocyte transfusions and ABELCETT® should not be given concurrently. Other nephrotoxic medications: Concurrent use of amphotericin B and agents such as aminoglycosides and pentamidine may enhance the potential for drug-induced renal toxicity. Aminoglycosides and pentamidine should be used concomitantly with ABELCETT® only with great caution. Intensive monitoring of renal function is recommended in patients requiring any combination of nephrotoxic medications. Skeletal muscle relaxants:: Amphotericin B-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g., tubocurarine) due to hypokalemia. When administered concomitantly with ABELCETT®, serum potassium levels should be closely monitored. Zidovudine:: Increased myelotoxicity and nephrotoxicity were observed in dogs when either ABELCET® (at doses 0.16 or 0.5 times the recommended human dose) or amphotericin B desoxycholate (at 0.5 times the recommended human dose) were administered concomitantly with zidovudine for 30 days. If zidovudine is used concomitantly with ABELCETT®, renal and hematologic function should be closely monitored. Carcinogenesis, Mutagenesis, and Impairment of Fertility:: No long-term studies in animals have been performed to evaluate the carcinogenic potential of ABELCETT®. The following in vitroo (with and without metabolic activation) and in vivo studies to assess ABELCETT® for mutagenic potential were conducted: bacterial reverse mutation assay, mouse lymphoma forward mutation assay, chromosomal aberration assay in CHO cells, and in vivoo mouse micronucleus assay. ABELCETT® was found to be without mutagenic effects in all assay systems. Studies demonstrated that ABELCET® had no impact on fertility in male and female rats at doses up to 0.32 times the recommended human dose (based on body surface area considerations).

anesthesiology, pharmacology and therapeutics at the University of British Columbia, in Vancouver. The result of this realization was the current study, in which Dr. Lauder and her colleagues analyzed patient safety and pharmacy data for potential critical incidents in patients receiving parenteral opioid infusions, between Decem-

ADVERSE REACTIONS The total safety data base is composed of 921 patients treated with ABELCETT® (5 patients were enrolled twice and counted as separate patients), of whom 775 were treated with 5 mg/kg/day. Of these 775 patients, 194 patients were treated in four comparative studies; 25 were ADVERSE EVENTSa WITH AN INCIDENCE OF *3% (N=556) treated in open-label, non-comparative studies; and 556 patients were treated Adverse Event Percentage (%) of Patients in an open-label, emergency-use Chills 18 program. Most had underlying hemaFever 14 tologic neoplasms, and many were reIncreased Serum Creatinine 11 ceiving multiple concomitant medicaMultiple p Organ g Failure 11 tions. Of the 556 patients treated with Nausea 9 ABELCETT®, 9% discontinued treatment Hypotension yp 8 due to adverse events regardless of Respiratory p y Failure 8 presumed relationship to study drug. Vomitingg 8 In general, the adverse events most Dyspnea yp 7 commonly reported with ABELCETT® Sepsis p 7 were transient chills and/or fever durrDiarrhea 6 ing infusion of the drug. Headache 6 Cardiac Arrest Hypertension yp Hypokalemia yp Infection Kidneyy Failure Pain Thrombocytopenia y p Abdominal Pain Anemia Hyperbilirubinemia yp Gastrointestinal Hemorrhage g Leukopenia p Rash Respiratory p y Disorder Chest Pain Nausea and Vomitingg

6 5 5 5 5 5 5 4 4 4 4 4 4 4 3 3

The following adverse events have also been reported in patients using ABELCETT® in open-label, uncontrolled clinical studies. The causal association between these adverse events and ABELCETT® is uncertain. Body as a whole:: malaise, weight loss, deafness, injection site reaction including inﬂammation Allergic:: bronchospasm, wheezing, asthma, anaphylactoid, and other allergic reactions a The causal association between these adverse events and ABELCET® is Cardiopulmonary:: cardiac failure, uncertain. pulmonary edema, shock, myocardial infarction, hemoptysis, tachypnea, thrombophlebitis, pulmonary embolus, cardiomyopathy, pleural effusion, arrhythmias including ventricular ﬁbrillation Dermatological:: maculopapular rash, pruritus, exfoliative dermatitis, erythema multiforme Gastrointestinal:: acute liver failure, hepatitis, jaundice, melena, anorexia, dyspepsia, cramping, epigastric pain, venoocclusive liver disease, diarrhea, hepatomegaly, cholangitis, cholecystitis Hematologic:: coagulation defects, leukocytosis, blood dyscrasias including eosinophilia Musculoskeletal:: myasthenia, including bone, muscle, and joint pains Neurologic:: convulsions, tinnitus, visual impairment, hearing loss, peripheral neuropathy, transient vertigo, diplopia, encephalopathy, cerebral vascular accident, extrapyramidal syndrome and other neurologic symptoms Urogenital:: oliguria, decreased renal function, anuria, renal tubular acidosis, impotence, dysuria Serum electrolyte abnormalities:: hypomagnesemia, hyperkalemia, hypocalcemia, hypercalcemia Liver function test abnormalities:: increased AST, ALT, alkaline phosphatase, LDH Renal function test abnormalities:: increased BUN Other test abnormalities:: acidosis, hyperamylasemia, hypoglycemia, hyperglycemia, hyperuricemia, hypophosphatemia To report SUSPECTED ADVERSE REACTIONS, contact Sigma-Tau Pharmaceuticals, Inc., at 1-888-393-4584 or by email at drugsafety@sigmatau.com or contact the FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch. Special Populations Hepatic Impairment:: The effect of hepatic impairment on the disposition of ABELCETT® is not known. Renal Impairment:: The effect of renal impairment on the disposition of ABELCETT® is not known. The effect of dialysis on the elimination of ABELCETT® has not been studied; however, amphotericin B is not removed by hemodialysis when administered as amphotericin B desoxycholate. Pediatric and Elderly Patients: The pharmacokinetics and pharmacodynamics of pediatric patients ()16 years of age) and elderly patients (*65 years of age) have not been studied. Pregnancy:: There are no reports of pregnant women having been treated with ABELCETT®. Teratogenic Effects. Pregnancy Category B: Reproductive studies in rats and rabbits at doses of ABELCETT® up to 0.64 times the human dose revealed no harm to the fetus. Because animal reproductive studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women, ABELCETT® should be used during pregnancy only after taking into account the importance of the drug to the mother. Nursing Mothers:: It is not known whether ABELCETT® is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants from ABELCET®, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use:: One hundred eleven children (2 were enrolled twice and counted as separate patients), age 16 years and under, of whom 11 were less than 1 year, have been treated with ABELCET® at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. In one single-center study, 5 children with hepatosplenic candidiasis were effectively treated with 2.5 mg/kg/day of ABELCETT®. No serious unexpected adverse events have been reported. Geriatric Use:: Forty-nine elderly patients, age 65 years or over, have been treated with ABELCET® at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. No serious unexpected adverse events have been reported. OVERDOSAGE Amphotericin B desoxycholate overdose has been reported to result in cardio-respiratory arrest. Fifteen patients have been reported to have received one or more doses of ABELCETT® between 7-13 mg/kg. None of these patients had a serious acute reaction to ABELCETT®. If an overdose is suspected, discontinue therapy, monitor the patient’s clinical status, and administer supportive therapy as required. ABELCETT® is not hemodialyzable.

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ber 2004 and December 2009. The incidents were graded on their severity and the probability of recurrence. Those that scored at least an 8 out of 10 were selected for root cause analysis. The researchers identified 166 potential incidents. “There was no evidence of a relevant incident in 108 of them,” Dr. Lauder told Pharmacy Practice News. The 58 remaining charts included one (n=45) or more than one (n=13) relevant critical incidents. The most common incident was opioid administration error, which affected 39 cases (67%), according to the investigators, who presented their findings at the 2012 annual meeting of the Canadian Anesthesiologists’ Society (abstract 1341704). Fourteen charts were selected for root cause analysis, which identified 31 root causes. The most frequent and significant ones involved defective preprinted order sheets for opioid infusions; lack of nursing guidelines for the infusion adjustment rate and weaning off the medication; and inadequate policies and guidelines for monitoring and recording pain, vital signs and arousal. Generally, the root causes were classified as policies/procedures/rules (49%), communication (13%), environment/ equipment (17%) and training (21%). “We couldn’t really analyze fatigue and scheduling because [the study] was retrospective,” Dr. Lauder said. “So, we ended up looking at the four above categories and got information about things we could change in the system.” One problem that the group identified was the transfer of patients between units. “At that time, we didn’t have standard policies and procedures for our opioid infusions and we didn’t have standard opioid concentrations,” she said. “So, if a patient was transferred between units, there was a greater chance an incident could occur.” The researchers have used the analysis to generate a series of recommenda-

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Critical Care ‘We didn’t have standard policies and procedures for our opioid infusions and we didn’t have standard opioid concentrations. So, if a patient was transferred between units, there was a greater chance an incident could occur.’ —Gillian Lauder, MD distractions during tasks,” he said. “And when you added paper-based ordering in the intensive care unit, it became extremely problematic.” Dr. McDonnell also found common ground in the potential for errors

to occur when patients are transferred between units. “Our ICUs have different methods for ordering medications and making up concentrations and infusions, so it can create a lot of inconsistency when patients are transferred out

again. As a result, we have also moved to things like standard concentrations and preprinted order sets for our acute pain service around the hospital.” —Michael Vlessides

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Right at Your Fingertips tions for improving patient safety and the quality of analgesia for children with acute pain. These recommendations include: 1) promoting uniform hospital-wide monitoring, documentation and policies related to opioid administration, opioid weaning and opioid conversion in children transferred to and from the pediatric intensive care unit; 2) enhancing education in pediatric acute pain management for residents and other health care professionals to include an awareness of the pharmacokinetic variability of opioid medications in children; and 3) promoting the timely involvement of the acute pain service. “Fortunately, we now have standard concentrations, preprinted orders, and nursing policies and procedures that span the entire hospital,” Dr. Lauder said. “I think the next thing to do would be to make sure that all incidents have root cause analyses performed prospectively.” Conor McDonnell, MD, the director of safety and quality in the Department of Anesthesia at The Hospital for Sick Children, in Toronto, Canada, who was not involved with the study, said the findings help confirm previous research into medication errors in children. “One of the things we uncovered in some of our work is that administration errors definitely seem to be an issue, particularly around the time of handovers and patient transfers,” Dr. McDonnell told Pharmacy Practice News. Indeed, Dr. McDonnell and a colleague, in a study published last year examined 10-fold medication errors in children ((Pediatrics 2012;129:916-924). “When it came to opioid infusions, we found several common causes, including incorrect equipment programming, programming multiple infusions and

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14 Clinical

Pharmacy Practice News • July 2013

Medication Safety

Unsafe Injection Practices Remain All Too Common E

velyn McKnight, AuD, has firsthand knowledge of the devastating consequences of unsafe injection practices. In 2001, she contracted hepatitis C while undergoing chemotherapy for breast cancer. An investigation into the source of Dr. McKnight’s infection by the state health department and Centers for Disease Control and Prevention (CDC) uncovered “dumbfounding and unsettling” findings, she said. For 16 months, a clinic nurse had been reusing syringes to draw saline solution from a common IV bag during portflushing procedures in advance of administering chemotherapy. In the process, hepatitis C virus (HCV) infection from a previously infected patient was spread to 99 others. “The irony is that I traded one lifethreatening disease for another,” Dr. McKnight, founder of HONOReform Foundation, a national advocacy organization dedicated to safeguarding injection practices, said during a Institute for Safe Medication Practices (ISMP) webinar on May 9. Matthew Fricker, RPh, MS, a program director at ISMP, said he worries that outbreaks like the one Dr. McKnight was involved in are only the tip of the iceberg and many others remain unreported. Results from the 2011 ISMP Medication Safety Self Assessment for Hospitals support this concern, he said. Of the more than 1,300 hospitals that completed the assessment, 2% had not implemented any policy prohibiting the use of multiple-dose vials for saline and heparin flush solutions or for local anesthetics, and 24% had only partially implemented such a policy. Two percent had only partially implemented a hospitalwide policy prohibiting the reuse of the same syringe in more than one patient even if the needle had been changed between patients. According to Mr. Fricker, 2% may seem like an insignificant number, but when it comes to injection practices, small mistakes can have significant consequences. “We need to be at 100% adherence for these practices,” he emphasized. Recent reports of insulin pens being reused—including one reported shortly after the webinar (Whitman V. “Catskill hospital warns that insulin pens may have been reused” Times Herald-Record, May 21, 2013)—have placed nearly 5,000 patients at risk for HIV, hepatitis B virus (HBV) or

of the needle contaminated the syringe, which was then reused to draw medication from the single-use vial, contaminating the vial and initiating a chain of infection transmission. “What happened there was not unique to Vegas,” Dr. Perz said during the webinar. “We see this over and over.”

Need for Education

‘We need to train our providers just to read the label. Unless it is a manufactured vial with the term “multidose vial” printed on it, it is not a multidose vial.’ —Joseph Perz, DrPH

HCV infections, Mr. Fricker noted. In the ISMP hospital assessment, 9% of hospitals said they had not taken any formal steps to implement a policy prohibiting the use of multidose pens as unit stock. The misuse of insulin pens has prompted the ISMP to recommend that hospitals consider transitioning away from using pen devices. “Issuing this recommendation was not a decision we made lightly,” Mr. Fricker said. A look at the outbreak of HCV that occurred in Las Vegas in 2008 illustrates how reuse of syringes and single-dose vials can lead to rapid exposure to infectious diseases in large numbers of individuals, Joseph Perz, DrPH, a team leader in Ambulatory and Long-Term Care in the Prevention and Response Branch at the CDC’s Division

of Healthcare Quality Promotion, told webinar attendees. That outbreak started with a clean needle and syringe that had initially been used to draw from a single-use vial and administer the medication to an HCV-infected patient. Backflow from the injection or from the removal

Dr. Perz said he believes that many of these lapses in safe practice are due to a lack of understanding as to what constitutes safe injection practices. “To even get nurses to recognize the da ifference between a single- and multiple-dose vial requires significant effort,” Dr. Perz told ISMP webinar attendees. “We need to train our providers just to read the label. Unless it is a manufactured vial with the term ‘multidose vial’ printed on it, it is not a multidose vial.” Results from a 2010 survey of 5,000 health care workers, most of whom were nurses, illustrates the disparity between how well clinicians believe they are doing in preventing infections and how they behave, Mr. Fricker said (Am ( J Infect Cont ro l 2 0 1 0 ; 3 8 : 7 8 9 -7 9 8 ) . Although most respondents said they followed recommended infection control practices, 6% said they sometimes or always used single-dose vials for multiple patients and 1% said they reused a syringe for more than one patient after discarding the needle. “There is a misconception that changing a needle is enough to be safe,” Mr. Fricker said. “Many of these respondents were unaware of the risk for spreading disease after changing a needle but reusing the same vial.” Dr. Perz urged webinar attendees to share the CDC’s Injection Safety Checklist ((www.cdc.gov/ injectionsafety) y and to visit ONEandONLYcampaign. org for free staff training activities, brief how-to videos and posters emphasizing the importance of using single-dose vials and insulin pens in only one individual. Dr. Perz concluded, “I don’t think we can do enough to educate providers on what safe practices are.” —David Wild

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16 Clinical

Pharmacy Practice News • July 2013

Medication Safety

DIFFICULT DRUGS continued from page 1

associated with use of insulin syringes. He explained that because a nurse has to draw every insulin dose into the syringe from the vial, there’s a chance of drawing and then administering the wrong amount to the patient. Insulin pens, in contrast, include preset doses, so the chance of a dose error is very small. Errors with the syringes themselves also can be a problem. If a nurse draws insulin into a tuberculin instead of an insulin syringe, dosing errors occur because the syringes use different units of calibration, Dr. Meisel pointed out. Insulin pens also offer operational advantages, such as eliminating the need for a member of the care team to “double-check” a nurse-drawn syringe. Additionally, pens have been shown to reduce waste and cost because they eliminate the problem of a multiuse insulin vial, which can contain as many as 100 doses, being used for only one or two insulin syringe preparations. (Many patients need only a few insulin doses during their hospital stay, Dr. Meisel noted.) On the downside—and it’s a considerable one, Dr. Meisel acknowledged—is the fact that pen reuse creates the potential for exposure to blood-borne pathogens. Although no such transmissions have been documented, numerous incidents of shared use, some on a large scale, have made headlines. In January, more than 700 patients at the Buffalo, N.Y., Veterans Administration Center may have been exposed to HIV, hepatitis B and/ or hepatitis C when insulin pens were accidentally reused for multiple patients. Within days of the Buffalo report, Olean (N.Y.) General Hospital announced that 1,915 patients might have been subjected to pen reuse from November 2009 to January 2013. At least three of these patients have filed lawsuits alleging that they contracted hepatitis as a result. Safety alerts from the Centers for Disease Control and Prevention, the FDA, Veterans Health Administration and the Institute for Safe Medication Practices (ISMP) underscore the risk. A February 2013 ISMP alert urged hospitals to “closely reexamine the safe use of these pen devices, with strong consideration given to transitioning away from insulin pens for routine inpatient use.” Based on the alerts, Fairview revisited the decision to use insulin pens. According to Dr. Meisel, an interdisciplinary team of pharmacists, nurses, patient safety and risk management reviewed the background, science, risks, benefits and alternatives. Among their findings were the following: • The likelihood of cross-patient use exists with both pens and vials, although the possible consequence of cross use is much higher with pens.

‘[Insulin] pens weren’t made for use in hospitals, that’s the bottom line. Sooner or later, your patients are going to be at risk, and sooner or later we’ll see someone infected.’ —Michael R. Cohen, RPh, MS, ScD • Dosing errors are more likely with vials. • At Fairview, pens are configured for bar coding of the product, not the order; thus, if a pen is used on the wrong patient, it won’t trigger an alert. After weighing the evidence, Fairview opted for the pens, but included several enhancements, such as adding a line to the competency sign-off form for insulin pens acknowledging their singlepatient nature; posting “One Insulin/ One Pen” posters across care units; and working with the software vendor to enhance the bar-code system for pens. Dr. Meisel added that he knows of seven instances since 2007 when a pen was used on multiple patients. “Everything we think about has to be in the context of relative risk,” he said. “We will never be risk-free, and every alternative poses independent problems. What you try to do is exchange your current set of problems for a better set of problems, but recognize that you’ll always have a set of problems.” Not surprisingly, some medication safety experts remain concerned about the use of insulin pens in hospitals. Patricia Kienle, RPh, MPA, FASHP, the director of accreditation and medication safety with Cardinal Health Pharmacy Solutions, said that Dr. Meisel “did a great job explaining the risk assessment” but cautions that hospitals choosing this route need to take a great deal of care to ensure that pens are not used on multiple patients. “Re-use of insulin pens on the inpatient side can cause considerable safety risks of their own.” Michael R. Cohen, RPh, MS, ScD, the president of ISMP, who moderated the session, also remarked on Fairview’s balanced evaluation but still harbors doubts. “The pens weren’t made for use in hospitals, that’s the bottom line,” Dr. Cohen said. “Sooner or later, your patients are going to be at risk, and sooner or later we’ll see someone infected.” Dr. Meisel does not dismiss his critics. “I’m certainly not saying we’re right and everybody else is wrong,” he said. “Everybody’s got to make their own judgment of relative risks within their organizations.”

Targeting Acetaminophen Overuse and Toxicity Pharmacists at St. Luke’s Episcopal Hospital in Houston undertook a very different mission: putting the brakes on acetaminophen overuse and toxicity—a problem that rarely attracts the level

of attention commensurate with the threat it presents. In fact, that threat is enormous. Acetaminophen overuse was the leading cause of acute liver failure in the United States from 1998 to 2003 ((Hepatology 2005;42:1364-1372). From 1990 to 1998, an estimated 56,000 emergency room visits, 26,000 hospitalizations and 458 deaths annually were attributed to acetaminophen-associated overdoses (Pharmacoepidemiol ( Drug Saf 2006;15:398-405). Acetaminophen is ubiquitous in health care settings and is a constituent in hundreds of over-the-counter and prescription drugs (http://www.knowyourdose. org/common-medications). Clinicians administer it freely and perceive it as safe and effective. But little heed is paid to how quickly a patient’s daily intake can climb beyond the recommended maximum daily dose of 4,000 mg per day, said B. Jane Adams, MS Pharm, pharmacy manager, Quality and Safety at St. Luke’s. “We wondered if [such cavalier use] was happening here,” Dr. Adams added.

above 6,000 mg per day plummeted from 203 to zero. Ms. Adams reported that resistance to the new system was minimal—a result, she said, of her team’s concerted effort to communicate with the affected staff well before the system was running. That communication included newsletters, presentations to the nursing staff and presentations at grand rounds to the medical staff. “Did we reach every prescriber who touched that patient? No, but we clearly made an impact,” she said.

Making Oral Chemotherapy A Safer Option James Hoffman, PharmD, medication outcomes and safety officer at St. Jude Children’s Research Hospital in Memphis, took on the task of strengthening safety protocols for oral chemotherapy. Oral chemotherapy drugs can be misperceived as safer than IV chemotherapy agents, resulting in less attention to safety, according to Dr. Hoffman. He added that at least half of the new oncology agents approved recently have been oral drugs: four of six in 2011,

‘Accidental intrathecal vincristine administration has been happening for more than 50 years, and we’ve got a strategy that can dramatically reduce the likelihood of it occurring.’ —Nicole Mollenkopf MacLaughlin, PharmD, BCPS “Spot audits revealed that we not only had the potential for excessive dosing, but that some patients had received far more than the recommended dose.” No evidence of acetaminophen toxicity was found, she pointed out. In 2008, Ms. Adams and her colleagues collaborated with the Information Management Department to integrate a dose calculator into the electronic medical record. If a patient receives more than 4,000 mg of acetaminophen within a 24-hour period, an alert fires off to a floor nurse and the patient’s physician of record. Before the system’s installation, a baseline review of patient records showed that 19.3 alerts would have been generated had the system been operational. By the end of 2012, the average had dropped to 1.5 per day. In the first quarter of 2009, there were 500 alerts for patients whose daily dose was 5,000 to 6,000 mg. Two years later there were seven. Alerts for daily doses

and seven of 13 in 2012. “The experience of IV chemotherapy versus taking a pill is so different that it’s easy to forget that the oral drugs carry substantial risks for patients,” Dr. Hoffman said. Perceptions are changing, however. He attributes the shift in part to a pivotal 2007 survey of 42 U.S. cancer centers that found that few of the safeguards routinely applied to infusion chemotherapy have been adopted for oral chemotherapy. The authors found “no apparent consensus among oncology professionals about safe practices for these drugs,” and recommended that safe medication practice guidelines be adopted at an accelerated rate. ((BMJ J 2007;334:407). “That paper was a turning point and raised awareness of the need for oral chemotherapy safety practices,” Dr. Hoffman said. Several years ago, St. Jude sought to ensure that oral chemotherapy safety practices reached the same high level as

•

see DIFFICULT DRUGS, page 19

Clinical 17

Pharmacy Practice News • July 2013

Pediatrics

Acid-Suppressing Drugs Overprescribed in Infants New Orleans—Acid-suppressing drugs are overprescribed in infants and children, and this is a “risky business,” according to a pediatric gastroenterologist Eric Hassall, MBChB. Dr. Haskell, a professor of pediatrics at the University of British Columbia, in Vancouver, acknowledged that proton pump inhibitors (PPIs) have huge benefits for symptomatic relief and healing of esophagitis when prescribed for children over the age of 1 year who have proven gastroesophageal reflux disease (GERD). However, he said, these medications often are prescribed for infants who are spitting up or just irritable, and GERD is seldom responsible.

For Most Babies, Spitting Up Is Normal, Not a Sign of Disease “For the great majority of thriving, healthy infants, spitting up is ‘life,’ not a disease,” said Dr. Hassall. Spitting up that occurs several times a day in healthy infants is normal, and diminishes over time. By definition, this is “physiologic reflux,” not reflux disease. Dr. Hassall said that the “flood of direct-to-consumer marketing since the mid-1990s” has created a demand for drugs to treat symptoms in infants who generally do not have classic GERD. “Most infants [have] reflux, but it’s not acid d reflux. The advertiserinvented term acid reflux suggests that an acid-suppressing drug is required,” Dr. Hassall said. “This creates demand by consumers for a drug that is very seldom indicated in infancy.” Common symptoms of unexplained crying and refusal to feed in infants more often are due to causes such as difficulty to “change state,” that is, to self-calm from a state of fussiness, whatever the initial cause. This is a function of immaturity of the nervous system, and it improves over time. GERD is less common than many other causes of infant irritability, such as food allergy, gassiness, difficulty sucking, swallowing air, constipation, or occasionally, infection or other underlying systemic disease. Dr. Hassall proved his point in a study of 162 infants with symptoms attributed to GERD. After failing one week of nonpharmacologic treatment, babies were randomized to four weeks of treatment with a PPI or placebo. In each group, 54% were considered to be “responders.” “The drug was no better than placebo, and there were more treatment-related adverse effects with the PPI,” Dr. Hassall said. “In otherwise normal infants with unexplained crying, there is no

evidence to support acid suppresson.” After about 6 months of age, ongoing irritability, especially with feedings, is more likely to be related to GERD, Dr. Hassall said. Clinicians should appreciate that certain conditions do make GERD more likely: neurologic impairment (such as cerebral palsy); repaired esophageal atresia (or other congenital esophageal condition); chronic lung disease (such as cystic fibrosis); hiatal hernia; obesity; and a family history of GERD, Barrett’s esophagus or adenocarcinoma. Outside of these potential causes, chronic GERD is a relatively uncommon occurrence. “It becomes a disorder when the reflux of gastric contents is the cause of troublesome symptoms or complications, and that’s when we define it as GERD. But the question is, ‘troublesome for whom?’” Of course, infants cannot give a reliable account of the nature of what is

troublesome. “If it is just troublesome for the parents, is this really reflux disease, and should we treat it? Probably no, on both counts,” Dr. Hassall said.

Prescriptions Skyrocketing The use of acid-suppressing drugs in young children with presumed GERD increased sevenfold between 1999 and 2004, according to findings from a health claims database, which also demonstrated that prescriptions for a child-friendly liquid formation increased 16-fold (J ( Pediatr Gastroenterol Nutr 2007;45:421-427). Overall, about 0.5% of roughly 1 million infants in the database received a PPI during their first year of life, half of them by the age of 4 months. In a more recent claims database, the diagnosis of GERD or “acid-related disorder” in infants and children quadrupled between 2000 and 2005 ((J Med Econ 2009;12:348-355). “It’s not as though the developed

world is experiencing an epidemic of reflux disease in infants—rather, there are drugs marketed to treat symptoms that are not, in fact, reflux disease, and parents often desire a ‘quick fix,’” Dr. Hassall said.

Appropriate Use PPIs and histamine-2 receptor antagonists (H2RAs) can be used appropriately in infants and children. In children older than 1 year, with erosive and nonerosive esophagitis, PPIs are highly effective and well tolerated for healing (over three months) and maintenance (over two years). Once-daily dosing is usually adequate for healing severe cases, and higher doses on a per kilogram basis are required for children between the ages of 1 and 9 years. The duration of treatment with acid-suppressing drugs in children depends on the presence or absence of underlying predisposing conditions. In an Italian study, 46 children aged 3 to 13 years with erosive esophagitis were treated with omeprazole for three months and then randomized to receive omeprazole, ranitidine or placebo for six months ((Am J Gastroenterol 2007;102:1291-1297). At one year, all patients were able to discontinue treatment. Because the study excluded GERD-predisposing conditions, it showed that in most patients without underlying conditions, GERD is not chronic and short-term treatment is appropriate, Dr. Hassall said. In contrast, a study by Dr. Hassall and his colleagues of 166 children who required continuous PPI use showed that multiple attempts to wean the children off treatment was unsuccessful. In this study, 80% of children had at least one GERD-predisposing condition, and many had failed at least one fundoplication. PPIs were used in these children for up to 11 years (median, three years), and they responded extremely well to long-term PPI therapy ((J Pediatr 2007;150:262-267). Dr. Hassall noted that no particular PPI has proven to be superior to another.

Adverse Effects

‘Anecdotally, in everyday pediatrics, we see lots of breast-fed infants who should not have coughs, pneumonia or gastroenteritis, but they get these on acid-suppressing drugs.” —Eric Hassal, MBChB

“Gastric acid has physiologic/teleological purposes, so suppression of it, even for part of the day, may cause problems,” Dr. Hassall noted. A number of adverse effects of acid suppression with PPIs and H2RAs have been documented in children: • Acute gastroenteritis and community-acquired pneumonia in children aged 4 to 36 months receiving PPIs or H2RAs

•

see OVERPRESCRIBED, page 18

18 Clinical

Pharmacy Practice News • July 2013

Pediatrics

OVERPRESCRIBED continued from page 17

• Necrotizing enterocolitis in preterm infants receiving H2RAs • Candidemia in children in neonatal intensive care receiving H2RAs • Pneumonia in infants receiving PPIs • Pulmonary infections in children with asthma receiving PPIs “Anecdotally, in everyday pediatrics, we see lots of breast-fed infants who should not have coughs, pneumonia or gastroenteritis, but they get

these on acid-suppressing drugs,” Dr. Hassall said. Other adverse effects, infectious and nutritional, have been seen in adults and could potentially occur in children as well. “Acid-suppressing drugs are invaluable in the management of several conditions in childhood, but there’s no free lunch; all drugs have potential adverse effects. So, the real risk is not in the prescribing of these drugs, it’s the overprescribing in patients who don’t warrant acid suppression.”

Unit Dose Done Right

Dr. Hassall takes a risk–benefit approach in his practice. “If the child has erosive esophagitis or demonstrable reflux disease, the benefits of acid suppression outweigh the risk,” he said.In the children who are not candidates for acid suppression, treatments include positioning, burping, avoidance of cigarette smoke, calming, temporizing, and very importantly, a trial of a change in diet. “Only as a lastditch effort do you prescribe an acidsuppressing drug,” Dr. Hassall said, adding that his first-line option is a

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Rogue Prescribers Christopher Jolley, MD, a professor and the chief of pediatric gastroenterology, hepatology and nutrition at the University of Florida College of Medicine, in Gainesville, agreed that the “dramatic increase in PPI usage is concerning” and said that Dr. Hassall’s comments regarding the risks associated with PPI usage in a population not at risk for significant GERD are “right on target.” Dr. Jolley concurred that “not all that cries or spits up is acid reflux disease. Most of it probably isn’t.” Regarding the overprescribing of PPIs, he said, “Although the marketing of these agents has played a role, I would bet that the change in prescribing practice represents greater perceived familiarity with PPIs among primary care physicians and perhaps more importantly, their numerous extenders. I don’t think the majority of PPI prescription increase represents gastroenterologists’ practice.” In addition to physicians, parents should be educated about treating infants for suspected GERD. A recent study published in the May issue of Pediatrics showed that parents who were told their infants had a diagnosis of GERD were interested in medication, even when they were told that the medications are likely ineffective (2013;13:839-845). In this study, researchers surveyed parents in a general pediatric clinic who were given a hypothetical clinical scenario describing an infant who “cries and spits up excessively but is otherwise healthy.” Parents were randomized to receive a scenario in which a doctor gave a diagnosis of GERD or did not provide a disease label. The researchers found that parents who received a GERD diagnosis for their infants were interested in medication, regardless of potential efficacy. Dr. Jolley observed that oftentimes infants coming to see a gastroenterologist have already been prescribed PPI therapy. “By the time the gastroenterologist sees these infants, they’re often drowning in PPIs, and failing,” he said. “I think we need to look first at who’s prescribing these drugs, and reeducate accordingly. Certainly, gastroenterologists need to be reminded, but to overlook a larger PPI-prescribing base at the primary care level misses the target.” —Caroline Hel wick Dr. Haskell delivered a plenary address on this topic at the 2012 American Academy of Pediatrics National Conference and Exhibition. For further reading, see Hassall E. Over-prescription of acid-suppressing medications in infants: how it came about, why it’s wrong, and what to do about it. J Pediatr 2012;160:193-198.

Clinical 19

Pharmacy Practice News • July 2013

Medication Safety

DIFFICULT DRUGS continued from page 16

those surrounding injectable chemotherapy. “Despite our very careful implementation of CPOE [computerized prescriber order entry] for chemotherapy, we found that the nursing check for oral chemotherapy had been lost in the transition,” he said. “We added back that safety check so that an oncology nurse [reviews] the prescription and documents [the findings] in our electronic health record [EHR]. This was an important accomplishment and an improvement over our paper process, because the nurse’s check is now documented in the EHR.” Patients admitted to the hospital who are already on oral chemotherapy present a thorny dilemma: Should the hospital allow patients to bring the drugs with them or add infrequently used and expensive medications to the formulary? “Cancer hospitals like St. Jude will always stock oral chemotherapy,” Dr. Hoffman said, “but community hospitals are going to be confronted with a challenge because they’re likely to admit patients for many reasons who also happen to be taking oral chemotherapy.” When patients are allowed to use their own oral chemotherapy, he emphasized several key precautions: Using a patient’s own medications in the hospital should be rare; there must be an order from the prescriber specifying the use of the home medication; home medications used by inpatients must be identified and documented by the pharmacist before administration; and home medications should not be stored at the bedside. “There are always opportunities to improve,” he said. “You can never be complacent with safety practices for high-risk drugs like chemotherapy.”

Preventing Rare but Lethal Intrathecal Drug Errors Nothing more true can be said about the IV chemotherapy drug vincristine. If the drug is administered intrathecally, patient death is nearly certain. Although the error is extremely rare, pharmacists at the Children’s Center of The Johns Hopkins Hospital, in Baltimore wanted to take the risk even lower. “Our main motivation was how serious the consequences of this mistake are,” said Nicole Mollenkopf MacLaughlin, PharmD, BCPS, a medication safety officer for pediatrics. “We also realized that other institutions were using safety strategies that were better than the ones we had in place.” The standard practice at Johns Hopkins had been to dispense concentrated vincristine in a syringe. But safety agencies such as ISMP, the World Health Organization and the FDA warn against using syringes. Now, the Children’s Center uses only 25-mL mini-bags to deliver vincristine (50-mL bags are the

norm for adults). The packaging is so distinctive that accidentally administering the drug via the wrong route becomes as close to zero as possible. Additionally, the volume contained in mini-bags is too high to fit into the intrathecal space. The facility adjusted its workflow to accommodate the change. For example, drug preparation and drug infusion take more time and can be major barriers to implementing the change. Additionally, determining appropriate concentrations and volumes for dispensing, especially for pediatric patients, is vital.

Throughout the infusion, a nurse must stay with the patient to monitor for signs of peripheral line infiltration and drug extravasation. The risk for vincristine extravasation—which can cause severe tissue damage and necrosis—is lower with mini-bags than with syringes, according to published information ((J Oncol Pharm Practt 2006;12:113-118; ISMP Medication Safety Alertt Feb. 23, 2006). “Accidental intrathecal vincristine administration has been happening for more than 50 years, and we’ve got a strategy that can dramatically reduce the like-

lihood of it occurring,” said Dr. Mollenkopf MacLaughlin. “We should embrace it, recognizing that there are barriers to making this change but that these barriers can be overcome. In the end it’s worth the effort. Since the change, our pharmacists, pharmacy technicians, nurses and physicians all feel more comfortable than they did before.” —Steve Frandzel Drs. Meisel, Hoffman and Cohen and Ms. Adams reported no relevant ﬁnancial conﬂicts of interest.

20 Clinical

Pharmacy Practice News • July 2013

Critical Care

Pre-Op Sedative May Blunt Post-Op Cognitive Dysfunction Washington—Although sevoflurane anesthesia can cause declines in shortterm cognitive function after surgery in elderly patients, preoperative infusion of dexmedetomidine can mitigate these effects, a new study suggests. Lead investigator Hui Xu, MD, a consultant anesthesiologist at the University of Science and Technology, in Wuhan, China, and her colleagues enrolled 60 patients (aged 65-75 years) into the

randomized, double-blind trial. Before undergoing anesthesia with sevoflurane, half the patients received an infusion of 1 mcg/kg dexmedetomidine (Precedex, Hospira) over 15 minutes, the other half received saline. Both groups underwent an otherwise identical standardized anesthetic regimen. As part of that regimen, 0.6 mg/kg of rocuronium was used to facilitate tracheal intubation. Anesthesia was induced with sevoflurane and a sin-

gle IV injection of 5 mcg/kg of fentanyl. Rocuronium was titrated throughout the procedure as needed. The researchers evaluated cognitive function using the Mini-Mental State Examination (MMSE), assessing patients preoperatively and one, three, six, 24 and 72 hours postoperatively. A postoperative decline of at least 2 points in at least two of the tested domains was defined as cognitive function decline.

As Dr. Xu reported at the American Society of Anesthesiologists’ 2012 annual meeting (abstract 149), the time to eye opening and extubation were comparable between groups. However, the time to react on command occurred sooner in patients given dexmedetomidinesevoflurane than in those receiving only sevoflurane ((P<0.05). MMSE scores showed no statistically significant differences between groups before surgery. Although these scores decreased significantly in both groups at one and three hours postoperatively ( <0.05), they were significantly lower (P in the sevoflurane-only group ((P<0.05). MMSE scores took six hours to recover to preoperative levels in the dexmedetomidine-sevoflurane group compared with 24 hours in the sevoflurane-only group. Two markers of brain injury, serum 100B and C-reactive protein (CRP), also appeared to be elevated in patients who received sevoflurane alone ((P<0.05). “These results show that although sevoflurane anesthesia can cause shortterm postoperative cognitive dysfunction, dexmedetomidine is effective at improving cognitive function associated particularly with respect to return to preoperative levels,” Dr. Xu said.

Critical Care Pharmacist’s View John W. Devlin, PharmD, an associate professor of pharmacy practice at Northeastern University, in Boston, noted that mounting evidence suggests that inhalational anesthetics may be neurotoxic to the aging brain, leading to postoperative cognitive dysfunction that can persist long after surgery. “In their rigorous, double-blind study, Dr. Xu and colleagues report that a high dose of dexmedetomidine administered prophylactically over a short period before sevoflurane anesthesia leads to faster postsurgical cognitive recovery,” Dr. Devlin said. “The fact that postoperative serum CRP and serum 100B concentrations were lower in the dexmedetomidine-treated patients suggests that the drug may exert a protective effect against the effects of inhalational anesthetics in the brain through both anti-inflammatory and decreased blood–brain permeability mechanisms. “While additional, larger studies are needed to evaluate the safety of dexmedetomidine in this setting and the benefits of its administration on longer-term cognitive and clinical outcomes,” Dr. Devlin added, “this important study suggests that the prophylactic use of dexmedetomidine may play an important role in improving short-term outcome in elderly patients who require surgery with an inhalational anesthetic.” —Michael Vlessides

Clinical 21

Pharmacy Practice News • July 2013

Critical Care

Etomidate Linked to Worse Post-Op Outcomes vs. Propofol Risk for death more than doubled for critically ill in retrospective study Washington—Noncardiac patients given etomidate may be up to three times more likely than those given propofol to die within 30 days, a new study suggests. “Although etomidate is sometimes used for general anesthesia induction in critically ill patients, the drug is known to cause prolonged adrenal impairment by blocking cortisol release,” said Ryu Komatsu, MD, a resident at the Cleveland Clinic in Ohio. “However, the potential link between etomidate and worsened postoperative outcomes has not been systematically studied in general surgical patients.” Dr. Komatsu and his colleagues evaluated the electronic records of 31,148 adult patients who underwent noncardiac surgery under general anesthesia requiring at least one night of hospitalization at the institution between 2005 and 2009. Anesthesia was induced with etomidate in 2,616 patients; 28,532 received propofol. The researchers performed propensity score matching for 2,143 patients who received etomidate and 5,231 given propofol using a host of potential demographic and intraoperative confounders. The matched groups were compared with respect to duration of postoperative hospitalization and 30-day mortality. Dr. Komatsu’s group found that 139 patients given etomidate died within 30 days of surgery, versus 134 in the propofol group (odds ratio, 2.3; 97.5% confidence interval, 1.73-3.06; P<0.001). The mean length of stay was seven days for patients given etomidate (range, three to 13) and six days for those who received propofol (range, two to 11). Patients who received etomidate were 18% less likely to be discharged from the hospital at any time after surgery than were those treated with propofol. “We also looked at the systolic blood pressure profile during surgery,” added Dr. Komatsu, who reported the findings at the 2012 annual meeting of the American Society of Anesthesiologists (abstract 015). “We found that from intubation to incision, propofol patients had lower systolic blood pressure, with mean difference of 8 to 9 mm Hg, which I think could be clinically significant.” Dr. Komatsu acknowledged the limitations of the retrospective study. “We could only show an association between worse outcomes and etomidate use,” he said. “Randomized controlled trials are necessary to determine if there is another relationship between etomidate use and outcomes, as well as to define precisely the effect of etomidate. In the meantime, however, [clinicians] should use etomidate judiciously, considering that etomi-

date’s improved hemodynamic stability at induction might be accompanied by substantially worse longer-term outcomes.” Jesse Ehrenfeld, MD, an assistant professor of anesthesiology at Vanderbilt University School of Medicine, in Nashville, Tenn., said the authors did the best analysis they could with the available data, However, “while their analysis

adjusted for a number of important variables [that] impact mortality and length of stay, it is still unclear what the potential impact of unmeasured confounding might be,” he said. “In my experience, most clinicians choose to use etomidate in sicker patients under particular clinical scenarios. And without a prospective randomized trial, those unaccounted-for

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22 Clinical

Pharmacy Practice News • July 2013

Gastroenterology

Hypertension Drug Linked To Sprue-Like Enteropathy

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lmesartan medoxomil (Benicar, Daiichi-Sankyo), a commonly prescribed blood pressure medication, has been reported to cause severe, spruelike enteropathy in some patients, according to several gastroenterologists. One of seven angiotensin receptor blockers approved by the FDA, olmesartan is unique because its prodrug activity occurs in the small bowel. Margot Herman, MD, of the Department of Medicine at the Mayo Clinic in Rochester, Minn., uncovered several Mayo patients who experienced this problem. She came across the first patient, a 59-year-old with a history of hypertension, when the patient came in for a second opinion after struggling for a year with severe diarrhea and weight loss. “She had total villous atrophy in her small bowel that had been refractory to all treatments for sprue. She was on [total parenteral nutrition] and was desperate for an answer,” Dr. Herman said. The patient asked if her symptoms could be due to her blood pressure medication, which seemed unlikely, because she had been taking olmesartan for more than a year before the onset of her symptoms, Dr. Herman said. But that same week another patient asked a similar question, prompting Mayo researchers to look back at a cohort of patients with collagenous sprue. The researchers found about 30% of those patients were taking olmesartan. “At that point, we asked our patients to change their blood pressure medication,” Dr. Herman said. “These patients improved inexplicably.” She and her team published a paper in August 2012, describing 22 patients diagnosed with idiopathic sprue or refractory celiac disease who recovered after discontinuing olmesartan ((Mayo Clinic Proceedings 2012;87:732-738). (They later identified at least 60 more probable cases.) The patients (13 women, 9 men) were a median age of 69 years and most were taking up to 40 mg per day of olmesartan. They were experiencing severe and protracted diarrhea for a mean duration of 19.2 months. Weight loss was common, and in many cases patients lost up to half their body weight; most of them required hospitalization for dehydration and other symptoms. The most significant symptom was the change in small bowel histology. All 22 of the patients had villous atrophy; 15 had total villous atrophy and seven had subepithelial collagen deposition. Laboratory results did not indicate celiac disease, and gluten-free diets and systemic steroids were ineffective in treating these patients.

Once the patients were taken off olmesartan, all had complete resolution of diarrhea and required no further therapies. Many were able to gain weight, and all were able to return to a gluten diet, without any recurrence of symptoms. Of the 18 patients who had a biopsy, 17 had complete histologic recovery of the duodenum. “Ethically it is impossible to rechallenge these patients to prove causality,” Dr. Herman said. “However, anecdotally, challenge was redone in three patients prior to making this connection, all of whom developed severe diarrhea, nausea and vomiting.” These findings may be just the tip of the iceberg, she added, but evidence may be hard to obtain due to the long delay between the time patients start taking olmesartan and the onset of symptoms. Sheila E. Crowe, MD, a professor of medicine, University of California, San Diego, in La Jolla, said she is interested in the Mayo study because it recalled a few of her patients with celiac disease whose conditions resisted treatment, or mysteriously worsened after first improving. “The first patient had ulcerative celiac disease. Her husband alerted us that ‘every time she takes Benicar, she gets worse,’” Dr. Crowe said. Another patient’s refractory celiac disease improved after treatment with steroids and immunosuppressives, but when he regained weight and resumed taking his blood pressure medication—olmesartan—his condition deteriorated. When the patient switched to another antihypertensive medication, his symptoms improved. Dr. Crowe saw this pattern in a few patients, but she said it’s impossible at this point to determine what caused the symptoms to subside. “Maybe it was just a longer time on a gluten-free diet,” she said. “But I definitely believe this drug—and I don’t know how—is causing a problem.” She noted that although her patients are a somewhat different group from those described in the Mayo study, there may be some overlap. “I think more research needs to be done, but this certainly warrants reconsidering [using] that drug for anyone who has other choices for an antihypertensive [medication].” —Monica J. Smith Based on presentations at recent gastroenterology conferences.

Clinical 23

Pharmacy Practice News • July 2013

Critical Care

When Anti-TNF Fails, Is It Time for Another Biologic?

oss of response to an anti–tumor necrosis factor (TNF) agent should not prompt an immediate switch to another biologic because the likelihood of a renewed response decreases with each successive biologic switch, according to Gary Lichtenstein, MD, the director of the Center for Inflammatory Bowel Disease at the University of Pennsylvania, in Philadelphia. The question of whether to switch to a second or third biologic is significant given that 77% of patients with Crohn’s disease (CD) lose response to infliximab (Remicade, Janssen Biotech) within two years of starting treatment (Value Health 2008;11:820-829). Dr. Lichtenstein urged clinicians to rule out disease complications that may be causing symptoms, minimize potentially disease-aggravating environmental factors and intensify the dosage of treatment before considering switching agents. “Many patients quickly lose response after switching to another biologic and some also develop adverse events,” Dr. Lichtenstein said, as demonstrated by results from the GAIN trial ((Ann Intern Med d 2007;146:829-838). Switching to a third drug may reduce further the chance of achieving a sustained response, while also heightening the risk for adverse events, Dr. Lichtenstein said. In one study, 67 patients with CD who had lost response to two prior anti-TNF agents were administered either adalimumab or certolizumab (Cimzia, UCB) ((Aliment Pharmacol Ther 2010;31:92-101). After a median follow-up of 26 weeks, 36 patients had discontinued the drug—13 due to intolerance and 23 due to lack of response. “These data suggest that before switching to another biologic, we should be evaluating our patients for disease complications, enteric infections and other variables that might be managed, as well as using dose intensification strategies,” Dr. Lichtenstein said. Some symptoms are related to disease complications that require surgical instead of medical treatment, he said. These include fibrostenotic disease, intraabdominal and pelvic abscesses, and toxic megacolon. Similarly, bacterial infections—such as Clostridium difficile—parasitic diseases and cytomegalovirus can mimic inflammatory bowel disease symptoms. Patients should be examined for these and treated before switching biologics. Dr. Lichtenstein said that patients also should be evaluated for the use of nonsteroidal anti-inflammatory drugs, cigarette smoking and poor medication adherence because these can cause symptoms. Once other potential causes have been evaluated and addressed, clinicians should consider increasing the

dose of the anti-TNF medication. Data from the ACCENT 1 and 2 trials of infliximab support this strategy (Lan( cet 2002;359:1541-1549; N Engl J Med 2004;350:876-885), according to Dr. Lichtenstein. In those studies, 89.3% and 57.1% of a subset of patients in the two trials, respectively, who had lost response were able to regain response after the dose of infliximab was raised from 5 to 10 mg/kg.

Shortening the dosing interval is another strategy for increasing the dosage of drug, according to Dr. Lichtenstein, who presented on this topic at a 2012 CD research meeting He pointed to results from a study of 33 infliximab recipients and 14 adalimumab-treated patients who had their dosing intervals shortened following a loss of response (Digestive Disease Week 2011; abstract Mo1239). Sixty-seven percent of inflix-

imab recipients and 36% of adalimumab recipients regained response, and about half of these patients were able to return to a normal dosing schedule. —David Wild Dr. Lichtenstein has received research funding, served as an advisory board member or received honoraria from Abbott Laboratories Janssen Pharmaceuticals and UCB.

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

Important Risk Information NEXTERONE (amiodarone HCl) Premixed Injection is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE, including iodine • Cardiogenic shock • Marked sinus bradycardia • Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available • NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits fi of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment. • Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported in 16% (288/1836) of patients treated with intravenous amiodarone. Clinically significant fi hypotension during infusions was seen most often in the first several hours of treatment and appeared to be related to the rate of infusion. Monitor the initial rate of infusion closely and do not exceed the recommended rate. In some cases, hypotension may be refractory and result in a fatal outcome. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including: vasopressors, positive inotropic agents and volume expansion. • In 4.9% (90/1836) of patients in clinical trials, drug-related bradycardia that was not dose-related occurred while patients were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available. • Elevations of blood hepatic enzyme values ALT, AST, GGT are commonly seen in patients with immediately life-threatening VT/VF. / In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE for evidence of progressive hepatic injury. In such cases, consider reducing the rate of administration or withdrawing NEXTERONE. • Like all antiarrhythmics, NEXTERONE may cause worsening of existing arrhythmias or precipitate a new arrhythmia. Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent. • There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with intravenous amiodarone. Findings included pulmonary infi filtrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death. Two percent (2%) of patients were reported to have acute respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy. Pulmonary toxicity including pulmonary fifibrosis is a well-recognized complication of long-term amiodarone use. • Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone can cause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function tests may persist for several weeks or even months following NEXTERONE withdrawal. • The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%). • Drug Interactions • Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone. • Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein. HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with amiodarone have been associated with reports of myopathy/rhabdomyolysis. Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required. • Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in effi ficacy. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. 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NEXTERONE (amiodarone HCl) Premixed Injection for intravenous use Brief Summary of Prescribing Information. See PI for Full Prescribing Information. 1 INDICATIONS AND USAGE NEXTERONE is indicated for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation (VF) and hemodynamically unstable ventricular tachycardia (VT) in patients refractory to other therapy. NEXTERONE also can be used to treat patients with VT/VF for whom oral amiodarone is indicated, but who are unable to take oral medication. During or after treatment with NEXTERONE, patients may be transferred to oral amiodarone therapy [see Dosage and Administration (2) in full prescribing information]. Use NEXTERONE for acute treatment until the patient’s ventricular arrhythmias are stabilized. Most patients will require this therapy for 48 to 96 hours, but NEXTERONE may be safely administered for longer periods if necessary. 4 CONTRAINDICATIONS NEXTERONE is contraindicated in patients with: • Known hypersensitivity to any of the components of NEXTERONE Premixed Injection, including iodine. Hypersensitivity reactions may involve rash, angioedema, cutaneous/mucosal hemorrhage (bleeding), fever, arthralgias (joint pains), eosinophilia (abnormal blood counts), urticaria (hives), thrombotic thrombocytopenic purpura, or severe periarteritis (inflammation around blood vessels). • Cardiogenic shock. • Marked sinus bradycardia. • Second- or third-degree atrio-ventricular (AV) block unless a functioning pacemaker is available. 5 WARNINGS AND PRECAUTIONS NEXTERONE should be administered only by physicians who are experienced in the treatment of life-threatening arrhythmias, who are thoroughly familiar with the risks and benefits of amiodarone therapy, and who have access to facilities adequate for monitoring the effectiveness and side effects of treatment. 5.1 Hypotension Hypotension is the most common adverse reaction seen with intravenous amiodarone. In clinical trials, treatment-emergent, drug-related hypotension was reported as an adverse effect in 288 (16%) of 1836 patients treated with intravenous amiodarone. Clinically significant hypotension during infusions was seen most often in the first several hours of treatment and was not dose related, but appeared to be related to the rate of infusion. Hypotension necessitating alterations in intravenous amiodarone therapy was reported in 3% of patients, with permanent discontinuation required in less than 2% of patients. Treat hypotension initially by slowing the infusion; additional standard therapy may be needed, including the following: vasopressor drugs, positive inotropic agents, and volume expansion. Monitor the initial rate of infusion closely and do not exceed the recommended rate [see Dosage and Administration (2) in full prescribing information]. In some cases, hypotension may be refractory and result in a fatal outcome [see Adverse Reactions (6.2) in full prescribing information]. 5.2 Bradycardia and Atrio-ventricular Block In 90 (4.9%) of 1836 patients in clinical trials, drug-related bradycardia that was not dose-related occurred while they were receiving intravenous amiodarone for life-threatening VT/VF. Treat bradycardia by slowing the infusion rate or discontinuing NEXTERONE. In some patients, inserting a pacemaker is required. Despite such measures, bradycardia was progressive and terminal in 1 patient during the controlled trials. Treat patients with a known predisposition to bradycardia or AV block with NEXTERONE in a setting where a temporary pacemaker is available. 5.3 Liver Enzyme Elevations Elevations of blood hepatic enzyme values [alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT)] are commonly seen in patients with immediately life-threatening VT/VF. Interpreting elevated AST activity can be difficult because the values may be elevated in patients who have had recent myocardial infarction, congestive heart failure, or multiple electrical defibrillations. Approximately 54% of patients receiving intravenous amiodarone in clinical studies had baseline liver enzyme elevations, and 13% had clinically significant elevations. In 81% of patients with both baseline and on-therapy data available, the liver enzyme elevations either improved during therapy or remained at baseline levels. Baseline abnormalities in hepatic enzymes are not a contraindication to treatment. Acute, centrolobular confluent hepatocellular necrosis leading to hepatic coma, acute renal failure, and death has been associated with the administration of intravenous amiodarone at a much higher loading dose concentration and much faster rate of infusion than recommended [see Dosage and Administration (2) in full prescribing information]. In patients with life-threatening arrhythmias, the potential risk of hepatic injury should be weighed against the potential benefit of NEXTERONE therapy. Carefully monitor patients receiving NEXTERONE for evidence of progressive hepatic injury. In such cases, consider reducing the rate of administration or withdrawing NEXTERONE. 5.4 Proarrhythmia Like all antiarrhythmic agents, NEXTERONE may cause a worsening of existing arrhythmias or precipitate a new arrhythmia. Proarrhythmia, primarily torsade de pointes (TdP), has been associated with prolongation, by intravenous amiodarone, of the QTc interval to 500 ms or greater. Although QTc prolongation occurred frequently in patients receiving intravenous amiodarone, TdP or new-onset VF occurred infrequently (less than 2%). Monitor patients for QTc prolongation during infusion with NEXTERONE. Reserve the combination of amiodarone with other antiarrhythmic therapies that prolong the QTc to patients with life-threatening ventricular arrhythmias who are incompletely responsive to a single agent. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP , in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly [see Drug Interactions (7) in full prescribing information].

Amiodarone causes thyroid dysfunction in some patients, which may lead to potentially fatal breakthrough or exacerbated arrhythmias. 5.5 Pulmonary Disorders Early-onset Pulmonary Toxicity There have been postmarketing reports of acute-onset (days to weeks) pulmonary injury in patients treated with intravenous amiodarone. Findings have included pulmonary infiltrates and masses on X-ray, bronchospasm, wheezing, fever, dyspnea, cough, hemoptysis, and hypoxia. Some cases have progressed to respiratory failure or death. ARDS Two percent (2%) of patients were reported to have adult respiratory distress syndrome (ARDS) during clinical studies involving 48 hours of therapy. Pulmonary Fibrosis Only 1 of more than 1000 patients treated with intravenous amiodarone in clinical studies developed pulmonary fibrosis. In that patient, the condition was diagnosed 3 months after treatment with intravenous amiodarone, during which time the patient received oral amiodarone. Pulmonary toxicity is a well-recognized complication of long-term amiodarone use (see package insert for oral amiodarone). 5.6 Loss of Vision Cases of optic neuropathy and optic neuritis, usually resulting in visual impairment, have been reported in patients treated with oral amiodarone. In some cases, visual impairment has progressed to permanent blindness. Optic neuropathy and neuritis may occur at any time following initiation of therapy. A causal relationship to the drug has not been clearly established. Perform an ophthalmic examination if symptoms of visual impairment appear, such as changes in visual acuity and decreases in peripheral vision. Re-evaluate the necessity of amiodarone therapy if optic neuropathy or neuritis is suspected. Perform regular ophthalmic examination, including fundoscopy and slit-lamp examination, during administration of NEXTERONE. 5.7 Long-Term Use There has been limited experience in patients receiving intravenous amiodarone for longer than 3 weeks. See package insert for oral amiodarone. 5.8 Thyroid Abnormalities Amiodarone inhibits peripheral conversion of thyroxine (T4) to triiodothyronine (T3) and may cause increased T4 levels, decreased T3 levels, and increased levels of inactive reverse T3 (rT3) in clinically euthyroid patients. Amiodarone is also a potential source of large amounts of inorganic iodine and can cause either hypothyroidism or hyperthyroidism. Evaluate thyroid function prior to treatment and periodically thereafter, particularly in elderly patients, and in any patient with a history of thyroid nodules, goiter, or other thyroid dysfunction. Because of the slow elimination of amiodarone and its metabolites, high plasma iodide levels, altered thyroid function, and abnormal thyroid function tests may persist for several weeks or even months following NEXTERONE withdrawal. There have been postmarketing reports of thyroid nodules/thyroid cancer in patients treated with amiodarone. In some instances hyperthyroidism was also present [see Adverse Reactions (6.2) in full prescribing information]. Hyperthyroidism and Thyrotoxicosis Hyperthyroidism occurs in about 2% of patients receiving amiodarone, but the incidence may be higher among patients with prior inadequate dietary iodine intake. Amiodarone-induced hyperthyroidism usually poses a greater hazard to the patient than hypothyroidism because of the possibility of thyrotoxicosis and arrhythmia breakthrough or aggravation, all of which may result in death. There have been reports of death associated with amiodarone-induced thyrotoxicosis. Consider the possibility of hyperthyroidism if any new signs of arrhythmia appear. Identify hyperthyroidism by relevant clinical signs and symptoms, subnormal serum levels of thyroid stimulating hormone (TSH), abnormally elevated serum free T4, and elevated or normal serum T3. Since arrhythmia breakthroughs may accompany amiodarone-induced hyperthyroidism, aggressive medical treatment is indicated, including, if possible, dose reduction or withdrawal of amiodarone. Amiodarone hyperthyroidism may be followed by a transient period of hypothyroidism. The institution of antithyroid drugs, Ƶ-adrenergic blockers or temporary corticosteroid therapy may be necessary. The action of antithyroid drugs may be especially delayed in amiodarone-induced thyrotoxicosis because of substantial quantities of preformed thyroid hormones stored in the gland. Radioactive iodine therapy is contraindicated because of the low radioiodine uptake associated with amiodarone-induced hyperthyroidism. When aggressive treatment of amiodarone-induced thyrotoxicosis has failed or amiodarone cannot be discontinued because it is the only drug effective against the resistant arrhythmia, surgical management may be an option. Experience with thyroidectomy as a treatment for amiodarone-induced thyrotoxicosis is limited, and this form of therapy could induce thyroid storm. Therefore, surgical and anesthetic management require careful planning. Neonatal Hypo- or Hyperthyroidism Amiodarone can cause fetal harm when administered to a pregnant woman. Although amiodarone use during pregnancy is uncommon, there have been a small number of published reports of congenital goiter/hypothyroidism and hyperthyroidism associated with oral administration. Inform the patient of the potential hazard to the fetus if NEXTERONE is administered during pregnancy or if the patient becomes pregnant while taking NEXTERONE. Hypothyroidism Hypothyroidism has been reported in 2% to 4% of patients in most series, but in 8% to 10% in some series. This condition may be identified by relevant clinical symptoms and particularly by elevated serum TSH levels. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the NEXTERONE dose and considering the need for thyroid hormone supplement. However, therapy must be individualized, and it may be necessary to discontinue oral amiodarone in some patients.

5.9 Surgery Perform close perioperative monitoring in patients undergoing general anesthesia who are on amiodarone therapy as they may be more sensitive to the myocardial depressant and conduction defects of halogenated inhalational anesthetics.

Nervous System: hallucination, confusional state, disorientation, and delirium, pseudotumor cerebri

5.10 Corneal Refractive Laser Surgery Advise patients that most manufacturers of corneal refractive laser surgery devices contraindicate corneal refractive laser surgery in patients taking amiodarone.

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

5.11 Electrolyte Disturbances Correct hypokalemia or hypomagnesemia whenever possible before initiating treatment with NEXTERONE, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or in patients receiving concomitant diuretics.

Thyroid: d thyroid nodules/thyroid cancer

6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reﬂect the rates observed in practice. In a total of 1836 patients in controlled and uncontrolled clinical trials, 14% of patients received intravenous amiodarone for at least one week, 5% received it for at least 2 weeks, 2% received it for at least 3 weeks, and 1% received it for more than 3 weeks, without an increased incidence of severe adverse reactions. The mean duration of therapy in these studies was 5.6 days; median exposure was 3.7 days. The most important adverse reactions were hypotension, asystole/cardiac arrest/pulseless electrical activity (PEA), cardiogenic shock, congestive heart failure, bradycardia, liver function test abnormalities, VT, and AV block. Overall, treatment was discontinued for about 9% of the patients because of adverse reactions. The most common adverse reactions leading to discontinuation of intravenous amiodarone therapy were hypotension (1.6%), asystole/cardiac arrest/PEA (1.2%), VT (1.1%), and cardiogenic shock (1%). Table 4 lists the most common (incidence *2%) adverse reactions during intravenous amiodarone therapy considered at least possibly drug-related. These data were collected in clinical trials involving 1836 patients with life-threatening VT/VF. Data from all assigned treatment groups are pooled because none of the adverse reactions appeared to be dose-related. Table 4: ADVERSE REACTIONS IN PATIENTS RECEIVING INTRAVENOUS AMIODARONE IN CONTROLLED AND OPEN-LABEL STUDIES (> 2% INCIDENCE) Study Event

Body as a whole Fever Cardiovascular System Bradycardia Congestive heart failure Heart arrest Hypotension Ventricular tachycardia Digestive System Liver function tests normal Nausea

Controlled Studies (n=814)

Open-Label Studies (n=1022)

Total (n=1836)

Body as a whole

Body as a whole 13 (1.2%)

Body as a whole 37 (2.0%)

24 (2.9%) Cardiovascular 49 (6.0%) 18 (2.2%) 29 (3.5%) 165 (20.2%) 15 (1.8%) Digestive System 35 (4.2%) 29 (3.5%)

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

Cardiovascular 90 (4.9%) 39 (2.1%) 55 (2.9%) 288 (15.6%) 45 (2.4%) Digestive System 64 (3.4%) 72 (3.9%)

Other adverse reactions reported in less than 2% of patients receiving intravenous amiodarone in controlled and uncontrolled studies included the following: abnormal kidney function, atrial ﬁbrillation, diarrhea, increased ALT, increased AST, lung edema, nodal arrhythmia, prolonged QT interval, respiratory disorder, shock, sinus bradycardia, Stevens-Johnson syndrome, thrombocytopenia, VF, and vomiting. 6.2 Post-Marketing Experience The following adverse reactions have been identiﬁed during post-approval use of amiodarone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: anaphylactic/anaphylactoid reaction (including shock), fever

Pancreatic: pancreatitis Renal:l renal impairment, renal insufﬁciency, acute renal failure

Vascular: r vasculitis 7 DRUG INTERACTIONS Since amiodarone is a substrate for CYP3A and CYP2C8, drugs/substances that inhibit these isoenzymes may decrease the metabolism and increase serum concentration of amiodarone. Amiodarone inhibits p-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A. This inhibition can result in unexpectedly high plasma levels of other drugs which are metabolized by those CYP450 enzymes or are substrates for p-glycoprotein. HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with amiodarone has been associated with reports of myopathy/rhabdomyolysis. Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required. Some drugs/substances are known to accelerate the metabolism of amiodarone by stimulating the synthesis of CYP3A (enzyme induction). This may lead to low amiodarone serum levels and potential decrease in efficacy. Fluoroquinolones, macrolide antibiotics, and azoles are known to cause QTc prolongation. There have been reports of QTc prolongation, with or without TdP, in patients taking amiodarone when fluoroquinolones, macrolide antibiotics, or azoles were administered concomitantly. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D Reproductive and teratology studies performed in rabbits and rats at doses of up to 100 mg/kg per day (about 1.4 times the maximum recommended human dose on a body surface area basis) revealed no evidence of embryotoxicity at 5 mg/kg and no teratogenicity was observed at any dosage in rabbits. Maternal toxicity and embryotoxicity were observed in rats in the 100 mg/kg group. Use NEXTERONE during pregnancy only if the potential benefit to the mother justifies the risk to the fetus. 8.2 Labor and Delivery It is not known whether the use of amiodarone during labor or delivery has any immediate or delayed adverse effects. 8.3 Nursing Mothers Amiodarone and one of its major metabolites, desethylamiodarone (DEA), are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. 8.4 Pediatric Use The safety and effectiveness of amiodarone in pediatric patients have not been established; therefore, the use of amiodarone in pediatric patients is not recommended. 8.5 Geriatric Use Clinical studies of amiodarone did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Carefully consider dose selection in an elderly patient. 10 OVERDOSAGE There have been cases, some fatal, of amiodarone overdose. Effects of an inadvertent overdose of intravenous amiodarone include hypotension, cardiogenic shock, bradycardia, AV block, and hepatotoxicity. Treat hypotension and cardiogenic shock by slowing the infusion rate or with standard therapy: vasopressor drugs, positive inotropic agents, and volume expansion. Bradycardia and AV block may require temporary pacing. Monitor hepatic enzyme concentrations closely. Amiodarone is not dialyzable.

Baxter Healthcare Corporation Deerﬁeld, IL 60015 Baxter, Galaxy, Nexterone and the Sphere Graphic are trademarks of Baxter International Inc.

Cardiovascular: r hypotension (sometimes fatal), sinus arrest Dermatologic: toxic epidermal necrolysis (sometimes fatal), exfoliative dermatitis, erythema multiforme, Stevens-Johnson syndrome, skin cancer, pruritus, angioedema

Sourced from: 07-19-68-241 Rev. January 2012

Endocrine: syndrome of inappropriate antidiuretic hormone secretion (SIADH) Hematologic: pancytopenia, neutropenia, hemolytic anemia, aplastic anemia, thrombocytopenia, agranulocytosis, granuloma Hepatic: hepatitis, cholestatic hepatitis, cirrhosis Injection Site Reactions: pain, erythema, edema, pigment changes, venous thrombosis, phlebitis, thrombophlebitis, cellulitis, necrosis, and skin sloughing Musculoskeletal:l myopathy, muscle weakness, rhabdomyolysis

111923 04/13

Hem/Onc Pharmacy

Pharmacy Practice News • July 2013

In Focus

Oral Oncology Drugs Rife With Challenges Los Angeles—In recent years, oral oncology agents have flooded the market, providing new therapeutic options. Although these drugs are seen as more convenient for patients, they come with a unique set of challenges, according to a panel of experts at the 2013 annual meeting of the Hematology/Oncology Pharmacy Association. Food–drug and drug–drug interactions, limited access, reimbursement problems and monitoring requirements are all obstacles associated with oral cancer drugs, said panelist Robert

Ignoffo, PharmD, a professor of pharmacy at Touro University California and a clinical professor emeritus at the University of California, San Francisco. Educating patients about these agents can be particularly challenging, according to Beth Chen, PharmD, BCOP, an oncology clinical specialist at Biologics Inc., in Cary, N.C. Patients may be overwhelmed by the sheer amount of information on drug administration, side effects, drug interactions and safe handling concerns. They also may receive instructions from several sources at the

clinic and the pharmacy. “While the information provided may be correct, differences in wording or focus may confuse the patient,” Dr. Chen said. Despite educational efforts, a number of factors, including the drug’s administration schedule and side effects, can make medication adherence difficult for the patient. “In some cases, patients may feel worse while taking the medication,” Dr. Chen noted. “When an immediate benefit is not felt by the patient, it can be difficult for that patient to feel motivated to continue [his or her] regimen.”

Interactions With Foods And Other Drugs Robert Mancini, PharmD, BCOP, an oncology pharmacist and a PGY2 oncology residency director at St. Luke’s Mountain States Tumor Institute, in Boise, Idaho, said one important aspect of educating patients about the use of oral medications is they need to be informed about the effects of food (Table 1). For example, high-fat meals can increase the absorption of some drugs, such as nilotinib (Tasigna, Novartis) and abiraterone (Zytiga, Janssen), but can decrease the exposure of other drugs such as eltrom-

‘‘Our patients [often] are leaving our clinics with oral chemotherapy agents and are faced with astronomical copays.’ —Sarah Hudson-DiSalle, PharmD

Table 1. Examples of Drug and Food Interactions Oral Oncology Drug

Drug Interactions

Food Interactions

Abiraterone (Zytiga, Janssen)

CYP2D6 substrates and CYP3A4 inhibitors and inducers

Must be taken on an empty stomach; high-fat meals can increase exposure 10-fold

Capecitabine (Xeloda, Genentech)

Phenytoin and warfarin

Must be taken with food to reduce side effects

Dasatinib (Sprycel, Bristol-Myers Squibb)

Requires acidic environment, must evaluate patients on acid suppressors

Grapefruit juice may increase drug plasma concentration

Erlotinib (Tarceva, Genentech)

Warfarin, acid suppressors, CYP3A4 substrates

Must be taken on an empty stomach to avoid polyvalent cations from binding medication and reducing absorption

Imatinib (Gleevec, Novartis)

CYP3A4, CYP2C19 and CYP2D6 inhibitors

Must be taken with food to reduce gastrointestinal irritation

Lapatinib (Tykerb, GlaxoSmithKline)

CYP3A4 inhibitors and inducers

Must be taken on an empty stomach; grapefruit juice may increase drug plasma concentration

Nilotinib (Tasigna, Novartis)

CYP3A4 inhibitors and inducers; requires acidic environment, must evaluate patients on acid suppressors

Must be taken on an empty stomach

Sorafenib (Nexavar, Bayer)

CYP3A4 inhibitors and inducers, CYP2C9 inhibitors

Must be taken on an empty stomach

Temozolomide (Temodar, Schering-Plough)

Valproic acid can increase systemic levels of temozolomide

Must be taken on an empty stomach or at bedtime to reduce nausea and vomiting

CYP, cytochrome enzyme Based on prescribing information.

bopag (Promacta, GlaxoSmithKline). Patients often do not understand what a high-fat meal is, and this is where a referral to a dietitian can be helpful, Dr. Mancini said. Another complication is drugs that are prescribed in combination but have different instructions about whether they should be taken with meals. For example, abiraterone and prednisone are prescribed together, but abiraterone is to be taken on an empty stomach and prednisone is taken with food. Pharmacists can help patients wade through this confusing maze of instructions by setting up an eating schedule. Drug–drug interactions are more of a problem with oral agents, with the cytochrome enzyme CYP3A4 and warfarin interactions being common, Dr. Mancini noted. He highlighted results from a Medco study, presented at the 2012 annual meeting of the American Society for Clinical Pharmacology and Therapeutics, that reviewed pharmacy claims of approximately 11,600 patients taking nine commonly used oral tyrosine kinase inhibitors. The investigators evaluated the number of patients taking at least one other drug that had the potential to cause a drug interaction. “What they found was that depending on the drug, anywhere from one-quarter to three-quarters of the patients were on at least one drug that would interact with that agent, either decreasing the efficacy of that agent or increasing the toxicity,” he said. For help in educating patients, Dr. Mancini suggested that pharmacists could turn to the American Society of Clinical Oncology’s Quality Oncology Practice Initiative (QOPI). QOPI includes patient education parameters regarding food and drug interactions, how to handle missed doses, potential side effects and a slew of other topics.

Cost Can Be a Barrier Cost is another huge stumbling block to medication procurement, according to another panelist. “Our patients [often] are leaving our clinics with oral chemotherapy agents and are faced with astronomical copays,” said Sarah Hudson-DiSalle, PharmD, RPh, a specialty practice pharmacist at the Arthur G. James Cancer Hospital and Richard Solove Research Institute at The Ohio State University, in Columbus. Insurance plans place oral chemotherapy into the specialty tier benefit, which decreases drug costs for payers at the expense of patients, according to Dr. Hudson-DiSalle. A 25 mg dose of lenalidomide, which on average costs $11,016, requires a copay of $1,200; 150 mg of nilotinib, with an

•

see ORAL ONCOLOGY, page 30

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April 2013

CO24-0413

Hem/Onc Pharmacy

Pharmacy Practice News • July 2013

In Focus Table 2. Copays of Selected Oral Oncology Drugs

ORAL ONCOLOGY continued from page 28

average cost of $9,849, demands a copay of $2,800. Other drugs carry similarly hefty price tags (Table 2). “Patients with costs more than $200 per month are three times more likely to not fill prescriptions,” Dr. Hudson-DiSalle said. Patients who are underinsured— Medicare patients who don’t qualify for low-income subsidies or who fall into high-copay specialty tiers, patients on Medicaid who have a high spend–down, patients on commercial insurance who have high deductibles and copays or may be plagued by formulary restrictions— often slip through the cracks.

Medication

Average Pricea

Amount Of Copayb

Lenalidomide (Revlimid, Celgene) 25 mg

$11,016

$1,200

Nilotinib (Tasigna, Novartis) 150 mg

$9,849

$2,800

Temozolomide (Temodar, Schering-Plough) 250 mg

$2,400

$400

Crizotinib (Xalkori, Pfizer) 250 mg

$11,768

$1,000

Abiraterone (Zytiga, Janssen) 250 mg

$5,821

$580

Capecitabine (Xeloda, Genentech) 500 mg

$11,590

$1,500

Based on retail prices at Walgreens store at Wexner Medical Center.

Based on copays from patients at James Cancer Hospital.

the federal laws need to work together to have all patients covered for parity to be impactful for patients,” Dr. HudsonDiSalle explained. “Some employers are covered by federal regulations (ERISA plans) and then others [are covered] via state plans.” —Kate O’Rourke Drs. Chen, Hudson-DiSalle and Ignoffo had no relevant disclosures. Dr. Mancini disclosed participation in the speaker’s bureau for Millennium Pharmaceuticals and a paid consultantship for GlaxoSmithKline.

Helping Patients Overcome Financial Obstacles Pharmacists have a role in helping patients overcome financial obstacles, Dr. Hudson-DiSalle said. The first step is to assess the patient’s ability to pay for medication. If there is a problem, the pharmacist should determine whether it is a medication copay issue that involves one or multiple medications or if it is coveragespecific, for example involving the donut hole. Next, pharmacists should attempt to resolve coverage problems with the insurer by, for example, re-tiering a medication or persuading the insurance company to make a formulary exception. The third step is to seek available assistance; this could include drug manufacturer copay cards, nonprofit copay assistance foundations and manufacturer patient assistance programs (PAPs). Dr. Hudson-DiSalle suggested that when a new oncology agent is released, pharmacists should meet proactively with pharmaceutical company representatives to discuss coverage resources, including PAP forms, disease-based assistance and discount cards. Then they should work proactively with patients who are candidates for the new medication. “Work with those patients to find out which specialty pharmacy they use, who they are contracting with, and any type of financial information [pertinent to] that patient to expedite the patient getting that medication,” she said. Oral chemotherapy parity legislation that ensures equal coverage for oral and intravenous chemotherapy may improve access, but it has been slow-moving. As of press time, 25 states and the District of Columbia had passed oral chemotherapy parity legislation. Dr. Hudson-DiSalle said, “At this rate, it is going to take us 10 years for all these states to have some type of legislation in place.” She said federal legislation is another avenue through which parity might occur. The House of Representatives introduced the Cancer Drug Coverage Parity Act (H.R. 2746) on April 26. The bill was assigned to a committee for consideration. “The state and

INDICATION: Venofer ® (iron sucrose injection, USP) is indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). IMPORTANT SAFETY INFORMATION: • Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been lifethreatening and fatal, have been reported in patients receiving Venofer ® (iron sucrose injection, USP). Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer ® immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Venofer ® administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer® when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. • Venofer ® may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer ®. Hypotension following administration of Venofer ® may be related to rate of administration and total dose delivered. Leading anemia management.™

Hem/Onc Pharmacy 31

Pharmacy Practice News • July 2013

In Focus

Lenalidomide Approved for Mantle Cell Lymphoma

he FDA has expanded its approval of lenalidomide (Revlimid, Celgene) to include mantle cell lymphoma (MCL). Lenalidomide is now approved for the treatment of patients with MCL whose disease has recurred or progressed following two previous therapies, one of which was bortezomib. Lenalidomide is the first oral therapy approved to treat this type of lymphoma, according to a press release from Cel-

gene. The drug is already approved for previously treated multiple myeloma and transfusion-dependent anemia due to deletion 5q myelodysplastic syndromes. The expanded indication is based on the results of MCL-001, a Phase II, multicenter, open-label, single-arm trial that included 134 patients with MCL who had received prior treatment with rituximab, cyclophosphamide, an anthracycline (or mitoxantrone) and bortezomib. Patients

were required to have refractory or recurring disease. Celgene reported that in this trial, the overall response rate (the primary end point) for lenalidomide was 26% (34 of 133; 95% confidence interval [CI], 18.4%-33.9%). The complete response rate was 7% (nine of 133; 95% CI, 3.1%12.5%). The median duration of response was 16.6 months (95% CI, 7.7-26.7). Lenalidomide carries a black box warning for embryo-fetal toxicity as

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• Venofer ® is contraindicated in patients with known hypersensitivity to Venofer ®. Do not administer to patients with evidence of iron overload. • In efficacy studies in non-dialysis dependent-CKD patients (N=139), the most frequent adverse events ( 5%) whether or not related to Venofer® administration, were nausea (8.6%), taste disturbance (7.9%), peripheral edema (7.2%), diarrhea (7.2%), dizziness (6.5%), hypertension (6.5%), infusion site pain or burning (5.8%), dyspnea (5.8%), and vomiting (5.0%). • In multi-dose efficacy studies in hemodialysis dependent-CKD patients (N=231), the most frequent adverse events (>5%) whether or not related to Venofer® administration, were hypotension (39.4%), muscle cramps (29.4%), nausea (14.7%), headache (12.6%), graft complications (9.5%), vomiting (9.1%), dizziness (6.5%), hypertension (6.5%), chest pain (6.1%), and diarrhea (5.2%). In the study of peritoneal dialysis-CKD patients (N=75), the most frequent adverse events, whether or not related to Venofer ®, reported by 5% of these patients were infections and infestations (nasopharyngitis, sinusitis, upper respiratory tract, pharyngitis) (16.0%), diarrhea (8.0%), vomiting (8.0%), hypertension (8.0%), peripheral edema (5.3%), and nausea (5.3%). *100 mg vials and ampules worldwide from 1992 to February 2011. Reference: 1. Data on file. American Regent, Inc. Shirley, NY.

Please see brief Prescribing Information on adjacent page.

well as hematologic toxicity and venous thromboembolism. Allergic reactions and tumor lysis syndromes (some fatal) have been reported, along with serious tumor flare reactions, hepatic failure and a higher incidence of second primary malignancy. Distribution is restricted to a program called REVLIMID REMS (Risk Evaluation and Mitigation Strategy). —George Ochoa

Hem/Onc Pharmacy

Pharmacy Practice News • July 2013

In Focus

Posaconazole and Sirolimus Not Always a Bad Mix Los Angeles—Despite manufacturer’s recommendations to avoid concomitant administration of sirolimus (Rapamune, Wyeth) and posaconazole (Noxafil, Merck), attempts have been made to safely administer them together by reducing the dose of sirolimus. A study presented at the annual meeting of the Hematology/Oncology Pharmacy Association (HOPA) identifies a dose reduction that does the trick.

“In contrast to the package insert, sirolimus and posaconazole can be used concurrently in hematopoietic stem cell transplant (HSCT) patients with an initial empiric 50% to 66% reduction in sirolimus dose,” said Doreen Pon, PharmD, BCOP, BCPS, an assistant professor of pharmacy practice and administration at the, Western University of Health Sciences College of Pharmacy, in Pomona, Calif.

(Table 1. Continued)

BRIEF SUMMARY OF PRESCRIBING INFORMATION

Adverse Reactions (Preferred Term)

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Venofer safely and effectively. See full prescribing information for Venofer. Initial U.S. Approval: 2000 RECENT MAJOR CHANGES Warnings and Precautions 6/2011 INDICATIONS AND USAGE Venofer is an iron replacement product indicated for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). DOSAGE AND ADMINISTRATION Administer Venofer intravenously either by slow injection or by infusion. CKD patients on hemodialysis: 100 mg undiluted slow intravenous injection over 2 to 5 minutes or as an infusion of 100 mg, diluted in a maximum of 100 mL of 0.9% NaCl, over a period of at least 15 minutes. CKD patients not on dialysis: 200 mg undiluted slow IV injection over 2 to 5 minutes. • CKD patients receiving peritoneal dialysis: infuse 300 mg over 1.5 hours given on two occasions 14 days apart followed by a single infusion 14 days later of 400 mg given over 2.5 hours. Dilute each Venofer dose in a maximum volume of 250 mL of 0.9% NaCl. DOSAGE FORMS AND STRENGTHS • 10 mL single use vial / 200 mg elemental iron (20 mg/mL) • 5 mL single use vial / 100 mg elemental iron (20 mg/mL) • 2.5 mL single use vial / 50 mg elemental iron (20 mg/mL) CONTRAINDICATIONS • Known hypersensitivity to Venofer WARNINGS AND PRECAUTIONS • Hypersensitivity Reactions: Observe for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of each administration. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. • Hypotension:Venofer may cause hypotension. Monitor for signs and symptoms of hypotension during and following each administration of Venofer. • Iron Overload: Regularly monitor hematologic responses during Venofer therapy. Do not administer Venofer to patients with iron overload. ADVERSE REACTIONS • The most common adverse reactions (≥ 2%) following the administration of Venofer are diarrhea, nausea, vomiting, headache, dizziness,hypotension,pruritus,pain in extremity,arthralgia,back pain,muscle cramp,injection site reactions,chest pain,and peripheral edema. To report SUSPECTED ADVERSE REACTIONS, contact American Regent, Inc. at 1-800-734-9236 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION 2 DOSAGE AND ADMINISTRATION Venofer must only be administered intravenously either by slow injection or by infusion. The dosage of Venofer is expressed in terms of mg of elemental iron. Each mL contains 20 mg of elemental iron. The usual total treatment course of Venofer is 1000 mg. Venofer treatment may be repeated if iron deficiency reoccurs. 2.1 Adult Patients with CKD on dialysis Administer Venofer 100 mg undiluted as a slow intravenous injection over 2 to 5 minutes, or as an infusion of 100 mg diluted in a maximum of 100 mL of 0.9% NaCl over a period of at least 15 minutes, per consecutive hemodialysis session.Venofer should be administered early during the dialysis session. 2.2 Adult Patients CKD not on dialysis Administer Venofer 200 mg undiluted as a slow IV injection undiluted over 2 to 5 minutes on 5 different occasions over a 14 day period. There is limited experience with administration of an infusion of 500 mg of Venofer, diluted in a maximum of 250 mL of 0.9% NaCl, over a period of 3.5 to 4 hours on day 1 and day 14. 2.3 Adult Patients with CKD receiving peritoneal dialysis Administer Venofer in 3 divided doses, given by slow intravenous infusion, within a 28 day period: 2 infusions each of 300 mg overr 1.5 hours 14 days apart followed by one 400 mg infusion over 2.5 hours 14 days later. Dilute Venofer in a maximum of 250 mL of 0.9% NaCl. 5 WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity Reactions Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal, have been reported in patients receiving Venofer. Patients may present with shock, clinically significant hypotension, loss of consciousness, and/or collapse. If hypersensitivity reactions or signs of intolerance occur during administration, stop Venofer immediately. Monitor patients for signs and symptoms of hypersensitivity during and after Venofer administration for at least 30 minutes and until clinically stable following completion of the infusion. Only administer Venofer when personnel and therapies are immediately available for the treatment of serious hypersensitivity reactions. Most reactions associated with intravenous iron preparations occur within 30 minutes of the completion of the infusion. 5.2 Hypotension Venofer may cause clinically significant hypotension. Monitor for signs and symptoms of hypotension following each administration of Venofer. Hypotension following administration of Venofer may be related to the rate of administration and/or total dose administered. 5.3 Iron Overload Excessive therapy with parenteral iron can lead to excess storage of iron with the possibility of iatrogenic hemosiderosis. Patients receiving Venofer require periodic monitoring of hematologic and iron parameters (hemoglobin, hematocrit, serum ferritin and transferrin saturation). Do not administer Venofer to patients with evidence of iron overload. Transferrin saturation values increase rapidly after intravenous administration of iron sucrose; do not perform serum iron measurements for at least 48 hours after intravenous dosing. 6 ADVERSE REACTIONS Venofer injection may cause serious hypersensitivity reactions and hypotension. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug may not reflect the rates observed in practice. 6.1 Adverse Reactions in Clinical Studies The frequency of adverse reactions associated with the use of Venofer has been documented in six clinical trials involving 231 patients with HDD-CKD, 139 patients with NDD-CKD and 75 patients with PDD-CKD. Treatment-emergent adverse events reported by ≥ 2% of treated patients in the six clinical trials for which the rate for Venofer exceeds the rate for comparator are listed by indication in Table 1. Patients with HDD-CKD received 100 mg doses at 10 consecutive dialysis sessions until a cumulative dose of 1000 mg was administered. Patients with NDD-CKD received either 5 doses of 200 mg over 2 weeks or 2 doses of 500 mg separated by fourteen days, and patients with PDD-CKD received 2 doses of 300 mg followed by a dose of 400 mg over a period of 4 weeks. Table 1. Treatment-Emergent Adverse Reactions Reported in ≥ 2% of Study Populations and for which the Rate for Venofer Exceeds the Rate for Comparator Adverse Reactions (Preferred Term) Subjects with any adverse reaction Ear and Labyrinth Disorders Ear Pain Eye Disorders Conjunctivitis Gastrointestinal Disorders Abdominal pain Diarrhea Dysgeusia Nausea Vomiting

HDD-CKD Venofer (N=231) %

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

Venofer (N=75) %

PDD-CKD EPO* Only (N=46) %

78.8

76.3

73.4

72.0

65.2

2.2

0.7

0.4

2.7

2.9 10.1 0 12.2 8.6

4.0 8.0 0 5.3 8.0

6.5 4.3 0 4.3 2.2

3.5 5.2 0.9 14.7 9.1

1.4 7.2 7.9 8.6 5.0

Posaconazole’s package insert states that the drug is contraindicated with use of sirolimus because the combination can increase sirolimus blood concentrations by approximately ninefold, inducing sirolimus toxicity (Curr Med Res Opin 2009;25:701-707). Posaconazole, an extended-spectrum triazole, is an inhibitor of the cytochrome P450 (CYP) isoenzyme CYP3A4. Sirolimus, an immunosuppressant, is a substrate of the enzyme.

General Disorders and Administration Site Conditions Asthenia Chest pain Feeling abnormal Infusion site painor burning Injection site extravasation Peripheral edema Pyrexia Infections and Infestations Nasopharyngitis, Sinusitis, Upper respiratory tract infections, Pharyngitis Injury, Poisoning and Procedural Complications Graft complication Metabolism and Nutrition Disorders Fluid overload Gout Hyperglycemia Hypoglycemia Musculoskeletal and Connective Tissue Disorders Arthralgia Back pain Muscle cramp Myalgia Pain in extremity Nervous System Disorders Dizziness Headache Respiratory, Thoracic and Mediastinal Disorders Cough Dyspnea Nasal congestion Skin and Subcutaneous Tissue Disorders Pruritus Vascular Disorders Hypertension Hypotension

HDD-CKD Venofer (N=231) %

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

Venofer (N=75) %

PDD-CKD EPO* Only (N=46) %

2.2 6.1 3.0 0 0 2.6 3.0

0.7 1.4 0 5.8 2.2 7.2 0.7

2.2 0 0 0 0 5.0 0.7

2.7 2.7 0 0 0 5.3 1.3

0 0 0 0 0 10.9 0

2.6

2.2

4.3

16.0

4.3

9.5

1.4

3.0 0 0 0.4

1.4 2.9 2.9 0.7

0.7 1.4 0 0.7

1.3 0 0 4.0

0 0 2.2 0

3.5 2.2 29.4 0 5.6

1.4 2.2 0.7 3.6 4.3

2.2 3.6 0.7 0 0

4.0 1.3 2.7 1.3 2.7

4.3 4.3 0 0 6.5

6.5 12.6

6.5 2.9

1.4 0.7

1.3 4.0

4.3 0

3.0 3.5 0

2.2 5.8 1.4

0.7 1.4 2.2

1.3 1.3 1.3

0 2.2 0

3.9

2.2

4.3

2.7

6.5 39.4

6.5 2.2

4.3 0.7

8.0 2.7

6.5 2.2

Dr. Pon said she and her colleagues wanted to explore this contraindication further because the broad-spectrum antifungal agent posaconazole is an important part of supportive care in patients who undergo allogeneic stem cell transplantations (ASCTs) to prevent invasive fungal infection. Sirolimus also is an important supportive care option, in part because it is used to treat steroid-refractory acute graft-versus-host disease (GVHD) as a salvage therapy in patients who undergo ASCT. Because there are cases where clinicians want to use both drugs together, attempts have been made to safely administer them by adjusting the sirolimus dose with the aim of preventing potentially significant toxicities, such as transplantation-associated thrombotic microangiopathy (TA-TMA) and hepatic veno-occlusive disease.

Study Detailed

*EPO=ERYTHROPOIETIN 6.2 Adverse Reactions from Post-Marketing Spontaneous Reports In the post-marketing safety studies in 1,051 treated patients with HDD-CKD, the adverse reactions reported by > 1% were: cardiac failure congestive, sepsis and dysgeusia. The following additional adverse reactions have been identified with the use of Venofer from postmarketing spontaneous reports: Anaphylactic-type reactions, shock, loss of consciousness, collapse, bronchospasm, dyspnea, convulsions, light-headedness, confusion, angioedema, swelling of the joints, hyperhidrosis, back pain, bradycardia, and chromaturia. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Symptoms associated with Venofer total dosage or infusing too rapidly included hypotension, dyspnea, headache, vomiting, nausea, dizziness, joint aches, paresthesia, abdominal and muscle pain, edema, and cardiovascular collapse. Symptoms may respond to IV fluids, hydrocortisone, and/or antihistamines. Slowing the infusion rate may alleviate symptoms. 7 DRUG INTERACTIONS Drug interactions involving Venofer have not been studied. However, Venofer may reduce the absorption of concomitantly administered oral iron preparations. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B There are no adequate and well-controlled studies in pregnant women. Venofer should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers It is not known whether iron sucrose is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Venofer is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of Venofer in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of Venofer did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects. Greater sensitivity of some older individuals cannot be ruled out. In general, dose administration to an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 10 OVERDOSAGE No data are available regarding overdosage of Venofer in humans. excessive dosages of Venofer may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. do not administer Venofer to patients with iron overload. 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How supplied Venofer is supplied sterile in 10 mL, 5 mL, and 2.5 mL single use vials. Each 10 mL vial contains 200 mg elemental iron, each 5 mL vial contains 100 mg elemental iron, and each 2.5 mL vial contains 50 mg elemental iron (20 mg/mL). 16.2 Stability and storage Contains no preservatives. Store in original carton at 25°C (77°F). Excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature]. Do not freeze. Do not dilute to concentrations below 1 mg/mL. Do not mix Venofer with other medications or add to parenteral nutrition solutions for intravenous infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to infusion. 17 PATIENT COUNSELING INFORMATION Prior to Venofer administration: • Question patients regarding any prior history of reactions to parenteral iron products. • Advise patients of the risks associated with Venofer • Advise patients to report any symptoms of hypersensitivity that may develop during and following Venofer administration, such as rash, itching, dizziness, light-headedness, swelling, and breathing problems.

AMERICAN REGENT, INC. SHIRLEY, NY 11967 Venofer is manufactured under license from Vifor (International) Inc., Switzerland.

IN2340BS, Rev. 6/2011

In the study (abstract PP4) presented at the HOPA meeting, researchers conducted a retrospective medical record review of adult allogeneic HSCT patients admitted to City of Hope National Medical Center, between January 2008 and December 2011, who received concurrent sirolimus and posaconazole as well as tacrolimus. The investigators determined sirolimus doses and trough concentrations before initiation of posaconazole and for 28 days after initiation of posaconazole. Sirolimus trough concentrations were measured twice weekly. To be included in the study, patients were required to have stable sirolimus trough concentrations before initiation of posaconazole. Patients were excluded if sirolimus or posaconazole was held for at least five consecutive days during the study period, steady-state sirolimus levels were not reached within 28 days after initiation of posaconazole, they had unstable renal or hepatic function, or they were on antifungal azoles prior to HSCT. After dividing the patients into two groups based on initial empiric sirolimus dose reduction—50% or more (n=37) or less than 50% (n=38)—the investigators found that the steady-state sirolimus concentration/dose ratio increased 2.61-fold after initiation of posaconazole (Table). The mean steady-state sirolimus dose after initiation of posaconazole was 38% of the dose prior to posaconazole. The mean maximum and steady-state sirolimus concentration/dose ratios occurred an average of 11 and 18 days, respectively, after initiation of posaconazole. The group receiving more than a 50% initial empiric sirolimus dose reduction had lower mean maximum

Hem/Onc Pharmacy 33

Pharmacy Practice News • July 2013

In Focus sirolimus trough concentrations (9.15 vs. 11.0 ng/mL; P=0.013) and fewer patients with sirolimus trough concentrations greater than 15 ng/mL (0 vs. 9; P=0.004). Based on the results, “close monitoring of sirolimus trough concentrations after initiation of posaconazole is recommended, with new steady-state sirolimus concentration/dose ratios expected to be achieved approximately 18 days after initiation of posaconazole,” Dr. Pon said.

Study Has Limitations, But Safety Signal Remains Dr. Pon acknowledged that the study was limited, in part because consistent oral administration of the drugs could not be ensured. Additionally, “we did not look at specific adverse effects related to the sirolimus–posaconazole interaction, only the effect on serum concentrations of sirolimus.” She added, however, that “some of the common side effects of sirolimus, such as hyperlipidemia, are not clearly related to serum concentrations. And myelosuppression [caused by] sirolimus would be difficult to definitively attribute to the drug in the patient population we studied.” Dr. Pon stressed that “we did look at the number of patients with supratherapeutic sirolimus concentrations, which we considered trough levels greater than 15 [ng/mL], since the goal range for our institution was 5 to 10. We found that significantly fewer patients (actually no patients) in the [higher] dose-reduction group had troughs greater than 15, whereas nine patients in the [lower] dose reduction group had troughs less than 15.” Noting that the product package information “states that coadministration is contraindicated based on elevations in serum drug concentrations,” Dr. Pon said that “the ‘safe’ administration of sirolimus is extrapolated from being able to maintain patients within the target serum concentration range, without resulting in supratherapeutic concentrations.” Sara Kim, PharmD, BCOP, a clinical pharmacy specialist at the Tisch Cancer Institute at Mount Sinai Medical Center, in New York City, said Dr. Pon’s study is consistent with a report on 15 patients undergoing allogeneic SCT, which concluded that “concurrent sirolimus and posaconazole use seems to be well tolerated with a 33% to 50% empiric sirolimus dose reduction” ((Biol Blood Marrow Transplant 2012;18:1462-1465). “At our center, we also reduce the dose of sirolimus by 50% when it is concomitantly administered with posaconazole,” Dr. Kim said. “I have not looked back to compare sirolimus-induced toxicities,

Table. Sirolimus Dose and Trough Concentrations After Initiation of Posaconazole Prior to Posaconazole

After Initiation Of Posaconazole

Mean sirolimus dose, mg per day

3.02

1.16

Mean sirolimus dose trough concentration, ng/mL

6.04

5.81

Sirolimus concentration/dose (ng/mL)/(mg per day)

2.29

5.98 Eunah Cho, PharmD, formerly a Western University pharmacy student, conducted the data collection and analysis; she is now a staff pharmacist at California Paciﬁc Medical Center, in San Francisco.

Sirolimus dose reduction: 1.16/3.02=0.38 Concentration/dose ratio increase: 5.98/2.29=2.61

but I would like to think that empirical dose reduction of sirolimus lowered the

by Shayani S, et al ((Biol Blood Marrow Transplantt 2013;19:298-304) showed that a high level of sirolimus (>10) was associated with increased risk of TA-TMA in bone marrow transplant patients. —Kate O’Rourke

rate of TA-TMA.” Dr. Kim added that a recent study

Drs. Pon and Kim disclosed no relevant ﬁnancial conﬂicts of interest.

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34 Operations & Management

Pharmacy Practice News • July 2013

Adherence

Adherence in CAD Can Improve Outcomes and Save Money

etter medication adherence can improve outcomes and reduce costs of care for patients with coronary artery disease (CAD), according to a systematic review of literature representing several decades. The study, a collaboration between CVS Caremark and Brigham and Women’s Hospital, in Boston, showed that improved adherence potentially could save up to $868 per patient annually. The results of the partnership appear in The American Journal of Medicine (2013;126:357.e7-357.e27, doi: 10.1016/j. amjmed.2012.09.004). Lead investigator Asaf Bitton, MD, MPH, an associate physician and an instructor in medicine at Brigham and Women’s and Harvard Medical School, also in Boston, and his team conducted a systematic review of 45 years of literature on the association between better medication adherence and CAD outcomes and costs. After reviewing 2,636 articles published between 1966 and 2011, the team analyzed 25 studies in greater detail that

met their inclusion criteria related to adherence and CAD outcomes. The analysis showed a strong and consistent association between patients who had the highest medication adherence and improved CAD outcomes, including decreased mortality. Additionally, in the studies that measured costs, high adherence rates were associated with 17% lower costs per year. The studies used a variety of measures to define high versus low adherence. These measures included medication possession ratio (MPR), where an MPR >80% was defined as high adherence and an MPR <80% was defined as low adherence; proportion of days covered (PDC), where a PDC >80% was considered high adherence and a PDC <80% was considered low adherence; direct pill counts; and patient questionnaires, where overall medication adherence

was measured according to a Likert scale. “CAD and cardiovascular disease in general has an annual health care cost of about $475 billion. Our analysis showed that adherence not only improved health outcomes, it also … reduced total annual CAD costs consistently from $294 to $896 per patient,” Dr. Bitton told Pharmacy Practice News. Pharmacy involvement plays a major role in getting patients to be more compliant with their medication, he added. “I practice in a patient-centered medical home here at Brigham and Women’s. We are one of the new team-based models of primary care and because we find that adherence is so important in determining the outcomes that our patients have, we have a full-time outpatient pharmacist in our clinic who works with patients on adherence, helps manage and do medication rec-

onciliation, and guides those patients who have many different medications. We find it immensely helpful to have the pharmacist expertise and input on our team,” he said. Troyen A. Brennan, MD, MPH, an executive vice president and the chief medical officer at CVS Caremark, noted that CVS Caremark has been working with Brigham and Women’s Hospital to research pharmacy claims data in order to better understand patient behavior, particularly patient adherence. Dr. Brennan added that he considered this study to be “significant because it broadens the discussion within the medical community and among policy makers about ways that we can best serve patients and meet their needs while reducing spending within the health care system … [and] presents evidence that medication adherence strategies and interventions for CAD patients may be one way to do this.” —Fran Lowry

Critical Care

Operating Room Noise May Pose Risks to Clinicians, Patients San Diego—When it comes to safety in the operating room, critical care pharmacists often focus on the “stat” medications used by the surgical team as a way to ensure patient safety. But a new sudy suggests that noise in the OR frequently exceeds guidelines set by various workplace and patient safety organizations. Thus, it may be time to suggest that your facility take steps to take the volume down a few notches. The study, from the University of Kentucky (UK), found that nearly 90% of anesthesiologists, and an even greater share of nurses, reported having trouble hearing in the OR. “We have established enough evidence and data here at the University of Kentucky to state that the noise level does, in fact, exceed health regulatory guidelines, and that most OR staff do perceive that elevated noise levels may have a negative impact on communication and, therefore, on performance,” said Rosalind Ritchie, MD, who presented the findings at the 2013 annual meeting of the Society for Ambulatory Anesthesia (abstract 37). Many groups have issued guidance on health levels of noise in hospitals, including the Occupational Safety and Health Administration, the Joint Commission, the World Health Organization and the National Institute for Occupational Safety and Health. But these evidently are not closely observed. In her role as medical director of the

Center for Advanced Surgery at UK Healthcare, in Lexington, Dr. Ritchie, an assistant professor of anesthesia, received a patient comment regarding the noise level in the OR, which prompted her to survey surgical staff to determine their level of comfort with the noise, and whether OR noise ever interfered with their ability to perform their jobs effectively. She also measured noise levels in the OR at critical times during a variety of operations. Perceptions of noise levels may vary by the different roles individuals play in the surgery, Dr. Ritchie explained, and their location in the OR relative to other team members. Of those who responded to the survey, 88% of anesthesiologists and 92% of nurses reported difficulty hearing in the OR—far more than the 35% of surgeons who reported trouble hearing. Similarly, 53.5% of anesthesiologists and 46.2% of nurses compared with 4.3% of surgeons reported that OR

noise levels were too high in general. Noise in the OR also has implications for patient safety, Dr. Ritchie said. “When you add multiple contributing factors such as beepers, cell phones, overheard pages, monitors and music, conversations and instruments, the ability to communicate effectively becomes impaired—critical communications about the patient’s care may be heard incorrectly or not heard at all.” OR staff in her survey stated that they had misheard comments ranging from requests about the positioning of a bed or table to the type and dose of local anesthetic. “It is my experience that the OR is way too loud, and communication between health care practitioners is handicapped by the noise level,” said Edward Nemergut, MD, an associate professor of anesthesiology and neurosurgery at the University of Virginia Health System, in Charlottesville. “When communication is adversely

affected, patient care can suffer.” Dr. Nemergut moderated a session on patient safety at the recent International Anesthesia Research Society meeting, where Dr. Ritchie’s abstract also was named best in category. To combat excessive noise levels and increase awareness, Dr. Ritchie and her colleagues have implemented a number of interventions at UK Healthcare. They now have tracking lights in the entrance hallway to the operating suites that change from green to yellow to red when noise levels reach preset decibel limits, and signs posted in the OR remind staff that noise should be kept to a minimum during critical points in surgery. She noted that UK Healthcare also has implemented educational programs and formed a task force to help ensure that the OR environment is optimal for all OR team members. Dr. Ritchie urges her colleagues around the country to look critically at OR noise levels in their institutions. “I am most confident that this is a growing national problem. I have discussed this with many of my colleagues, and many have indicated that they too perceived noise levels in the operating suite as a growing hazard to patient safety and personnel health. I think guidelines should be instituted by an executive level committee at each hospital.” —Keely Savoie

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36 Operations & Management

Pharmacy Practice News • July 2013

IVIG

Ig Nursing Group Eyes Certification Program

s immunoglobulin (Ig) therapies are used to treat an increasing number of disorders in patients, the development of a certification program for Ig nurses who work in concert with clinical pharmacists is generating support. “We are developing a certification program that will assess, validate and document the clinical competence and knowledge of nurses who manage and administer Ig therapy, which is now used

in a growing number of clinical indications,” said Luba Sobolevsky, PharmD, the program director of the Immunoglobulin Nursing Society (IgNS), the primary driver of the new initiative. “When it launches in February 2014, it will be the first national certification program to recognize Ig nursing as a specialty, and will result in the standardization of the Ig nursing practice and a higher level of professionalism.”

In addition to the certification program, the IgNS is creating standards of care and guidelines and is organizing annual national conferences to help train Ig nurses. IgNS also is relaunching its website. It will offer an Educational Resources Center containing continuing education programs, recorded sessions from its national conferences and a professional resources area with information on patient advocacy

organizations and medical societies. It also will feature a dedicated portal for knowledge sharing between all health care professionals, where members and non-members alike can post questions and make comments. Dr. Sobolevsky is expecting more than 300 attendees at the group’s second national conference, scheduled for Sept. 20-22, in Dallas. “We’ll offer the latest news on Ig products and pipeline, developments in disease-state management, advanced practice workshops on administration of IV and subcutaneous Ig, reimbursement and advocacy, and interdisciplinary collaboration.” The conference is open to all health care professionals, but the programs are accredited for—and especially relevant to—Ig nurses and pharmacists. “The team approach is important because nurses and pharmacists make decisions together relating to patients’ Ig therapy,” Dr. Sobolevsky said. “From which product, administration system and ancillary supplies to use; to management and documentation of adverse reactions; to advocating for patients regarding product access and reimbursement issues—it’s really both the pharmacists and nurses working together that drives the field forward.”

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Jerry Siegel, PharmD, FASHP, a clinical associate professor at the Ohio State University College of Pharmacy, in Columbus, and a leader in the Ig community who has trained both nurses and pharmacists, agrees that the two professions benefit from collaboration. Dr. Siegel has no affiliation with the IgNS, but he supports a certification program for Ig nurses. “Everyone understands that you need to be certified to be a chemotherapy nurse, but Ig can be equally dangerous if given by a nurse who doesn’t understand it,” he said. Every patient has a maximum tolerated rate of infusion, and a skilled nurse knows how to escalate safely, Dr. Siegel noted. Infusing a patient too rapidly can lead to adverse events such as headache, fever, chills and muscle aches. Rapid infusion also can cause renal insufficiency and thromboembolic disorders in patients with comorbidities such as diabetes, or a history of thrombosis. “Whether a patient can tolerate an Ig product may have more to do with the nurse than the product,” he said. “If a patient receiving Ig gets chills, an untrained nurse will respond by getting a blanket instead of turning down the rate of infusion. By the time they get back with the blanket, chills may have escalated to rigors.” —Dana Hawkins-Simons

Operations & Management 37

Pharmacy Practice News • July 2013

Collaborative Care

Adding a Pharmacist Improves Diabetes Care, Study Finds

ncluding a pharmacist in the care of adults with type 2 diabetes improved short-term surrogate markers and long-term cardiovascular risks, according to a study conducted in an HMO primary care environment. “Based on our data, there is no need to wait to put a pharmacist on a primary care diabetes team,” lead author Eric J. Ip, PharmD, BCPS, CDE, the director of pharmacy practice curriculum at Touro University California College of Pharmacy, in Vallejo, told Pharmacy Practice News. In the study’s enhanced care group ((Am J Health Syst Pharm 2013;70:877886), 147 patients with diabetes at Kaiser Permanente (KP) Mountain View Medical Clinics were managed by a clinical pharmacist and a primary care physician (PCP). Following a collaborative practice agreement, the 16 physicians at the site referred diabetes patients with poor glycemic control (i.e., hemoglobin [Hb]A1c ≥7%) to the sole clinical pharmacist (Dr. Ip) for intensive follow-up, giving him full autonomy to prescribe medications and adjust dosages, monitor labs, make diet and exercise recommendations, perform physical assessments and initiate specialist referrals. The control group consisted of 147 patients at KP Santa Clara Medical Center, who were matched to the enhanced care group on the basis of age, gender, HbA1c levels and comorbidities, and who received only the usual care of a PCP. During the 12 months of the study, the mean HbA1c value fell from 9.5% to 6.9% in the enhanced care group, compared with a drop from 9.3% to 8.4% in the control group ((P<0.001). The enhanced care group also improved more than the control group with reference to lowdensity lipoprotein cholesterol (LDL-C) and blood pressure values. Patients in the enhanced care group were likelier to reach goals for HbA1c (odds ratio [OR], 3.9), LDL-C (OR, 2.0) and blood pressure reduction (OR, 2.0). The estimated 10-year risk of coronary heart disease fell from 16.4% to 9.3% in the enhanced care group compared with a decrease from 17.4% to 14.8% in the control group ( <0.001). The enhanced care group also (P showed significantly greater reductions in estimated 10-year risks for the combination of fatal coronary heart disease and stroke, although not fatal stroke alone. A follow-up study based on these data determined that, with a minimum time horizon of four to five years, the enhanced care model “has a higher chance of being considered as a cost-effective strategy” ((J Manag Care Pharm 2013;19:102-114). Dr. Ip said that he and his colleagues had tried to address the limitations of

previous studies, such as small sample size. He added, “A randomized prospective study would provide the best evidence. Our study, which matched baseline characteristics and utilized a two-site design, was the next best type.” Diego LiTeh Chang, MD, a diabetes expert at KP Mountain View Clinics, was one of the physicians who participated in the study. “From the primary physicians’ point of view, it’s nice to have diabetes

taken off their plate,” he said. “It takes a lot of energy to take phone calls, check on dose and so on.” He added, “I would recommend pharmacist–physician collaboration with the caveat that the pharmacist has to be well trained.” The study “is not the first of its kind,” commented Brian Irons, PharmD, an associate professor in the Department of Pharmacy Practice at Texas Tech University Health Sciences Center’s School of

high in botic risk is When throm thrombin deficiency ti hereditary an

Pharmacy, in Lubbock. “Its value is that it adds more fuel for the fire.” However, “we don’t need another study to confirm the results,” Dr. Irons stressed. “[Pharmacists] can be more cost-effective than physicians in routine management of chronic diseases.” —George Ochoa Drs. Chang, Ip and Irons reported no relevant ﬁnancial conﬂicts of interest.

To learn more, visit www.thrombate.com

FELY PROCEED SA

Thrombate III® (antithrombin III [human])—proven effective for patients with hereditary antithrombin (AT) deficiency during surgery, childbirth, and in the prevention and treatment of thromboembolism1 Thrombate III provides predictable amounts of AT to replace what is normally present in the body AT concentrate purified from human plasma and pasteurized to inactivate viruses, with no confirmed cases of virus transmission In clinical studies, no cases of thrombotic complications during surgical and obstetrical procedures were reported

Easy to administer1

Convenient to store and reconstitute1

One dosing formula Bolus intravenous infusion (not continuous infusion) Pregnancy category B

500 IU vials with sterile water for injection Filter and transfer needles provided Room temperature storage

Important Safety Information Thrombate III® (antithrombin III [human]) is indicated for the treatment of patients with hereditary antithrombin deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism. In clinical studies with Thrombate III, the most common side effects were dizziness, chest discomfort, nausea, and dysgeusia. The anticoagulant effect of heparin is enhanced by concurrent treatment with Thrombate III in patients with hereditary AT-III deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with Thrombate III. Thrombate III is made from human plasma. Plasma products carry a risk of transmitting infectious agents, such as viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent, despite steps designed to reduce this risk. No cases of transmission of viral disease or CJD have ever been identified for Thrombate III. Please see brief summary of Thrombate III complete Prescribing Information on adjacent page. Reference: 1. Thrombate III® (antithrombin III [human]) [prescribing information]. Research Triangle Park, NC: Grifols Inc; 2012. © 2013 Grifols Inc.

February 2013

TH05-0113

38 Operations & Management

Pharmacy Practice News • July 2013

Continuity of Care

Discharge Plan Reduces COPD, HF Readmission Las Vegas—Pharmacists can help reduce hospital readmissions for older patients by participating in a coordinated hospital discharge system and providing medication reconciliation and education, a presenter at the recent Managed Health Care Associates Business Summit meeting said. Current statistics on readmissions support the need for such improvement programs. Almost one-fifth (19.6%) of

Medicare beneficiaries who had been discharged from a hospital were rehospitalized within 30 days, according to the speaker Joseph Lewarski, RRT, the vice president of clinical affairs for Invacare Corp., a manufacturer of wheelchairs, respiratory products and other medical equipment. Nearly 27% were readmitted for heart failure (HF) and 23% for chronic obstructive pulmonary disease (COPD). Hospitals have become increasingly

THROMBATE

III®

Antithrombin III (Human) BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

FOR INTRAVENOUS USE ONLY DESCRIPTION Antithrombin III (Human), THROMBATE IIIw is a sterile, nonpyrogenic, stable, lyophilized preparation of purified human antithrombin III (ATIII). THROMBATE III is prepared from pooled units of human plasma from normal donors by modifications and refinements of the cold ethanol method of Cohn. When reconstituted with Sterile Water for Injection, USP, THROMBATE III has a pH of 6.0–7.5, a sodium content of 110–210 mEq/L, a chloride content of 110–210 mEq/L, an alanine content of 0.075–0.125 M, and a heparin content of not more than 0.1 IU heparin/IU ATIII. THROMBATE III contains no preservative and must be administered by the intravenous route. Each vial of THROMBATE III contains the labeled amount of antithrombin III in international units (IU) per vial. The potency assignment has been determined with a standard calibrated against a World Health Organization (WHO) antithrombin III reference preparation. The capacity of the THROMBATE III manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model using a wide range of viruses with diverse physicochemical properties. There are two dedicated virus inactivation/removal steps included in the THROMBATE III manufacturing process: a heat treatment step at 60°C ± 0.5°C for not less than 10 hours for virus inactivation and a nanofiltration step for effective removal of viruses as small as 18 nm. The manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents. An individual production step in the THROMBATE III manufacturing process has been shown to decrease TSE infectivity of that experimental model agent. The TSE reduction step is the Effluent I to Effluent II + III fractionation step (6.0 log10). These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed. CLINICAL PHARMACOLOGY Antithrombin III, an alpha2-glycoprotein of molecular weight 58,000, is normally present in human plasma at a concentration of approximately 12.5 mg/dL and is the major plasma inhibitor of thrombin. Inactivation of thrombin by ATIII occurs by formation of a covalent bond resulting in an inactive 1:1 stoichiometric complex between the two, involving an interaction of the active serine of thrombin and an arginine reactive site on ATIII. ATIII is also capable of inactivating other components of the coagulation cascade including factors IXa, Xa, XIa, and XIIa, as well as plasmin. The neutralization rate of serine proteases by ATIII proceeds slowly in the absence of heparin, but is greatly accelerated in the presence of heparin. As the therapeutic antithrombotic effect in vivo of heparin is mediated by ATIII, heparin is ineffective in the absence or near absence of ATIII. The prevalence of the hereditary deficiency of ATIII is estimated to be one per 500 to 5000 in the general population. The pattern of inheritance is autosomal dominant. In affected individuals, spontaneous episodes of thrombosis and pulmonary embolism may be associated with ATIII levels of 40%–60% of normal. These episodes usually appear after the age of 20, the risk increasing with age and in association with surgery, pregnancy and delivery. The frequency of thromboembolic events in hereditary ATIII deficiency during pregnancy has been reported to be 70%, and several studies of the beneficial use of Antithrombin III (Human) concentrates during pregnancy in women with hereditary deficiency have been reported. In many cases, however, no precipitating factor can be identified for venous thrombosis or pulmonary embolism. Greater than 85% of individuals with hereditary ATIII deficiency have had at least one thrombotic episode by the age of 50 years. In about 60% of patients thrombosis is recurrent. Clinical signs of pulmonary embolism occur in 40% of affected individuals. In some individuals, treatment with oral anticoagulants leads to an increase of the endogenous levels of ATIII, and treatment with oral anticoagulants may be effective in the prevention of thrombosis in such individuals. In clinical studies of THROMBATE III conducted in 10 asymptomatic subjects with hereditary deficiency of ATIII, the mean in vivo recovery of ATIII was 1.6% per unit per kg administered based on immunologic ATIII assays, and 1.4% per unit per kg administered based on functional ATIII assays. The mean 50% disappearance time (the time to fall to 50% of the peak plasma level following an initial administration) was approximately 22 hours and the biologic half-life was 2.5 days based on immunologic assays and 3.8 days based on functional assays of ATIII. These values are similar to the half-life for radiolabeled Antithrombin III (Human) reported in the literature of 2.8–4.8 days. In clinical studies of THROMBATE III, none of the 13 patients with hereditary ATIII deficiency and histories of thromboembolism treated prophylactically on 16 separate occasions with THROMBATE III for high thrombotic risk situations (11 surgical procedures, 5 deliveries) developed a thrombotic complication. Heparin was also administered in 3 of the 11 surgical procedures. Eight patients with hereditary ATIII deficiency were treated therapeutically with THROMBATE III as well as heparin for major thrombotic or thromboembolic complications, with seven patients recovering. Treatment with THROMBATE III reversed heparin resistance in two patients with hereditary ATIII deficiency being treated for thrombosis or thromboembolism. During clinical investigation of THROMBATE III, none of 12 subjects monitored for a median of 8 months (range 2–19 months) after receiving THROMBATE III became antibody positive to human immunodeficiency virus (HIV-1). None of 14 subjects monitored for ⱖ 3 months demonstrated any evidence of hepatitis, either non-A, non-B hepatitis or hepatitis B. INDICATIONS AND USAGE THROMBATE III is indicated for the treatment of patients with hereditary antithrombin III deficiency in connection with surgical or obstetrical procedures or when they suffer from thromboembolism.

concerned with readmissions, especially as the Centers for Medicare & Medicaid Services is now penalizing them for “preventable readmissions” through its Readmission Reduction Program, which took effect Oct. 1, 2012. Some 2,000 hospitals received some level of penalty for fiscal year 2013, Mr. Lewarski said, and 307 received the maximum 1%. Although the causes of readmission are complex and not completely under-

Subjects with ATIII deficiency should be informed about the risk of thrombosis in connection with pregnancy and surgery and about the inheritance of the disease. The diagnosis of hereditary antithrombin III (ATIII) deficiency should be based on a clear family history of venous thrombosis as well as decreased plasma ATIII levels, and the exclusion of acquired deficiency. ATIII in plasma may be measured by amidolytic assays using synthetic chromogenic substrates, by clotting assays, or by immunoassays. The latter does not detect all hereditary ATIII deficiencies. The ATIII level in neonates of parents with hereditary ATIII deficiency should be measured immediately after birth. (Fatal neonatal thromboembolism, such as aortic thrombi in children of women with hereditary antithrombin III deficiency, has been reported.) Plasma levels of ATIII are lower in neonates than adults, averaging approximately 60% in normal term infants. ATIII levels in premature infants may be much lower. Low plasma ATIII levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deficiency. It is recommended that testing and treatment with THROMBATE III of neonates be discussed with an expert on coagulation. CONTRAINDICATIONS None known. WARNINGS Because THROMBATE III 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. No cases of transmission of viral diseases or CJD have ever been identified for THROMBATE III. Inform patients that THROMBATE III is made from human plasma and may contain infectious agents that can cause disease. While the risk that THROMBATE III can transmit an infectious agent has been reduced by screening plasma donors for prior exposure, testing donated plasma, and by inactivating or removing pathogens during manufacturing, patients should report any symptoms that concern them. 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 Therapeutics Inc. [1-800-520-2807]. The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hereditary ATIII deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with THROMBATE III. PRECAUTIONS General 1. Administer within 3 hours after reconstitution. Do not refrigerate after reconstitution. 2. Administer only by the intravenous route. 3. THROMBATE III, once reconstituted, should be given alone, without mixing with other agents or diluting solutions. 4. Product administration and handling of the needles must be done with caution. Percutaneous puncture with a needle contaminated with blood can transmit infectious virus including HIV (AIDS) and hepatitis. Obtain immediate medical attention if injury occurs. Place needles in sharps container after single use. Discard all equipment including any reconstituted THROMBATE III product in accordance with biohazard procedures. The diagnosis of hereditary ATIII deficiency should be based on a clear family history of venous thrombosis as well as decreased plasma ATIII levels, and the exclusion of acquired deficiency. Laboratory Tests It is recommended that ATIII plasma levels be monitored during the treatment period. Functional levels of ATIII in plasma may be measured by amidolytic assays using chromogenic substrates or by clotting assays. Drug Interactions The anticoagulant effect of heparin is enhanced by concurrent treatment with THROMBATE III in patients with hereditary ATIII deficiency. Thus, in order to avoid bleeding, reduced dosage of heparin is recommended during treatment with THROMBATE III. Pregnancy Category B Reproduction studies have been performed in rats and rabbits at doses up to four times the human dose and have revealed no evidence of impaired fertility or harm to the fetus due to THROMBATE III. It is not known whether THROMBATE III can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Pediatric Use Safety and effectiveness in the pediatric population have not been established. The ATIII level in neonates of parents with hereditary ATIII deficiency should be measured immediately after birth. (Fatal neonatal thromboembolism, such as aortic thrombi in children of women with hereditary antithrombin III deficiency, has been reported.) Plasma levels of ATIII are lower in neonates than adults, averaging approximately 60% in normal term infants. ATIII levels in premature infants may be much lower. Low plasma ATIII levels, especially in a premature infant, therefore, do not necessarily indicate hereditary deficiency. It is recommended that testing and treatment with THROMBATE III of neonates be discussed with an expert on coagulation. ADVERSE REACTIONS In clinical studies involving THROMBATE III, adverse reactions were reported in association with 17 of the 340 infusions during the clinical studies. Included were dizziness (8), chest discomfort (3), nausea (3), dysgeusia (3), chills (2), pain (cramps) (2), dyspnoea (1), chest pain (1), vision blurred (1), intestinal dilatation (1), urticaria (1), pyrexia (1), and wound secretion and hematoma (1). If adverse reactions are experienced, the infusion rate should be decreased, or if indicated, the infusion should be interrupted until symptoms abate. CAUTION & only U.S. federal law prohibits dispensing without prescription.

Grifols Therapeutics Inc. Research Triangle Park, NC 27709 USA U.S. License No. 1871

08941115-BS

stood, in many cases readmission can result from “post-hospitalization syndrome,” a generalized vulnerability to illness, Mr. Lewarski said. “Spending time in the ICU is like being in a casino in Vegas,” he told Pharmacy Practice News. “There’s lots of noise, lots of people moving around and you can’t tell what time it is. Add to the environment myriad drugs, including sedatives and pain medications, and it’s easy to become disoriented.” Out of routine, older patients can become sleep deprived or develop nutrition issues, lose muscle strength or have exacerbated dementia. “When you put it all together, a sick person may come in for one diagnosis but have other consequences.” Side effects of new drugs may complicate these issues. Long-term oxygen therapy may improve outcomes and survival among patients with COPD, as well as an HFassociated breathing difficulty called Cheyne-Stokes respiration, according to recent medical studies, he said. The key components to reducing readmissions for patients with COPD and HF are comprehensive predischarge planning, with attention to seamless transition and continuity of care; and patient education about medications and compliance, daily living skills, transportation and nutritional support, Mr. Lewarski said. Be aware of reductions in vision and hearing when educating older patients, he stressed.

More Discharge Recommendations Two pharmacy experts not at the meeting gave their own discharge recommendations to Pharmacy Practice News. There are three key things pharmacists should do before patients are discharged, said Michael “Mick” Murray, PharmD, MPH, a distinguished professor of pharmacy and the endowed chair of medication safety at Purdue University’s College of Pharmacy, West Lafayette, Ind., and the executive director of the Regenstrief Center for Healthcare Effectiveness Research, in Indianapolis. First, he said, tell the patient who you are and why you came to visit: “It sounds obvious, but when you show up on discharge, the patients see so many people they get confused.” Next, ask the patient how much time

Operations & Management 39

Pharmacy Practice News • July 2013

he or she has to talk before he or she is being picked up by a family member or taken off for an x-ray or other appointment. That allows you to tailor your instructions to the time allotted. Third, if there’s not a lot of time, ask the patient up front what questions he or she has about medications and address those first. Ask patients how likely it is that they will be able to follow medication instructions at home. This provides a chance to go over medication safety tips that otherwise could be overlooked. Sean Jeffery, PharmD, a clinical professor at the University of Connecticut School of Pharmacy, Storrs, and a clinical pharmacist in geriatrics for the VA Connecticut Healthcare System, West Haven, said he has been shocked by the number of patients with COPD who don’t know how to use their inhalers: “You cannot assume that because someone has a COPD medicine that they know how to use it or are using it properly.” It’s crucial to demonstrate how to use inhaled medications and spacers, as needed. “It is challenging to design an inhaler regimen that is simple to use, doesn’t require frequent dosing and doesn’t break the bank,” said Dr. Jeffery. “Each medicine has its own proprietary design.” In some cases, physicians also need to be educated about inhalers and their instructions and limitations, he said. Medication reconciliation also is important, especially among patients with HF who are taking multiple medications including angiotensin-converting enzyme (ACE) inhibitors, Dr. Jeffery said. If patients with HF transfer from one hospital to another, they may be prescribed a different ACE inhibitor from

New Product

Amneal Launches Haloperidol Decoanate Injection

‘I’ve seen patients on Zestil, Iisinopril and Prinivil, not realizing they’re the same thing, and they wonder why their blood pressure is low.’ —Sean Jeffery, PharmD each pharmacy. “I’ve seen patients on Zestril, lisinopril and Prinivil, not realizing they’re the same thing, and they wonder why their blood pressure is low.” One pilot program being tested by his VA system to improve patient health and reduce readmissions is shared medical appointments for veterans with diabetes. Six to eight patients with diabetes and a high risk for cardiovascular complica-

tions are brought in for quarterly outpatient appointments with a nurse educator, a health psychologist, a dietitian, a physician and a clinical pharmacist with prescriptive authority. Patients receive joint education but individual medication management by the pharmacist. The VA also plans to pair similar patients as “health buddies” to encourage each other to stay healthy, with the goal of

Continuity of Care improved health outcomes. “I absolutely think this model could work for HF and COPD patients,” Dr. Jeffery said. “We need to catch COPD patients early, make sure they’re on the right medications, they stop smoking and have training on the use of inhalers, diet and exercise.” For a resource guide from the VA on shared medical appointments for diabetes patients, see http://www.queri. research.va.gov/tools/diabetes/sharedmed-appt.pdf. f —Karen Blum

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e-Newsletters and e-Alerts Get the latest news from the best-read health-system m pharmacy pub blication in the country delive ered directly ectl to o your computerr or mo mobile device for free e! Each ch installment con ontains articles fro om the current ur month’s issue ahead of print, as well as links nk to podcasts and other Web-exc clusive s content

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mneal Institutional announced the launch of Haloperidol Decoanate Injection, a therapeutic equivalent to Haldol Decoanate. The product comes in two strengths— 50 mg/mL and 100 mg/mL—each offered in single-dose or multipledose vials. For more information, visit www.amneal. com/products, email sales@amnealinstitutional.com or call (866) 525-7270.

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iTunes

40 Technology

Pharmacy Practice News • July 2013

Automation

Hi-TECH TOOLS

done here is important because the same types of errors can occur in nonsterile compounding. They’re taking the available technology and making sure they’re preparing doses correctly. This would be particularly helpful in pediatric hospitals, which produce a high volume of compounded oral liquids.”

continued from page 1

and decrease costs and waste.

Not Only Sterile Compounding Needs Hi-Tech Help

Adding Pharmacist Verification To CPOE Boosts Safety

patient,” Mr. Speth said. In almost 90% of the interceptions, it turned out that the technician had taken the wrong stock drug. Because bar-code interceptions prevent doses from being prepared, waste is reduced. “Under the old system, that dose would have been prepared and then discarded after the pharmacist verification process,” Mr. Speth said. He estimated that over the first 21 weeks of 2013, the pharmacy prevented about $10,000 in waste from intercepted sterile and nonsterile compounding errors (Figure 1). Preparation time for nonsterile com-

pounding also has declined, from an average 27 minutes to 18 minutes. “That’s primarily because the pharmacist doesn’t have to physically get up to check the finished product,” Mr. Speth said. “We’ve become more efficient.” Allen Vaida, PharmD, BSc, the executive vice president of the Institute for Safe Medication Practices (ISMP), commented that the IUH initiative is something he’d like to see other facilities emulate. “A growing number of hospitals have begun to use bar-code scanning for IV drug compounding, where the greater risk is,” Dr. Vaida said. “What they’ve

‘Whether you’re doing sterile or nonsterile compounding, anytime you take an ingredient out of the manufacturer’s package, it’s no longer identifiable; therefore the risk for making a preparation error increases.’ —Stephen L. Speth, RPh, MS

12,000 10,000 8,000

Dollars

Bar-code scanning has become one of the most promising technologies for improving medication safety. In 2010, Indiana University Health (IUH) in Bloomington installed a bar-code medication preparation (BCMP) system in its IV room to improve the safety of compounded sterile products. Adapting the technology to nonsterile compounding was a logical next step to Stephen L. Speth, RPh, MS, the hospital’s inpatient pharmacy manager. “Whether you’re doing sterile or nonsterile compounding, anytime you take an ingredient out of the manufacturer’s package, it’s no longer identifiable; therefore, the risk for making a preparation error increases,” Mr. Speth said. The 355-bed hospital prepares about 160 compounded sterile doses and 40 nonsterile doses daily. Oral liquid syringe preparations and bulk liquids are the most common nonsterile compounded drugs. Before automating the process, activities such as tracking lot numbers, drug expiration dates and beyond-use dates were done manually and recorded in a handwritten logbook, raising issues of accuracy and the legibility of labels. “We’ve adapted the technology used in sterile compounding to nonsterile compounding,” Mr. Speth said. “It’s the same process: The technician scans the ingredients and takes pictures of the amounts. That information is electronically captured and used by the pharmacist for verification. In the old system, the pharmacist would have to walk over to the preparation area to verify the accuracy of the compounded drug and manually record the information. The potential for errors was much higher.” The system is configured to force entry of ingredient lot numbers and expiration dates during the compounding process. It alerts technicians when to prepare doses and alerts pharmacists when a dose is ready to be verified. All documentation is archived for reporting and retrieval. During the first five months after the system went live, 21 oral liquid syringe preparation errors were intercepted before pharmacist verification (0.9% of all doses processed). That compares closely to 1% intercept rate for compounded sterile products, according to Mr. Speth. After three months of barcode scanning for bulk liquid preparation, two errors were intercepted out of 140 batches (1.4%). “The intercepted doses don’t leave the pharmacy, much less reach the

6,000 4,000 2,000 0 0

Week

Figure 1. Avoided waste year-to-date.

At another facility in the IUH system, CPOE allowed the emergency department (ED) to convert its automated dispensing cabinets (ADCs) from total override—and, therefore, no advance pharmacist verification of medication orders—to limited override. About 300 patients visit the ED daily. “When the hospital installed CPOE, we decided it was a good time for us to make the change and enable a pharmacist to verify most of the orders,” said Eleni Drake, PharmD, the pharmacy operations manager at the IUH Methodist Hospital, in Indianapolis. Before the change, the ADC allowed total override, giving nurses access to every medication in the machine independent of patient orders. She noted that the Joint Commission recommends pharmacist review of all medication orders before they’re dispensed, and that maintaining ADCs on limited override is considered a “best practice.” Six ADC machines in the ED were removed from total override on the same day as CPOE implementation. In the first three months after CPOE initiation, the ED staff entered 2,700 average orders on a weekly basis. Approximately 1,485 (55%) of the orders entered for the ED qualified for auto-verification, and a pharmacist reviewed the rest before drug administration. For orders verified by a pharmacist, approximately 90% were verified in less than 15 minutes, with an average verification time of just less than three minutes (±5.5 minutes). The timely order verification has allowed the ADCs to remain in a limited override status with no effects on ED throughput and patient length of stay. “Forty-one percent of the medications in the ADCs are still on override, which accounts for 18% of actual drug removals,” Dr. Drake said. “Because we were successful in the ED with this initiative, we were able to roll it out to the rest of the hospital.” The ED staff was apprehensive at first, fearing the added time for pharmacy verification would delay care. But once they became aware that the turnaround time for orders was quick and predictable, they could plan their activities accordingly and return to the ADC when the orders became available. “We had very good nursing leadership helping us,” Dr. Drake said. “They knew

Technology 41

Pharmacy Practice News • July 2013

Automation

A $500,000 Savings From Clinical Surveillance Software At the CHRISTUS Spohn hospital system in South Texas, pharmacists are using TheraDoc clinical surveillance software to recommend thousands of interventions and achieve significant savings. The software includes a datamining component that the health system uses to help guide a variety of activities and measures, such as antibiotic stewardship, renal dosing, pharmacokinetics, IV-to-oral therapy conversion, anticoagulation monitoring and adverse drug events. “We were, for example, able to alert physicians in real time about patients who were receiving inappropriate antibiotics,” said lead author D. George Udeani, PharmD, a clinical pharmacy specialist at the CHRISTUS-Spohn Shoreline Hospital, in Corpus Christi. Although CHRISTUS Health acquired the clinical surveillance software for all 23 hospitals in its system, the organization decided to first use the pharmacy component in its six South Texas facilities, representing about 1,000 beds. Previously, the health system relied on its mainframe computer to document pharmacist interventions. But that approach was hampered by an inability to tabulate financial data associated with the interventions. “We’d spend days just trying to count the interventions we made in areas such as medication therapy management,” Dr. Udeani said. The new system automates the entire process, he noted. “Cumulatively, our pharmacists spent 1,017 hours over six months reviewing patient data with the new system and conducting interventions based on that information,” Dr. Udeani said. In all, 4,347 pharmacist interventions were documented, with an average time per intervention of 13.1 minutes. The system’s savings associated with those activities were calculated at $524,250, and pharmacist salaries were calculated at $55,985. “This is a system that can be very effective in saving lives,” Dr. Udeani said. “It’s not like when we had to wait

100

Incidence, %

the importance of the pharmacy verifying drug orders.” “There’s a perception that everything needs to be done immediately in the ED—that it can’t wait. But the fact is that in many cases a drug does not need to be obtained immediately and there’s time for pharmacist review,” said Dr. Vaida. “That same culture prevailed in other hospital areas, but now a majority of the drug orders are being verified by the pharmacy. In this case, there was concern about pushback from the ED staff, [but] the pharmacy department had a lot of support from nursing, and that’s an important factor.”

80 Ambulatory

Inpatient

20 9 0

Fluticasone/nasal fluticasone

Metoprolol/ metoclopramide

3.4

2.8

Nitroprusside/ nitroglycerin

Propranolol/ propofol

Figure 2. Incidence and location of alerts triggered by look-alike/sound-alike medications.

‘There’s a perception that everything needs to be done immediately in the ED—that it can’t wait. But the fact is that in many cases a drug does not need to be obtained immediately and there’s time for pharmacist review.’ —Allen Vaida, PharmD, BSc and run down to the lab and get results, or wait for cultures to become available. Now we can get that kind of information right away and act on it.” “We’ve been promoting the value of these surveillance systems for quite a while,” Dr. Vaida said. “They can be used to monitor safety data and clinical services and provide important information for making decisions that improve care and medication safety. And they can capture pharmacy interventions and assign them dollar values. We would really like to see more hospitals using them.” According to ISMP, only 12% of hospitals that responded to its most recent safety self-assessment survey had fully implemented data-mining systems.

Getting a Better Handle on Look-Alike/Sound-Alike Drugs One of the most persistent causes of medication errors is confusion between similar drug names. Researchers at the Center for Education and Research on Therapeutics (CERT) at the University of Illinois Chicago College of Pharmacy applied a clinical decision support system (CDSS) to check medication orders against patient indications to reduce such mistakes. The automated intervention activates when prescribers order a medication through the CPOE system that is intended for an indication not documented on the patient’s problem list. An alert prompts the prescriber either to cancel the order, ignore the alert or add

an indication to the problem list. If an order is cancelled and the same clinician orders a similar-sounding medication within 10 minutes, the system tallies the event as an intercepted medication error. “A lot of mistakes were discovered,” said Michelle L. Bryson, PharmD, a coinvestigator and a second-year resident at the time of the study. “Often, it was very clear that the mistakes were picklist errors where the prescriber made the wrong choice from several similar options, or the drug names were next to each other in certain order sets, as with nimodipine and famotidine.” Dr. Bryson and her colleagues conducted a retrospective chart review of all indication alerts triggered between 2006 and 2012 (127,320). They identified 176 instances (1.38 errors per 1,000 orders) in which the alert led to the ordering of a different, similar-sounding drug. High-alert medications were involved in about one-fourth of the interceptions. The researchers did not evaluate the reduction in actual patient harm in their analysis but said they “believe the use of CDSS during order entry may help reduce risk.” Forty unique pairs of similar-sounding drugs and several pairs of highalert medications were identified. The most commonly confused pairs were fluticasone/fluticasone nasal (86%), metoprolol/metoclopramide (9%), nitroprusside/nitroglycerin (3.4%) and propranolol/propofol (2.8%). Ambulatory settings represented roughly two-

thirds of events, and inpatient settings represented the remaining one-third (Figure 2). Of these drug pairs, 22% included high-alert medications such as opioids, metoprolol, nitroprusside, metformin and propranolol. The most commonly intercepted error was for fluticasone/fluticasone nasal spray, which occurred 100 times. “It’s pretty clear this was a pick-list error,” said Dr. Bryson. In addition to fluticasone inhalers, the choices for fluticasone include “fluticasone topical” and “fluticasone nasal.” If “fluticasone” (an inhaler) is chosen, an alert appears asking the prescriber if asthma should be added to the patient’s indications (unless it’s already an indication), and the prescriber realizes that he or she has mistakenly prescribed an inhaler instead of a nasal spray. “This is just the jumping off point for looking at the bigger picture,” said Dr. Bryson. “We want people to anticipate that inadvertent things can happen with CPOE and to design their systems to help avoid some of them from the start.” He added that such efforts have another payoff: The Joint Commission accreditation standards include a requirement for health organizations to develop a list of look-alike/sound-alike drugs that they stock. “In this initiative they moved the safety checks farther upstream in the drug order process, and we’re very much in favor of that,” Dr. Vaida said. “Matching indications to the therapy is something that ISMP promotes even when manual systems are being used.” He noted that ISMP is working with the University of Illinois CERT on a subsequent phase of this research project to further develop the system’s capabilities. —Steve Frandzel Mr. Speth and Drs. Bryson, Drake, Udeani and Vaida reported no relevant ﬁnancial conﬂicts of interest.

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42 Technology

Pharmacy Practice News • July 2013

Medication Safety

Real-Time Clinical Data Make All the Difference Dynamic monitoring can boost outcomes—and clinical pharmacists’ effectiveness on care team

he number of hospitals adopting electronic health records has more than tripled since 2009—a “revolution” in medical informatics that already has yielded major benefits in clinical pharmacy operations, according to David Bates, MD, MSc, the medical director of clinical and quality analysis-information systems at Partners HealthCare, in Wellesley, Mass. “Pharmacists have an opportunity to see a wide array of data about patients that wasn’t previously possible,” Dr. Bates said in a recent interview with Pharmacy Practice News. “With pharmacists caring for 80 to 120 patients at a time, depending on the hospital, having a synopsis on each makes it a lot easier to do what needs to be done.” Part of the synopsis Dr. Bates wants clinical pharmacists to be able to see in real time includes patient lab values, pharmaceutical orders and patient demographic data that, if acted on quickly, could help prevent adverse drug events (ADEs). ADEs can be quite costly to hospitals and patients, according to Dr. Bates, a long-time advocate of real-time dynamic monitoring as a tool for reducing the incidence and effect of medication mishaps. His latest co-authored research on the topic demonstrated the value of a targeted ADE monitoring system in a 140-bed community teaching hospital ((Drug Saff 2007;30:817-824). Over the six-month study period, 3,547 alerts were issued. A review of just the high-level alerts found two preventable ADEs—one led to a hypoglycemic episode in a patient with diabetes, and another led to hyperkalemia. Based on the results, the researchers projected that there would be 37 ADEs the hospital could detect early by fully implementing the dynamic-monitoring technology used in the study (VigiLanz). Given an average cost per preventable ADE of $4,685 (1997 value), the annual cost of the 37 events would be $173,345. By contrast, the cost to implement and maintain the technology was $124,600 in year 1 and $81,900 in subsequent years, according to the study results. Dr. Bates, who also serves as the chief quality officer for Brigham and Women’s Hospital, in Boston, said the hospital has developed a system with less frills than the one used in the Drug Safetyy study that currently saves the facility an estimated $950,000 per year. He also expects the hospital to implement Hospira’s TheraDoc technology later in 2013 to detect hospital-acquired infections. “Every institution should do something in dynamic monitoring,” Dr. Bates

John Muir Medical Centers’ Approach

John Russillo, RPh, the clinical pharmacy manager at John Muir Medical Centers, in Concord and Walnut Creek, Calif., uses VigiLanz Dynamic Monitoring Suite software to help prevent adverse drug events, detect health care–associated infections and improve medication safety and patient outcomes.

‘On the order of 90% of the time, when a pharmacist makes an action-oriented therapeutic suggestion based on dynamic monitoring, the provider team makes a change.’ —David Bates, MD, MSc urged. “There’s no doubt that automated real-time surveillance makes clinical pharmacists much more efficient at intervening in situations where it is likely to have a benefit.” Such an approach has the added benefit of resulting in “more cohesive work patterns” between pharmacists and other health care providers, he noted. When a hospital first adopts the technology, it’s understandable that “some

physicians resist listening to pharmacists. But as they realize pharmacists are armed with critical data and insights, physicians find it easier to accept suggestions,” Dr. Bates said. “We’ve tracked this. On the order of 90% of the time, when a pharmacist makes an action-oriented therapeutic suggestion based on dynamic monitoring, the provider team makes a change. That’s a high level of respect for pharmacists and also the underlying system.”

Real-time patient information such as the data shown above can be accessed via dynamic monitoring technology.

Indeed, at both campuses of John Muir Medical Centers, in Concord and Walnut Creek, Calif., which have a combined 600 beds, clinical pharmacy manager John Russillo, RPh, uses the VigiLanz Dynamic Monitoring Suite to help prevent ADEs, detect health care–associated infections, improve medication safety and patient outcomes—and, he emphasized, raise the clinical competency of the entire staff of 75 pharmacists. The rules-guided software package merges hospital-based drug therapy, laboratory findings, surgery, radiology, documentation and other clinical data for clinicians to quickly identify potential pharmacotherapy interventions where needed. Contrasting with an estimated 85% of U.S. hospitals that still lack clinical decision support in electronic health records, Mr. Russillo was glad to blaze the trail with VigiLanz as its first client eight years ago. “I saw we’d be able to write exception-based rules to our own protocols and practice,” he said. For example: What’s the patient’s latest lab value? Which new drug is ordered? Did the patient have prophylaxis? Did the patient just come out of surgery? These customized rules, he explained, trigger “intelligent,” clinically significant alerts, and thus Muir’s pharmacists feel confident these are actionable items. “I call it noise reduction—it’s huge for avoiding alert fatigue and building pharmacist acceptance,” Mr. Russillo said. He noted that Muir runs close to 1,000 rules, and VigiLanz issues 30 to 50 alerts per 100 patients each day. Pharmacists can’t ignore any alerts because the system issues them to the various hospital units where they work, he added. A critical alert reaches a pharmacist on his or her iPad or iPhone while they are making rounds with physicians, where decisions to change medication therapy can be made promptly. In case of questions about an alert, the software describes the rule that triggered it, gives guidance for action needed, and shows links to further references such as a page on the FDA website—for instance, one describing a black box warning. Pharmacist responses to alerts are also tracked, which ensures accountability with electronic audit trails. Mr. Russillo underscored the importance of this feature because clinical pharmacist interventions reduce the occurrence of avoidable ADEs, improve patient outcomes, and contribute to John Muir scoring higher on the 13

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see REAL-TIME DATA, page 44

44 Technology

Pharmacy Practice News • July 2013

Medication Safety

REAL-TIME DATA continued from page 42

Medicare clinical measures. This, in turn, could help Muir potentially be eligible to recover some or all of the Centers for Medicare & Medicaid Services’ 1% base-payment withholding in 2013-2016 or 2% in 2017, which is part of the agency’s Value-Based Purchasing Program. Muir initially used VigiLanz to help achieve safe and appropriate medication dosing, Mr. Russillo recalled. As trust in it built, he said John Muir

began to use the software to help achieve best practices in medication safety; deliver consistent care quality via the application of evidence-based rules and the knowledge gained by pharmacists; and improve drug utilization and core-measure compliance with Joint Commission standards for treating specific conditions such as acute myocardial infarction, pneumonia and thromboembolism. For example, John Muir has reduced its anticoagulation-related ADEs by more than 50% over a year’s time. This

occurred during the hospital’s second year of use, and the automated technology continues to sustain the lower rate. In absolute numbers, avoidable anticoagulation ADEs have fallen from 30 to less than 10 ADEs per year, which by itself translates into a savings of $230,000 annually, Mr. Russillo said. He estimated that the technology saves the hospital overall greater than five times its annual cost each year, while costing less than a full-time equivalent pharmacist to operate. Savings occur largely in pharmacists’ time—by

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making them more efficient, avoiding about two hours of manual screening time per pharmacist per day, and identifying more opportunities to improve medication oversight and utilization. Moreover, John Muir uses VigiLanz as an antimicrobial stewardship program aid that allows it to efficiently, voluntarily report the hospital’s infection rates and antibiotic utilization to the Centers for Disease Control National Health Safety Network. Mr. Russillo said that by being one of only about 50 U.S. hospitals to report both outcomes, John Muir could more effectively analyze its use of antibiotics, identify where it could improve and benchmark its performance against others. Other centers have had success with dynamic-monitoring protocols. The Methodist Hospital, a 900-bed unit of The Texas Medical Center in Houston, reported this year on its experience establishing seven pharmacotherapy alert rules to promote safe medication use. The rules were established to detect any improperly identified new medication orders for darbepoetin, filgrastim, fondaparinux and warfarin. In all, the real-time feedback from VigiLanz monitoring of newly verified orders reduced alerts by 36%, and the average number of alerts per day dipped from 1.0 to 0.6. The most frequently triggered rule targeted newly verified warfarin orders in the absence of a current documented international normalized ratio value. Pharmacists intervened within an average of 10.2 minutes of an alert, and their actions reduced the targeted ADEs by 39%, the researchers reported ((Am J Health Syst Pharm 2013;70:48-52). —Al Heller

Co-Chairs

Charles E. Argoff, MD

C Bill H. McCarberg, MD D

Professor of Neurology lb d l College ll Albany Medical Director, Comprehensive Pain Mana Manag ment Center Management Albany Medical Center Albany, New York

Founder h Chronic Pain Management Program i P Kaiser Permanente Ad Adj nct Assistant Clinical Professor Adjunct University of California, San Diego Sch d c ne Sc ooll of School o Medicine Med San Di Diego, g Californi California

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Mr. Russillo disclosed that he has consulted for VigiLanz. Dr. Bates disclosed that he has consulted for VigiLanz and has received research support from the company.

Supported by an educational grant from

• Pharmacy OneSource’s Sentri7 www.sentri7.com (800) 654-8395 • CareFusion’s MedMined www.carefusion.com (877) 849-6735

Policy 45

Pharmacy Practice News • July 2013

Generics

continued from page 1

the 11 drugs was estimated to increase from $33.6 billion in 2014 to $121 billion in 2024. In contrast, if the FDA were to approve 11 biosimilars included in the other scenario, spending in 2024 would be $81.3 billion, Express Scripts projected. The cumulative savings between 2014 and 2024 would be $250 billion if these 11 biosimilars were approved, Express Scripts reported (Figure). Although the savings could be higher than the forecast predicts, Molly Burich, MSc, a market analyst not involved in the research, said the figure also could be lower than the analysis suggests. “This report assumes biosimilars will be discounted at 30% relative to their branded competitors, but the thinking over the past few years has led to an erosion of this number down to between 20% and 25%,” said Ms. Burich, who is the assistant director of Reimbursement Strategy and Health Policy at Xcenda, an AmerisourceBergen Consulting Services company based in Charlotte, N.C.

Biosimilar Landscape Currently Hazy One reason expectations have been curbed is that the FDA may create an onerous biosimilar approval pathway, Ms. Burich noted. As a result, manufacturers might be required to submit extensive preapproval data and to conduct postmarketing studies. Express Scripts did not take the costs

‘In maligant diseases, where the first pass is critical, you want to come at the disease with your best guns first.’ —David Galardi, PharmD of gathering these data into consideration when constructing its 30% discount rate, Ms. Frazee said. Instead, Express Scripts based the discount assumption on the historical costs of biosimilars, including those currently available in Europe. Other costs that could bite into any savings include those associated with distributing drugs and providing physician reimbursement assistance and patient support programs. “All of these elements will require a big investment on the part of biosimilar manufacturers and will have a significant impact on the discounts they can offer,” she said. Both Ms. Burich and Ms. Frazee agreed that the extent to which a biosimilar will be used interchangeably with its branded competitor will mean the difference between small and large savings. Express Scripts assumed that 55% of the 11 biosimilars included in its model will be used interchangeably by payers and physicians

‘If there was any doubt in my mind that a biosimilar was not as effective as the biologic, I would choose the branded drug.’ —Leonard Zwelling, MD, MBA

140 Without biosimilars With biosimilars Savings

120

100

Dollars (in millions)

BIOSIMILARS

0 2012

2014

2016

2020

2022

2024

Figure. Projected U.S. spending on 11 specific biologics. Source: Express Scripts

by 2020, primarily in patients newly prescribed a biologic treatment. However, the degree of interchangeability could be lower or higher, Ms. Burich said. “Interchangeability is a critical unknown and could have a huge impact on

Table. Drugs Included in Express Scripts’ 10-Year Biosimilar Savings Model Brand

Generic

Manufacturer

Approval

Patent Expiration

2012 Sales

Avastin

Bevacizumab

Genentech

02/06/2004

06/18/2019

$2,662,842,000

Epogen

Epoetin alfa

Amgen

06/01/1989

05/26/2015

$2,254,245,000

Herceptin

Trastuzumab

Genentech

09/25/1998

08/27/2019

$1,837,693,000

Humira

Adalimumab

AbbVie

12/31/2002

12/31/2016

$4,505,380,000

Intron A

Interferon alfa-2a

Merck

06/04/1986

08/26/2020

$94,009,000

Neulasta

Pegfilgrastim

Amgen

01/31/2002

10/20/2015

$3,472,988,000

Neupogen

Filgrastim

Amgen

02/20/1991

11/10/2013

$1,007,172,000

PegIntron

Peginterferon alfa-2b

Merck

01/19/2001

08/26/2020

$121,828,000

Procrit

Epoetin alfa

Janssen

06/01/1989

05/26/2015

$1,127,024,000

Remicade

Infliximab

Janssen Biotech

08/24/1998

09/04/2018

$3,796,422,000

Rituxan

Rituximab

Genentech

11/26/1997

07/05/2015

$3,183,625,000

Source: Express Scripts Scriptts

2018

overall savings,” she noted. Ms. Burich added that payers likely will follow FDA policy. Based on preliminary guidance, she said, the administration likely will be conservative in granting interchangeability—at least initially. However, “if biosimilar manufacturers can offer huge discounts, payers may go ahead and mandate that a biosimilar be used in new patients, at least.”

Physicians Protest High Cost of Biologics Hagop Kantarjian, MD, the chairman of the Leukemia Department at the University of Texas MD Anderson Cancer Center in Houston, and 120 other chronic myeloid leukemia (CML) experts published an article protesting the high cost of biologics ((Blood 2013 April 25. doi:10.1182/blood-2013-03-490003). Dr. Kantarjian told Pharmacy Practice News that the FDA needs to implement an accelerated approval process. “Of course safety concerns need to be addressed, but they also shouldn’t delay in getting biosimilars to market,” he said. However, Dr. Kantarjian’s colleague, Leonard Zwelling, MD, MBA, a professor of medicine and pharmacology at

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see BIOSIMILARS, page 46

46 Policy

Pharmacy Practice News • July 2013

Generics

Biosimilar Approvals Face Many Hurdles Las Vegas—“The biosimilars game is a long game, a very long game, indeed.” So write the editors of Nature Biotechnology in the magazine’s April 5 online edition. This assessment neatly sums up the view of what’s coming with biosimilars shared by experts at the 2013 Armada Summit conference. In other words, despite the fact that the FDA has drafted three guidances on a new approval pathway aimed at getting these follow-on biologics to market (see sidebar below), it still could be several years before the first such product becomes available. The obstacles to getting a biosimilar to market are “huge,” said David Galardi, PharmD, the co-founder of the health care consulting firm Apogenics, during a session on the topic at the conference, which targets stakeholders in specialty pharmacy. “Biologics, by definition, are hard to make,” he said. “I can’t just go buy a tablet press and pour powder in there and watch it pour off some machine.” Unlike traditional small-molecule generic drugs, such as the current oral generic drugs, biosimilar versions of large-molecule drugs (biologics) will require successful clinical trials to get to FDA approval. “For the standard generic drug application, a 505( j) filing, there’s no trial required,” Dr. Galardi noted. “It’s effectively just a pharmacokinetics one-to-one analysis. But the filing for a biologic is a 301(k), which requires a full efficacy and safety workup, which means a clinical trial.” Developers of the innovator biologics also will have a much bigger advantage over their imitators than is the case with small-molecule generics, Dr. Galardi added. “The litigation process for biosimilars

is substantial. Effectively, the ‘bio-sponsor’ must disclose to the innovator their application and their manufacturing process, providing a clear advantage to the innovator company. [The innovator company] also likely will have a lower cost of production and deep roots in the supply chain for raw materials. Innovators are smart. Expect them to become aggressive in defending their turf.” Another obstacle for biosimilars is that providers initially may be reluctant to switch to these products, more so than is the case with small-molecule generics. “Vigilance to immunogenicity and related adverse events is an important safety concern with biologics,” Dr. Galardi noted. “Say you’ve had Mary on a particular drug and she’s tolerant, and somebody else comes along and says, ‘try another drug that looks similar.’ Mary goes to the infusion center and codes. Think that’s possible? Absolutely. It happens.” When biosimilars finally do come to market, they most likely will be covered under the medical benefit. “They’re large molecules, which with few exceptions get injected or infused into veins, although some are subcutaneous,” Dr. Galardi said. “In 64% of cases, that’s [covered by] the medical benefit. That means that biosimilars will live in the world of ASP [aveerage sales price] reimbu ursement, because the path p of least resistance ffor a Medicare patient w with an injectable drugg is Part D, which giives you more flexibilityy as to who can dispen nse the drug.”

BIOSIMILARS continued from page 45

MD Anderson, wants biosimilar manufacturers to conduct safety and efficacy studies before their product receives FDA approval. “In malignant diseases, where the first pass is critical, you want to come at the disease with your best guns first,” said Dr. Zwelling, who also has a research interest in health policy and economics. “If there was any doubt in my mind that a biosimilar was not as effective as the biologic, I would choose the branded drug.” Dr. Zwelling admitted that extensive clinical data requirements could discourage manufacturers from developing biosimilars altogether. In that case, he said, “the likelihood that big savings could result from biosimilars is about zero.” —David Wild Drs. Kantarjian and Zwelling and Ms. Burich reported no relevant ﬁnancial conﬂicts of interest.

‘Biologics, by definition, are hard to make. I can’t just go buy a tablet press and pour powder in there and watch it pour off some machine.’ —David Galardi, PharmD Biosimilars are almost certain to upset the current cost structure of specific biologics. “Supply and demand curves will shift,” Dr. Galardi predicted. “Unlike small-molecule generics, they will face a more complex pricing environment.” For example, inexperienced bio-sponsors may price a product in a way that means providers cannot achieve the necessary cost recovery to support their use. On the other hand, experienced innovators may make the mistake of contracting more aggressivelyy than necessary, thus cannibalizing their existin ng product’s potential prematurely. “Wh hat if you change your contract terms in anticipation of a biosimilar—and then it doesn’t come out?” Dr. Galardi said. There’s a lot of savings potential frrom biosimilars, but it won’t be the same kind of num mbers that were real-

ized with generics because biosimilars are not as closely related to the innovator drug as traditional generics are to their branded counterparts, according to Mike Ellis, Walgreens’ corporate vice president for specialty pharmacy and infusion. “There’s a reason they’re called biosimilars and not bioexacts,” said Mr. Ellis during another session at Armada. “I talked to a couple of large pharmaceutical companies, and they’re modeling about 40% off [the original product], not 80% like the generics were.” “These aren’t generic substitutes,” agreed Helen Sherman, PharmD, the vice president of clinical pharmacy consulting at Solid Benefit Guidance. “They will be a brand. But, in any case, despite all the press about biosimilars, I haven’t heard of one solid example indicating that there is a biosimilar coming out anytime soon.” —Gina Shaw

What the FDA Is Saying About the Biosimilar Approval Pathway

n a statement issued to Pharmacy Practice News on May 22, a representative from the FDA’s Center for Drug Evaluation and Research said, “The type and amount of data and information that will be sufficient to demonstrate biosimilarity will be determined on a program-specific basis.” The spokesperson noted that the FDA was still reviewing public comments on the subject and has yet to finalize three draft guidances. The administration still needs to decide how to develop future policies on biosimilars, the statement said, including guidance on what clinical pharmacology data they need from manufacturers to show biosimilarity to a reference product. “We will be able to provide meaningful advice on the scope and extent of necessary animal and human testing after a thorough review of data from structural and functional analyses [for a given product],” the FDA statement said. “Additional animal and clinical studies should be designed to address residual uncertainty about the biosimilarity between the two products to ensure such testing is appropriately targeted.” Draft guidance on the development and approval of biosimilars can be found at http:// www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm. —D.W.

SAMSCA AÂ® (tolvaptan) tablets for oral use Brief Summary of Prescribing Information. Please see Full Prescribing Information for complete product information. WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. INDICATIONS AND USAGE: 6$06&$ LV LQGLFDWHG IRU WKH WUHDWPHQW RI FOLQLFDOO\ VLJQLÂ¿FDQW K\SHUYROHPLF DQG HXYROHPLF K\SRQDWUHPLD VHUXP VRGLXP P(T / RU OHVV PDUNHG K\SRQDWUHPLD WKDW LV V\PSWRPDWLF DQG KDV UHVLVWHG FRUUHFWLRQ ZLWK Ã&#x20AC;XLG restriction), including patients with heart failure and Syndrome of Inappropriate Antidiuretic Hormone (SIADH). Important Limitations: 3DWLHQWV UHTXLULQJ LQWHUYHQWLRQ WR UDLVH VHUXP VRGLXP XUJHQWO\ WR SUHYHQW RU WR WUHDW VHULRXV QHXURORJLFDO V\PSWRPV VKRXOG QRW EH WUHDWHG ZLWK 6$06&$ ,W KDV QRW EHHQ HVWDEOLVKHG WKDW UDLVLQJ VHUXP VRGLXP ZLWK 6$06&$ SURYLGHV D V\PSWRPDWLF EHQHÂ¿W WR SDWLHQWV CONTRAINDICATIONS: SAMSCA is contraindicated in the following conditions: Urgent need to raise serum sodium acutely: SAMSCA has not been studied in a setting of urgent need to raise serum sodium acutely. Inability of the patient to sense or appropriately respond to thirst: 3DWLHQWV ZKR DUH XQDEOH WR DXWR UHJXODWH Ã&#x20AC;XLG EDODQFH DUH DW VXEVWDQWLDOO\ LQFUHDVHG ULVN RI LQFXUULQJ DQ RYHUO\ UDSLG FRUUHFWLRQ RI VHUXP VRGLXP K\SHUQDWUHPLD DQG K\SRYROHPLD Hypovolemic hyponatremia: 5LVNV DVVRFLDWHG ZLWK ZRUVHQLQJ K\SRYROHPLD LQFOXGLQJ FRPSOLFDWLRQV VXFK DV K\SRWHQVLRQ DQG UHQDO IDLOXUH RXWZHLJK SRVVLEOH EHQHÂ¿WV Concomitant use of strong CYP 3A inhibitors: .HWRFRQD]ROH PJ DGPLQLVWHUHG ZLWK WROYDSWDQ LQFUHDVHG WROYDSWDQ H[SRVXUH E\ IROG /DUJHU GRVHV ZRXOG EH H[SHFWHG WR SURGXFH ODUJHU LQFUHDVHV LQ WROYDSWDQ H[SRVXUH 7KHUH LV QRW DGHTXDWH H[SHULHQFH WR GHÂ¿QH WKH GRVH DGMXVWPHQW WKDW ZRXOG EH QHHGHG WR DOORZ VDIH XVH RI WROYDSWDQ ZLWK VWURQJ &<3 $ LQKLELWRUV VXFK DV FODULWKURP\FLQ NHWRFRQD]ROH LWUDFRQD]ROH ULWRQDYLU LQGLQDYLU QHOÂ¿QDYLU VDTXLQDYLU QHID]RGRQH DQG WHOLWKURP\FLQ Anuric patients: ,Q SDWLHQWV XQDEOH WR PDNH XULQH QR FOLQLFDO EHQHÂ¿W FDQ EH H[SHFWHG WARNINGS AND PRECAUTIONS: Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae (see BOXED WARNING): Osmotic demyelination syndrome is a risk associated with too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours). Osmotic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hours. Osmotic demyelination syndrome has been reported in association with SAMSCA therapy [see Adverse Reactions (6.2)]. Patients treated with SAMSCA should be monitored to assess serum sodium concentrations and neurologic status, especially GXULQJ LQLWLDWLRQ DQG DIWHU WLWUDWLRQ 6XEMHFWV ZLWK 6,$'+ RU YHU\ ORZ EDVHOLQH VHUXP VRGLXP FRQFHQWUDWLRQV PD\ EH DW JUHDWHU ULVN IRU WRR UDSLG FRUUHFWLRQ RI VHUXP VRGLXP ,Q SDWLHQWV UHFHLYLQJ 6$06&$ ZKR GHYHORS WRR UDSLG D ULVH LQ VHUXP VRGLXP GLVFRQWLQXH RU LQWHUUXSW WUHDWPHQW ZLWK 6$06&$ DQG FRQVLGHU DGPLQLVWUDWLRQ RI K\SRWRQLF Ã&#x20AC;XLG )OXLG UHVWULFWLRQ GXULQJ WKH Â¿UVW KRXUV RI WKHUDS\ ZLWK 6$06&$ PD\ LQFUHDVH WKH OLNHOLKRRG RI RYHUO\ UDSLG FRUUHFWLRQ RI VHUXP VRGLXP DQG VKRXOG JHQHUDOO\ EH DYRLGHG Liver Injury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see Adverse Reactions (6.1)]. Dehydration and Hypovolemia: 6$06&$ WKHUDS\ LQGXFHV FRSLRXV DTXDUHVLV ZKLFK LV QRUPDOO\ SDUWLDOO\ RIIVHW E\ Ã&#x20AC;XLG LQWDNH 'HK\GUDWLRQ DQG K\SRYROHPLD FDQ RFFXU HVSHFLDOO\ LQ SRWHQWLDOO\ YROXPH GHSOHWHG SDWLHQWV UHFHLYLQJ GLXUHWLFV RU WKRVH ZKR DUH Ã&#x20AC;XLG UHVWULFWHG ,Q PXOWLSOH GRVH SODFHER FRQWUROOHG WULDOV LQ ZKLFK K\SRQDWUHPLF SDWLHQWV ZHUH WUHDWHG ZLWK WROYDSWDQ WKH LQFLGHQFH RI GHK\GUDWLRQ ZDV IRU WROYDSWDQ DQG IRU SODFHER WUHDWHG SDWLHQWV ,Q SDWLHQWV UHFHLYLQJ 6$06&$ ZKR GHYHORS PHGLFDOO\ VLJQLÂ¿FDQW VLJQV RU V\PSWRPV RI K\SRYROHPLD LQWHUUXSW RU GLVFRQWLQXH 6$06&$ WKHUDS\ DQG SURYLGH VXSSRUWLYH FDUH ZLWK FDUHIXO PDQDJHPHQW RI YLWDO VLJQV Ã&#x20AC;XLG EDODQFH DQG HOHFWURO\WHV )OXLG UHVWULFWLRQ GXULQJ WKHUDS\ ZLWK 6$06&$ PD\ LQFUHDVH WKH ULVN RI GHK\GUDWLRQ DQG K\SRYROHPLD 3DWLHQWV UHFHLYLQJ 6$06&$ VKRXOG FRQWLQXH LQJHVWLRQ RI Ã&#x20AC;XLG LQ UHVSRQVH WR WKLUVW Co-administration with Hypertonic Saline: Concomitant use with hypertonic saline is not recommended. Drug Interactions: Other Drugs Affecting Exposure to Tolvaptan: CYP 3A Inhibitors: 7ROYDSWDQ LV D VXEVWUDWH RI &<3 $ &<3 $ LQKLELWRUV FDQ OHDG WR D PDUNHG LQFUHDVH LQ WROYDSWDQ FRQFHQWUDWLRQV [see Dosage and Administration (2.3), Drug Interactions (7.1)]. 'R QRW XVH 6$06&$ ZLWK VWURQJ LQKLELWRUV RI &<3 $ [see Contraindications (4.4)] DQG DYRLG FRQFRPLWDQW XVH ZLWK PRGHUDWH &<3 $ LQKLELWRUV CYP 3A Inducers: $YRLG FR DGPLQLVWUDWLRQ RI &<3 $ LQGXFHUV H J ULIDPSLQ ULIDEXWLQ ULIDSHQWLQ EDUELWXUDWHV SKHQ\WRLQ FDUEDPD]HSLQH 6W -RKQÂ¶V :RUW ZLWK 6$06&$ DV WKLV FDQ OHDG WR D UHGXFWLRQ LQ WKH SODVPD FRQFHQWUDWLRQ RI WROYDSWDQ DQG GHFUHDVHG HIIHFWLYHQHVV RI 6$06&$ WUHDWPHQW ,I FR DGPLQLVWHUHG ZLWK &<3 $ LQGXFHUV WKH GRVH RI 6$06&$ PD\ QHHG WR EH increased [see Dosage and Administration (2.3), Drug Interactions (7.1)]. P-gp Inhibitors: 7KH GRVH RI 6$06&$ PD\ KDYH WR EH UHGXFHG ZKHQ 6$06&$ LV FR DGPLQLVWHUHG ZLWK 3 JS LQKLELWRUV H J cyclosporine [see Dosage and Administration (2.3), Drug Interactions (7.1)]. Hyperkalemia or Drugs that Increase Serum Potassium: 7UHDWPHQW ZLWK WROYDSWDQ LV DVVRFLDWHG ZLWK DQ DFXWH UHGXFWLRQ RI WKH H[WUDFHOOXODU Ã&#x20AC;XLG YROXPH ZKLFK FRXOG UHVXOW LQ LQFUHDVHG VHUXP SRWDVVLXP 6HUXP SRWDVVLXP OHYHOV VKRXOG EH PRQLWRUHG DIWHU LQLWLDWLRQ RI WROYDSWDQ WUHDWPHQW LQ SDWLHQWV ZLWK D VHUXP SRWDVVLXP ! P(T / DV ZHOO DV WKRVH ZKR DUH UHFHLYLQJ GUXJV NQRZQ WR LQFUHDVH VHUXP SRWDVVLXP OHYHOV ADVERSE REACTIONS: Clinical Trials Experience: %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV DGYHUVH UHDFWLRQV UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW EH GLUHFWO\ FRPSDUHG WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHÃ&#x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Â&#x2022; PRUH WKDQ SODFHER VHHQ LQ WZR GD\ GRXEOH EOLQG SODFHER FRQWUROOHG K\SRQDWUHPLD WULDOV LQ ZKLFK WROYDSWDQ ZDV DGPLQLVWHUHG LQ titrated doses (15 mg to 60 mg once daily) were thirst, dry mouth, asthenia, constipation, pollakiuria or polyuria and hyperglycemia. ,Q WKHVH WULDOV RI WROYDSWDQ WUHDWHG SDWLHQWV GLVFRQWLQXHG WUHDWPHQW EHFDXVH RI DQ DGYHUVH HYHQW FRPSDUHG WR RI SODFHER WUHDWHG SDWLHQWV QR DGYHUVH UHDFWLRQ UHVXOWLQJ LQ GLVFRQWLQXDWLRQ RI WULDO PHGLFDWLRQ RFFXUUHG DW DQ LQFLGHQFH RI ! LQ WROYDSWDQ WUHDWHG SDWLHQWV 7DEOH OLVWV WKH DGYHUVH UHDFWLRQV UHSRUWHG LQ WROYDSWDQ WUHDWHG SDWLHQWV ZLWK K\SRQDWUHPLD VHUXP VRGLXP P(T / DQG DW D UDWH DW OHDVW JUHDWHU WKDQ SODFHER WUHDWHG SDWLHQWV LQ WZR GD\ GRXEOH EOLQG SODFHER FRQWUROOHG WULDOV ,Q WKHVH VWXGLHV SDWLHQWV ZHUH H[SRVHG WR WROYDSWDQ VWDUWLQJ GRVH PJ WLWUDWHG WR DQG PJ DV QHHGHG WR UDLVH VHUXP VRGLXP $GYHUVH HYHQWV UHVXOWLQJ LQ GHDWK LQ WKHVH WULDOV ZHUH LQ WROYDSWDQ WUHDWHG SDWLHQWV DQG LQ SODFHER WUHDWHG SDWLHQWV Table 1. Adverse Reactions (>2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials System Organ Class MedDRA Preferred Term Gastrointestinal Disorders Dry mouth Constipation General Disorders and Administration Site Conditions 7KLUVWa Asthenia 3\UH[LD Metabolism and Nutrition Disorders Hyperglycemiab $QRUH[LDc Renal and Urinary Disorders Pollakiuria or polyuriad

Tolvaptan 15 mg/day-60 mg/day (N = 223) n (%)

(N = 220) n (%)

Placebo

16 (7)

4 (2)

11 (5)

2 (1)

14 (6)

2 (1) 2 (1)

25 (11)

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SAMSCAÂ® (tolvaptan) JDVWURLQWHVWLQDO EOHHGLQJ ZDV UHSRUWHG LQ RXW RI WROYDSWDQ WUHDWHG SDWLHQWV DQG RXW RI SODFHER WUHDWHG SDWLHQWV 7KH IROORZLQJ DGYHUVH UHDFWLRQV RFFXUUHG LQ RI K\SRQDWUHPLFF SDWLHQWV WUHDWHG ZLWK SAMSCA and at a rate greater than placebo LQ GRXEOH EOLQG SODFHER FRQWUROOHG WULDOV 1 WROYDSWDQ 1 SODFHER RU LQ RI SDWLHQWV LQ DQ XQFRQWUROOHG WULDO RI SDWLHQWV with hyponatremia (N = 111) and are not mentioned elsewhere in the label: Blood and Lymphatic System Disorders: Disseminated LQWUDYDVFXODU FRDJXODWLRQ &DUGLDF 'LVRUGHUV ,QWUDFDUGLDF WKURPEXV YHQWULFXODU Â¿EULOODWLRQ ,QYHVWLJDWLRQV 3URWKURPELQ WLPH prolonged; Gastrointestinal Disorders: Ischemic colitis; Metabolism and Nutrition Disorders: Diabetic ketoacidosis; Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis; Nervous System: Cerebrovascular accident; Renal and Urinary Disorders: Urethral hemorrhage; Reproductive System and Breast Disorders (female): Vaginal hemorrhage; Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure; Vascular disorder: Deep vein thrombosis. Postmarketing Experience: 7KH IROORZLQJ DGYHUVH UHDFWLRQV KDYH EHHQ LGHQWLÂ¿HG GXULQJ SRVW DSSURYDO XVH RI 6$06&$ %HFDXVH WKHVH UHDFWLRQV DUH UHSRUWHG YROXQWDULO\ IURP D SRSXODWLRQ RI DQ XQNQRZQ VL]H LW LV QRW DOZD\V SRVVLEOH WR UHOLDEO\ HVWLPDWH WKHLU IUHTXHQF\ RU HVWDEOLVK D FDXVDO UHODWLRQVKLS WR GUXJ H[SRVXUH Neurologic: 2VPRWLF GHP\HOLQDWLRQ V\QGURPH Investigations: Hypernatremia 5HPRYDO RI H[FHVV IUHH ERG\ ZDWHU LQFUHDVHV VHUXP RVPRODOLW\ DQG VHUXP VRGLXP FRQFHQWUDWLRQV $OO SDWLHQWV WUHDWHG ZLWK WROYDSWDQ HVSHFLDOO\ WKRVH ZKRVH VHUXP VRGLXP OHYHOV EHFRPH QRUPDO VKRXOG FRQWLQXH WR EH PRQLWRUHG WR HQVXUH VHUXP VRGLXP UHPDLQV ZLWKLQ QRUPDO OLPLWV ,I K\SHUQDWUHPLD LV REVHUYHG PDQDJHPHQW PD\ LQFOXGH GRVH GHFUHDVHV RU LQWHUUXSWLRQ RI WROYDSWDQ WUHDWPHQW FRPELQHG ZLWK PRGLÂ¿FDWLRQ RI IUHH ZDWHU LQWDNH RU LQIXVLRQ 'XULQJ FOLQLFDO WULDOV RI K\SRQDWUHPLF SDWLHQWV K\SHUQDWUHPLD ZDV UHSRUWHG DV DQ DGYHUVH HYHQW LQ RI SDWLHQWV UHFHLYLQJ WROYDSWDQ YV RI SDWLHQWV UHFHLYLQJ SODFHER DQDO\VLV RI ODERUDWRU\ YDOXHV GHPRQVWUDWHG DQ LQFLGHQFH RI K\SHUQDWUHPLD RI LQ SDWLHQWV UHFHLYLQJ WROYDSWDQ YV LQ SDWLHQWV UHFH I LYLQJ placebo. DRUG INTERACTIONS: Effects of Drugs on Tolvaptan: Ketoconazole and Other Strong CYP 3A Inhibitors: 6$06&$ LV PHWDEROL]HG SULPDULO\ E\ &<3 $ .HWRFRQD]ROH LV D VWURQJ LQKLELWRU RI &<3 $ DQG DOVR DQ LQKLELWRU RI 3 JS &R DGPLQLVWUDWLRQ RI 6$06&$ DQG NHWRFRQD]ROH PJ GDLO\ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PJ NHWRFRQD]ROH GDLO\ RU ZLWK RWKHU VWURQJ &<3 $ LQKLELWRUV H J FODULWKURP\FLQ LWUDFRQD]ROH WHOLWKURP\FLQ VDTXLQDYLU QHOÂ¿QDYLU ULWRQDYLU DQG QHID]RGRQH DW WKH KLJKHVWW ODEHOHG GRVH ZRXOG EH H[SHFWHG WR FDXVH DQ HYHQ JUHDWHU LQFUHDVH LQ WROYDSWDQ H[SRVXUH 7KXV 6$06&$ DQG VWURQJ &<3 $ LQKLELWRUV should not be co-administered [see Dosage and Administration (2.3) and Contraindications (4.4)]. Moderate CYP 3A Inhibitors: 7KH LPSDFW RI PRGHUDWH &<3 $ LQKLELWRUV H J HU\WKURP\FLQ Ã&#x20AC;XFRQD]ROH DSUHSLWDQW GLOWLD]HP DQG YHUDSDPLO RQ WKH H[SRVXUH WR FR DGPLQLVWHUHG WROYDSWDQ KDV QRW EHHQ DVVHVVHG $ VXEVWDQWLDO LQFUHDVH LQ WKH H[SRVXUH WR WROYDSWDQ ZRXOG EH H[SHFWHG ZKHQ 6$06&$ LV FR DGPLQLVWHUHG ZLWK PRGHUDWH &<3 $ LQKLELWRUV &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PRGHUDWH &<3 $ LQKLELWRUV VKRXOG WKHUHIRUH JHQHUDOO\ EH DYRLGHG [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Grapefruit Juice: &R DGPLQLVWUDWLRQ RI JUDSHIUXLW MXLFH DQG 6$06&$ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. P-gp Inhibitors: Reduction in the dose of SAMSCA may be required in patients concomitantly treated with P-gp inhibitors, such as e.g., cyclosporine, based on clinical response [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. 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Nursing: $GYLVH SDWLHQWV QRW WR EUHDVWIHHG DQ LQIDQW LI WKH\ DUH WDNLQJ 6$MSCA >VHH 8VH ,Q 6SHFLÂ¿F 3RSXODWLRQV @ )RU PRUH LQIRUPDWLRQ DERXW 6$06&$ FDOO RU JR WR ZZZ VDPVFD FRP 0DQXIDFWXUHG E\ 2WVXND 3KDUPDFHXWLFDO &R /WG 7RN\R -DSDQ 'LVWULEXWHG DQG PDUNHWHG E\ 2WVXND $PHULFD 3KDUPDFHXWLFDO ,QF 5RFNYLOOH 0' SAMSCA is a registered g trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

FREE VVV2ATER Order SAMSCA® (tolvaptan) CLEARANCE

15 mg

30 mg

NDC: 59148-020-50

NDC: 59148-021-50

Unique oral treatment for clinically significant hypervolemic and euvolemic hyponatremia

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

IMPORTANT SAFETY INFORMATION SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. Contraindications: Urgent need to raise serum sodium acutely, inability of the patient to sense or appropriately respond to thirst, hypovolemic hyponatremia, concomitant use of strong CYP 3A inhibitors, and anuric patients. Warnings and Precautions: • Subjects with SIADH or very low baseline serum sodium concentrations may be at greater risk for too-rapid correction of serum sodium. In patients receiving SAMSCA who develop too rapid a rise in serum sodium or develop neurologic sequelae, discontinue or interrupt treatment with SAMSCA and consider administration of hypotonic fluid. Fluid restriction should generally be avoided during the first 24 hours • SAMSCA can cause serious and potentially fatal liver injury. Avoid use in patients with underlying liver disease, including cirrhosis, because the ability to recover may be impaired. Limit duration of therapy with SAMSCA to 30 days • Dehydration and hypovolemia can occur, especially in potentially volume-depleted patients receiving diuretics or those who are fluid restricted. In patients who develop medically significant signs or symptoms of hypovolemia, discontinuation is recommended • Co-administration with hypertonic saline is not recommended • Avoid use with: CYP 3A inhibitors and CYP 3A inducers. The dose of SAMSCA may have to be reduced if co-administered with P-gp inhibitors • Monitor serum potassium levels in patients with a serum potassium >5 mEq/L and in patients receiving drugs known to increase serum potassium levels Gastrointestinal Bleeding in Patients with Cirrhosis: In patients with cirrhosis in the hyponatremia trials, GI bleeding was reported in 10% of tolvaptan-treated patients vs 2% for placebo. Commonly Observed Adverse Reactions: (SAMSCA incidence ≥5% more than placebo, respectively): thirst (16% vs 5%), dry mouth (13% vs 4%), asthenia (9% vs 4%), constipation (7% vs 2%), pollakiuria or polyuria (11% vs 3%) and hyperglycemia (6% vs 1%).

Please see Brief Summary of FULL PRESCRIBING INFORMATION, including Boxed WARNING, on previous page. For more information, visit SAMSCA.com or call 1-877-726-7220. Manufactured by Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan. Distributed and marketed by Otsuka America Pharmaceutical, Inc., Rockville, MD 20850. SAMSCA is a registered trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan.

May 2013

0713A-7891G

PRINTER-FRIENDLY VERSION AVAILABLE AT PHARMACYPRACTICENEWS.COM

Perioperative Approach to Patients With Opioid Abuse and Tolerance BENJAMIN VAGHARI, MD

JAIME L. BARATTA, MD

KISHOR GANDHI, MD, MPH, CPE

Clinical Instructor Jefferson Medical College Thomas Jefferson University Department of Anesthesiology Philadelphia, Pennsylvania

Assistant Professor Director Fellowship in Regional Anesthesia and Acute Pain Jefferson Medical College Thomas Jefferson University Department of Anesthesiology Philadelphia, Pennsylvania

Associate Professor Director, Regional Anesthesia Jefferson Medical College Thomas Jefferson University Department of Anesthesiology Philadelphia, Pennsylvania

ubstance abuse in the United States is

increasing. Most of the rise in illicit drug use has been attributed to marijuana,

with the use of heroin remaining relatively stable over the past 10 years. Although heroin use has plateaued, overall use of opioid analgesics has increased dramatically.1 Sales of prescription opioids quadrupled between 1999 and 2010.2

Enough of these substances were prescribed in 2011 to medicate every American adult with a standard dose of 5 mg of hydrocodone every 4 hours for a month. In 2010 alone, 12 million Americans reported nonmedical use of prescription painkillers in the past year.2 As the use and abuse of opioids increases, the likelihood of encountering these patients also will increase. There are both anesthetic and analgesic implications of increased opioid use in patients undergoing surgery. First, as both illegal and prescription use of opioids increases, health care practitioners will encounter more patients exhibiting opioid tolerance. Second, as abusers of opioids seek treatment for their addiction, the numbers of patients receiving long-term opioid therapy for their addiction also will increase. Long-term medical therapy for opioid dependence introduces several issues in the management of patients that clinicians must consider when forming a treatment plan to address anesthetic and analgesic needs.

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

All anesthetic and analgesic plans can be divided into preoperative considerations, intraoperative management, and postoperative recovery and analgesia. For patients with known or suspected opioid abuse, this strategy is no different. Optimal patient care always begins in the preoperative period with the patient assessment. Obtaining information about patient drug use and potential ongoing treatment is critical in constructing an appropriate plan. If the patientâ&#x20AC;&#x2122;s history with opioids is limited or unknown to the anesthesia care team, patient care and satisfaction are likely to be compromised. Understanding and performing appropriate screening and assessment is paramount in these cases.

Patient Evaluation Screening and assessment of opioid use can be broken down into 2 main categories: subjective and objective data. Subjective data are gathered by the practitioner at time of interview, either in preadmission

P H A R M A C Y P R A C T I C E N E W S â&#x20AC;˘ J U LY 2 0 1 3

testing or in the preoperative holding area. Objective data largely are related to urinalysis and blood testing. The interviewing clinician will benefit from realizing that many patients with a history of abuse of or dependence on prescription opioids—including oxycodone, hydrocodone, fentanyl, and other drugs—will be evasive about that history or will attempt to minimize their use of these drugs. A helpful strategy when collecting the patient history is to focus on specific questions while preserving a nonjudgmental environment. For example, “What is the most you have ever used in a day,” can provide more useful information than simply asking about average daily use. Whenever possible, the interviewer should determine the time of the last dose of opioids and, if applicable, who is prescribing these medications. To help with this difficult task, several drug screening questionnaires have been developed.

CAGE-AID The CAGE-AID (Adapted to Include Drugs) is a modification of the common 4-question tool used to detect potential alcohol abuse (Table 1).3 A second, and perhaps easier, validated screening test is the single question: “How many times in the past year have you used an illegal drug or used a prescription medication for nonmedical reasons?”4 Regardless of which strategy is used in your hospital, most patients are unlikely to volunteer this important information without direct questioning. Drug screening, specifically urine drug screening (UDS), is an important tool in obtaining objective information about a patient’s use of opioids. However, these tests have several important limitations (Table 2).5 Immunoassay screening, which is the most common UDS, can detect the presence of specific opioids and their metabolites, but frequently it returns false-positive results and typically findings must be confirmed by gas chromatography-mass spectroscopy—a timeconsuming process. Also, a UDS, and even serum testing, have difficulty detecting fentanyl use. Finally, UDS cannot detect past abuse. Nevertheless, drug testing

Table 1. The CAGE-AID Questionnaire Have you ever felt that you ought to Cut down on your drinking or drug use? Have people Annoyed you by criticizing your drinking or drug use? Have you ever felt bad or Guilty about your drinking or drug use? Have you ever had a drink or used drugs first thing in the morning to steady your nerves or to get rid of a hangover (Eye opener)? Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and other drug abuse: criterion validity in a primary care practice. Wis Med J. 1995;94(3):135-140. Adapted from reference 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

can provide useful objective information as long as clinicians are aware of these limitations.

Long-Term Opioid Therapy When collecting patient information in the preoperative period, the clinician likely will encounter patients who have been taking opioids chronically. These include the opioid agonists methadone and buprenorphine-naloxone (Suboxone, Reckitt Benckiser), as well as the opioid antagonist naltrexone (Vivitrol, Alkermes). Having at least a working knowledge of these medications is helpful in understanding their anesthetic and analgesic implications.

METHADONE Methadone is by far the most commonly used longterm opioid treatment and has been widely available since the 1960s. Methadone is a long-acting opioid agonist with some activity as an N-methyl-D-aspartate antagonist. The major function of methadone is to suppress withdrawal symptoms, which in most patients can be achieved with as little as 30 to 40 mg per day. It is available only in outpatient treatment programs and is dispensed on a daily basis. If a patient reports having received methadone, clinicians should verify the dose by contacting the methadone clinic by telephone. The verified dose then can be administered. Administering methadone without the supervision of a methadone clinic is illegal. For that matter, treating opioid withdrawal with opioids is against guidelines from the Drug Enforcement Administration. The administration of opioids, including methadone, is reserved exclusively for treating pain and must be thoroughly documented in patients’ medical records.

BUPRENORPHINE Unlike methadone, buprenorphine is a partial opioid agonist. Buprenorphine relieves drug cravings without producing the “high” and dangerous side effects of other opioids. Suboxone is a combination of buprenorphine and naloxone that received FDA approval in 2002.6 If Suboxone is injected intravenously, the naloxone component will precipitate withdrawal symptoms. Its increased therapeutic window and deterrence of IV use allow Suboxone to be prescribed by certified physicians outside the context of a specialized treatment clinic and without the need for daily supervision. Given its relative ease of use for those seeking treatment, prescription use of this medication has been increasing steadily in recent years. Although opioid agonists, whether full or partial, are the most commonly used treatment modality by far, some opioid-dependent patients opt for therapy with an opioid antagonist. Historically, the main treatment was naltrexone, similar to naloxone. As a once-daily treatment, poor patient compliance limited the effectiveness of this agent. However, Vivitrol, an extendedrelease form of naltrexone, has gained acceptance as treatment for patients with dependence on alcohol, opioids, or both. Given as a monthly injection, this

medication has clear advantages over once-daily dosing in terms of patient compliance.

Table 2. Potential Limitations Of Urine Drug Screening for Opioids

Intraoperative Management With appropriate data collection and assessment in the preoperative period, intraoperative management of patients with opioid dependence or abuse relies heavily on 3 areas: managing intoxication, preventing or treating withdrawal, and achieving effective analgesia. Although most patients will not present for elective surgery when they are acutely intoxicated, urgent or emergent situations involving these patients often occur. In these incidents, monitoring respiratory rate and oxygen saturation is critical. Antagonist therapy should be reserved for patients with potentially life-threatening respiratory depression because precipitating withdrawal in such a patient may make both anesthetic and analgesic management more difficult. Although patients not receiving established agonist therapy, such as methadone, cannot be given opioids to treat withdrawal symptoms directly, they can be managed in other ways. First, patients on long-standing prescription opioids can be directed to take these medications as they normally would on the morning of surgery. Second, patients at risk for or entering withdrawal can have their symptoms managed. Clonidine commonly is used to treat symptoms of opioid withdrawal and can be given at a starting dose of 0.1 mg twice daily. Other medications, such as loperamide, also can be administered to target specific withdrawal symptoms. Analgesia strategies for patients with significant histories of opioid use should focus less on opioids as a foundational, single-agent therapy and more on opioid-sparing or multimodal techniques with nonopioid agents such as IV acetaminophen (Ofirmev, Cadence) or liposomal bupivacaine (Exparel, Pacira). Many of these agents can be initiated in the preoperative or intraoperative phases and continued into the postoperative period. Nonopioid analgesics such as acetaminophen and nonsteroidal antiinflammatory drugs, regional anesthesia when possible, α-2 agonists, and ketamine can have profound analgesic effects, particularly when used in combination. Pregabalin (Lyrica, Pfizer) and gabapentin also can be useful for managing neuropathic pain, which often is poorly controlled by opioids. An emphasis on multimodal analgesia is paramount in patients with neuropathic pain and should be continued through surgery and into the postoperative period. Goals for the postoperative period can be divided into 2 main categories: comfort and safety. Patient comfort consists of providing adequate analgesia and continued prevention or management of opioid withdrawal. Patient safety is equally important because this population typically manifests significant opioid tolerance. Patients with opioid tolerance generally will require at least 2 to 3 times more opioids than an opioid-naive patient. Yet despite their analgesic tolerance, they appear to be at risk for respiratory side effects. During the postoperative period, clinicians must

Standard UDS and tests used for pain management differ greatly in complexity Standard UDS frequently reported only as positive for opiates Oxycodone, oxymorphone, methadone, and buprenorphine often must be checked specifically Fentanyl cannot be detected in-office UDS, urine drug screening

continue to manage both a patient’s potential withdrawal symptoms and his or her analgesic needs. For opioiddependent patients, these 2 aspects often intersect. Opioid withdrawal, either real or potential, can complicate pain assessments; patients may overreport pain to obtain increased opioid dosages. Reassuring patients that their withdrawal symptoms will be managed, either with their current opioid agonist or by easing of their symptoms, is a good first step. Even patients on high doses of opioids in the postoperative period may suffer intermittent withdrawal symptoms given the waxing and waning effects of short-acting opioids. If appropriate, combining a long-acting opioid analgesic with shorter-acting agents, such as hydromorphone by patient-controlled analgesia during periods of breakthrough pain may help to alleviate patients’ withdrawal fear or symptoms. However, this strategy can be used only when treating pain and not for the management of withdrawal symptoms that are not life-threatening. In addition to managing a patient with opioid tolerance, patients on some type of long-standing opioid medical therapy require modifications to the analgesic plan. For those receiving methadone maintenance, management is relatively straightforward. After verifying the dose with a methadone clinic, the drug can be continued during the postoperative period. The dose can be divided into a 3-times-daily regimen to take advantage of methadone’s analgesic properties, which are much shorter than its withdrawal-preventing effects. Management can be significantly more complicated for patients receiving buprenorphine-naloxone therapy. As a partial μ-opioid agonist, buprenorphine has what is known as a ceiling effect. Similar to with full agonists, morphine, or methadone, initially increasing buprenorphine dosage will heighten both its analgesic properties and its unwanted side effects. Unlike full agonists, as the dose of buprenorphine increases, the effects will plateau, at which point further doses have no effect.7 This widens the drug’s therapeutic window by broadening its safe dosing range. Coupled with its long half-life, these attributes help make buprenorphine both relatively safe and effective in managing long-term opioid dependence.8 In the context of managing acute pain, however, buprenorphine is more difficult. The drug has a high

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affinity for μ receptors, about 1,000 times higher than that of morphine.9 With its long half-life and high receptor affinity, buprenorphine will persist on the receptor even when more potent, short-acting opioids are introduced in an attempt to provide analgesia. And because buprenorphine is only a partial agonist, effective analgesia will be difficult to provide. Given this profile, 4 recommendations for acute pain generally exist when dealing with buprenorphine.10 First, maintenance therapy can be continued and short-acting opioids can be titrated to effect.11 One must recognize that with buprenorphine present on the receptor sites, the patient likely will require higher than usual doses of a short-acting opioid to achieve an expected effect. A second option is to divide buprenorphine into 3-times-daily dosing to take advantage of its inherent analgesic properties in much the same way as methadone.12 This strategy may be helpful if the surgery or procedure is not likely to be particularly invasive or painful. A third option is to discontinue buprenorphine therapy and treat the patient with full opioid analgesics, while being mindful of potential withdrawal.11 A caveat here is for the clinician to realize that buprenorphine can continue to be present on the receptor up to 5 days after the last dose. Finally, a fourth option with buprenorphine is to convert to methadone at 30 to 40 mg per day. This total daily dose is usually sufficient to prevent withdrawal symptoms.13 However, because methadone cannot be prescribed for withdrawal outside a methadone clinic, this strategy requires the standard 3-times-daily dosing of methadone, and its primary purpose would need to be documented as treating pain, not managing withdrawal. Also, if buprenorphine has been held, clinicians should contact the prescribing physician for assistance,

as administration of buprenorphine can precipitate mild withdrawal symptoms.14 For the few patients on once-monthly extendedrelease naltrexone, acute pain management can be extremely difficult. The effect of opioid administration in the face of competitive antagonism is hard to predict.15,16 Further complicating management is the fact that response to opioids can vary depending on where the patient is in the dosing cycle. For example, more antagonism may be present soon after a dose than toward the end of the monthly period.17 Also, if patients missed a dose or recently finished a dosing regimen, they may be more sensitive to opioids. For these reasons, if a reasonable pain regimen would likely include opioids, then the safest option may be to postpone elective surgery until the patient is no longer undergoing treatment. If surgery cannot be delayed, use of nonopioid medications and techniques are of utmost importance. Although the competitive antagonism can be overcome with continued administration of opioids, effective dosages will be unpredictable, and careful titration and monitoring are recommended.

Conclusion The number of patients with significant opioid use histories is increasing. Appropriate preoperative data collection and assessment are crucial for deciding effective analgesic plans and alleviating the effects of withdrawal. Because opioids are less effective for this population, multimodal analgesia is an important strategy in managing these patients in the perioperative period. Although certainly challenging, with some background information and awareness, patients with known and unknown opioid use and abuse can be managed effectively and safely through the perioperative period.

References 1.

Substance Abuse and Mental Health Services Administration. Results from the 2011 National Survey on Drug Use and Health: Summary of National Findings, NSDUH Series H-44, HHS Publication No. (SMA) 12-4713. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2012.

2. Vital signs: overdoses of prescription opioid pain relievers—United States, 1999-2008, Centers for Disease Control and Prevention analysis. MMWR Morb Mortal Wkly Rep. November 4, 2011. 60(43);1487-1492. 3. Brown RL, Rounds LA. Conjoint screening questionnaires for alcohol and other drug abuse: criterion validity in a primary care practice. Wis Med J. 1995;94(3):135-140. 4. Smith PC, Schmidt SM, Allensworth-Davies D, Saitz R. A single-question screening test for drug use in primary care. Arch Intern Med. 2010;170(13):1155-1160. 5. Moeller K, Lee K, Kissack J. Urine drug screening: practical guide for clinicians. Mayo Clin Proc. 2008;83(1):66-76. 6. Ling W. Buprenorphine for opioid dependence. Expert Rev Neurother. 2009;9(5):609-616. 7. Johnson RE, Fudala PJ, Payne R. Buprenorphine: considerations for pain management. J Pain Symptom Manage. 2005;29(3):297-326. 8. Walsh SL, Eissenberg T. The clinical pharmacology of buprenorphine: extrapolating from the laboratory to the clinic. Drug Alcohol Depend. 2003;70(2 suppl):S13-S27. 9. Bryson EO, Lipson A, Gevirtz C. Anesthesia for patients on buprenorphine. Anesthesiol Clin. 2010;28(4):611-617.

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10. Alford DP, Compton P, Samet JH. Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med. 2006;144(2):127-134. 11. Mitra S, Sinatra RS. Perioperative management of acute pain in the opioid-dependent patient. Anesthesiology. 2004;101(1):212-227. 12. Moa G, Zetterström H. Sublingual buprenorphine as postoperative analgesic: a double-blind comparison with pethidine. Acta Anaesthesiol Scand. 1990;34(1):68-71. 13. Fultz JM, Senay EC. Guidelines for the management of hospitalized narcotics addicts. Ann Intern Med. 1975;82(6):815-818. 14. Center for Substance Abuse Treatment. Clinical Guideline for the Use of Buprenorphine in the Treatment of Opioid Addiction. Treatment Improvement Protocol (TIP) Series 40. DHHS publication no. (SMA) 04-3939. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2004. 15. Vivitrol Full Prescribing Information. Waltham, MA: Alkermes, Inc; rev October 2010. 16. Vivitrol Medication Guide. Cambridge, MA: Alkermes, Inc.; November 2010. 17. Dunbar JL, Turncliff RZ, Dong Q, Silverman BL, Ehrich EW, Lasseter KC. Single- and multiple-dose pharmacokinetics of long-acting injectable naltrexone. Alcohol Clin Exp Res. 2006;30(3):480-490.

The authors report no relevant financial conflicts of interest.

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JULY 2013

REPORT Outsourced Hospital Compounding: A New and Safer Era to Come or many years, compounding was performed at the bedside by staff nurses and physicians or through in-house pharmacy admixture services. However, several factors changed the landscape.1 Increases in the aging population and patient acuity warranted an increased demand for clinical pharmacy support at the bedside, which shifted pharmacy focus away from traditional drug distribution and compounding. These changes led to a greater demand for premixed or ready to administer compounded sterile preparations (CSPs). But medical errors and nosocomial infections were common due to poorly defined safety and quality standards.1 To address the growing public health threat, in 2004 the U.S. Pharmacopeial Convention (USP) published Chapter <797> Pharmaceutical Compounding—Sterile Preparations, the first enforceable guidelines for preparing and administering CSPs in the United States.2 The Joint Commission soon began to include certain USP Chapter <797> measures in its accreditation surveys and required all non-emergent CSPs to be prepared by the pharmacy under specific protocol.1 Due to staffing and space constraints, many hospitals were unable to comply with these guidelines and soon began to consider outsourcing some of their CSPs to an IV compounding vendor. Increased patient volume and acuity necessitated having a supply of anticipatory CSPs on hand rather than mixing doses on demand, with longer turnaround times. The advent of automated dispensing machines allowed rapid access to CSPs at the point of care; however, drug waste became a problem because many of the CSPs would expire and be discarded. Hospital pharmacies began to focus on identifying options to provide CSPs with longer stability at an affordable cost. Longer beyond-use dating requires expensive stability and quality testing and significant time and effort—all things hospitals did not have. As a result, many began to outsource CSPs based on anticipated prescribing patterns. Today, approximately 75% of US hospitals outsource at least some of their CSP volume.3 Of the $300 billion in prescription medications sold annually in the United States, up to 3% are filled by one of 3,000 entities considered to be a compounding pharmacy.4

Despite the vital service that outsourcing pharmacies provide, irresponsible practices by some vendors continue to threaten public health. The tragic New England Compounding Center (NECC) fungal infection outbreak resulted in 745 confirmed cases and 58 deaths to date.5 Given the devastating consequences, it is incumbent upon hospitals to understand how to identify responsible sterile compounding vendors, how these vendors should operate, and how to evaluate the ongoing services these vendors provide.

Responsible Compounding: Legislation and Beyond Compounding pharmacies fall into 2 categories: Traditional, those that prepare CSPs on a per-prescription basis; or Anticipatory, those that provide reasonable quantities of CSPs based on expected need to match the high-volume demands of today’s hospitals. These entities are exempt from FDA regulation provided they satisfy the following: they compound drugs only for individual patients with valid prescriptions; drugs must be compounded using approved ingredients and standard manufacturing processes; and drugs may not be copies of commercially available agents.6 Under the patchwork of current law, compounding pharmacies are primarily governed by individual state boards of pharmacy, which use safe-practice guidelines established in USP Chapter <797>7; however, as of June 2013, only 18 states require full compliance with Chapter <797>.2 This “one-sizefits-all” regulatory approach means that in order to engage in interstate commerce, anticipatory compounders must be licensed within multiple states, all with varying levels of regulatory and inspection standards.7 Consequently, hospitals must ensure the compounding pharmacies they partner with adhere to rigorous quality and safety standards and trust that state boards of pharmacy perform their duties to ensure quality and process controls are in place. The American Society of Health-System Pharmacists (ASHP) offers an extensive online resource center focused on sterile compounding, featuring its Guidelines on Outsourcing

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Burdens and Risks of In-House Compounding Hospitals and health systems face considerable obstacles related to in-house compounding, including: • Medication errors: The likelihood of medication errors increases when hospitals make sterile preparations without the proper facilities, training, or staff. For example, preparing syringes at the point of care has been linked with an increased rate of errors, particularly for unlabeled syringes.8 Many outsourcers offer innovative labeling to provide clarity and reduce errors. • Waste: Several institutions have shown that using outsourced CSPs decreases the amount of waste and the cost of waste incurred compared with manual preparation by in-house staff.9 • Training and education: Few large surveys have recently been conducted to measure the quality and thoroughness of CSP training at US pharmacy schools. A 2007 study found that only 21% offered a standalone course on CSPs. Although 89% taught students about USP Chapter <797>, only 13% of pharmacy school deans felt this training was adequate.10 • Dating, labeling, testing, and distribution: Unless the pharmacy has a comprehensive quality and testing program, most sterile admixtures compounded in-house have a shorter shelf life based on USP Chapter <797> regulations. In contrast, many outsourcers have performed the testing required to gather medication-specific, extended beyond-use dating. This longer dating is justified by measured, validated, and repeatable processes. • Costs: Equipping an in-house hospital compounding pharmacy that is fully compliant with USP Chapters <795> and <797> can be expensive as a result of the requirements for clean rooms and positive and negative pressure rooms, as well as storage for hazardous drugs, laminar flow hoods, isolators, and other high-cost capital expenditures. Moreover, the opportunity cost of in-house compounding is felt when valuable pharmacy resources must be allocated to mix CSPs rather than provide hands-on patient care.

Future Steps The NECC case may prove to be the tipping point for change. The Senate Committee on Health, Education, Labor, & Pensions, with considerable input from the FDA and other stakeholders, created legislation that draws clear lines between traditional pharmacy compounding and a new entity, compounding manufacturers.11 Introduced on May 15, 2013, the Pharmaceutical Compounding Quality and Accountability Act (S. 959) defines compounding manufacturers as “entities that compound sterile drugs without a prescription and engage in interstate commerce.”11 Any entity other than a hospital or health system that pools sterile products, or that repackages sterile, preservative-free vials also is defined as a compounding manufacturer.11 Approximately 3,000 hospitals currently utilize compounding services from entities in this new category. If the bill is enacted, the FDA would oversee compounding manufacturers and they will not be allowed to register as pharmacies in any state. Additionally, compounding manufacturers will be required to only provide compounded services under the oversight of a pharmacist and in compliance with applicable Good

Manufacturing Practices, and they must investigate and report adverse events.11 The legislation also preserves the role of states as the primary regulator for traditional pharmacies and clarifies that interstate shipment within a hospital system does not cause that system to be classified as a compounding manufacturer.11 The FDA can designate drugs or dosage forms that may not be compounded by any entity because of impediments to safe compounding, such as suspensions, emulsions, and controlled-release preparations. FDA-approved drugs that are available on the market may not be compounded unless they appear on the drug shortage list, with prior notice given to the FDA.11

Conclusion The old era of sterile compounding is drawing to a close. High volume, limited space and resources, and non-compliance with USP Chapter <797> all place hospitals, health systems, and patients in an untenable situation. A combination of clear lines of federal and state oversight, a data-driven approach to evaluating CSP vendors, and ongoing and effective monitoring of outside vendors is essential to rectify this situation. Stakeholders must voice these concerns to Congress by demanding strict, consistent processes to enact positive change and improve patient safety. Hospitals can outsource the responsibility for making CSPs, but they cannot outsource the responsibility for poor outcomes. —The content for this article is based on interviews with Ernest Anderson, RPh, William Churchill, RPh, and Thomas Van Hassel, RPh.

References 1. McCartney L. Sterile Compounding and Aseptic Technique: Concepts, Training, and Assessment for Pharmacy Technicians. St. Paul, MN: Paradigm Publishing; 2012. 2. Kostango ES. Compounding USP <797>: inspection, regulation, and oversight of sterile compounding pharmacies. JPEN J Parenter Enteral Nutr. 2012;36(2 suppl):38S-39S. 3. Wright S. Memorandum Report: High-Risk Compounded Sterile Preparations and Outsourcing by Hospitals That Use Them. Washington, DC: US Department of Health and Human Services; 2013. 4. International Academy of Compounding Pharmacists. http://www. iacprx.org/displaycommon.cfm?an=1&subarticlenbr=1. Accessed June 3, 2013. 5. Centers for Disease Control and Prevention. http://www.cdc.gov/hai/ outbreaks/meningitis-map-large.html. Accessed June 3, 2013. 6. National Association of Boards of Pharmacy. Model State Pharmacy Act and Model Rules. http://www.nabp.net/publications/model-act. Accessed June 3, 2013. 7. Gudeman J, et al. Potential risks of pharmacy compounding. Drugs R D. 2013;13(1):1-8. 8. Grissinger M. Reducing errors with injectable medications—unlabeled syringes are surprisingly common. P T. 2010;35(8):428-451. 9. Fortier CR, et al. Conversion to prefilled medication syringes reduces medication waste and costs. Presented at: Annual Meeting of the International Anesthesia Research Society; May 21-24, 2011; Vancouver, British Columbia. Abstract S-124. 10. Hellums M, et al. Instruction on compounded sterile preparations at U.S. schools of pharmacy. Am J Health Syst Pharm. 2007;64(1): 2267-2274. 11. United States Senate Committee on Health, Education, Labor, & Pensions. http://www.help.senate.gov/imo/media/One-Pager_ PCQA.pdf. Accessed June 3, 2013. Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, PharMEDium, and the authors neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of this monograph, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature. Copyright © 2013, McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

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Sterile Compounding Services. These are not regulations for compounding pharmacies, however, they are parameters for hospitals to use in selecting compounding pharmacies to serve their needs. The ASHP also offers the Outsourcing Sterile Products Preparation: Contractor Assessment Tool, a comprehensive questionnaire which can be used to develop a request for proposals. When used in conjunction with an on-site assessment and a USP Chapter <797> gap analysis tool (eg, Critical Point), it provides a wealth of information to aid hospital pharmacy leaders in the decision-making process.