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Volume 40 • Number 9 • September 2013

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in this issue UP FRONT

CDC: Opioid overdose deaths surging in women.

CLINICAL

Practice Pearl: Improving health literacy can boost drug adherence.

POLICY

NuVision compounding pharmacy takes another hit from FDA.

OPERATIONS & MGMT

30 31

Lessons on preparing for Joint Commission surveys. CMS gets kudos for untangling the billing unit web.

EDUCATIONAL REVIEW

Assessing Interactions With CholesterolLowering Drugs See page 6.

Compatibility of Commonly Used IV Drugs See insert after p. 14

Outsourced Hospital Sterile Compounding: A New and Safer Era To Come See insert after page 22.

Teﬂaro for the Treatment Of Community Acquired Pneumonia See insert after page 6.

Tips for Surviving ‘The Unthinkable’ In Patient Safety

Are You Confident About Your Sterile Compounding QI Plan? One hospital’s strategy for ensuring safety

Minneapolis—What keeps you up at night when it comes to medication safety? A misplaced decimal point leading to a 10-fold dosing error? A contaminated batch of compounded IV drugs? A medication given to the wrong patient? Serious clinical adverse events, some tragic, occur every day in health care; many involve drug therapy, which is the most common intervention in medicine. Whatever the source, no health system is invulnerable. Is your hospital prepared for the unthinkable? “Many health care systems think they have a crisis plan, but they don’t,” said Frank Federico, RPh, executive director at the Institute for Healthcare Improvement (IHI) in Cambridge, Mass. “Often it’s only in someone’s head. It’s not written, not practiced, not tested,” he noted during a crisis management session at the 2013 Summer Meeting of the American Society of Health-System Pharmacists.

Minneapolis—With public confidence in compounding pharma-cies badly shaken by last fall’s deadly fungal meningitis outbreak, some hospital pharmacies have reexamined the oversight of theirr sterile preparation facilities to ensure greater compliance with U.S. S. Pharmacopeia (USP) Chapter <797> standards. Unfortunately, the number of hospitals that have done so is meager, said Eric Kastango, K RPh, MBA, FASHP, a compounding quality expert who is the president and CEO of Clinical IQ. In the harsh light of the fungal meningitis crisis, he said, he would have anticipated that hospital pharmacies “would be more concerned about their state of compliance relative

see THE UNTHINKABLE, page 40

see QI PLAN, page 26

•

Data Fraud May Take the Bloom Off β-Blocker Rx London—The debate about using β-blockers perioperatively for noncardiac surgery patients continues with a new meta-analysis from British researchers indicating that starting the drugs specifically for surgery can increase the risk for death by 27%. Reporting in Heart (doi:10.1136/ heart-jnl-2013-304262 [Epub ahead of print]), investigators from Imperial College, in London, reviewed nine

•

see DATA FRAUD, page 22

•

Rapid Response Teams, Tech Tools Help Limit Drug Shortage Damage Minneapolis—With many critically needed medications in short supply over the past few years, pharmacists are looking at ways to improve how they handle drug shortages. Strategies for managing these scarcities by using informatics and collecting, analyzing and communicating information on medication shortfalls were presented at the American Society of Health-System Pharmacists (ASHP) 2013 Summer Meeting. “Shortages take a tremendous amount of time and labor to manage,” said Erin Fox, PharmD, the director of the Drug Informa-

tion Service at the University of Utah Hospitals and Clinics in Salt Lake City, and a noted expert on drug shortages. “It’s helpful to see published results like this on how to more efficiently manage shortages in the real world. It gives organizations ideas they can copy at their own institutions.”

Proactive Help via Informatics Dealing with drug shortages can be a huge drain on staff resources, noted Charles Burometto Jr., RPh, an information systems

•

see SHORTAGES, page 32

New Products Amneal launches ﬁve new oral solids.

TEVA introduces generic temozolomide.

See page 29.

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A Broad Range of Plasma Protein Therapies Albumin (Human), marketed as Albutein® 5%, Albutein® 25%, Plasbumin®-5 and Plasbumin®-25 Alpha1- Proteinase Inhibitor (Human), marketed as Prolastin®-C Antihemophilic Factor/von Willebrand Factor Complex (Human), marketed as Alphanate® Antithrombin III (Human), marketed as Thrombate III® Coagulation Factor IX (Human), marketed as AlphaNine® SD Factor IX Complex, marketed as Profilnine® SD Immune Globulin Intravenous (Human) or IVIG Immune Globulin Injection (Human) Hyperimmune Globulin Therapy Products, marketed as Hypermunes™: - Rabies Immune Globulin (Human), marketed as HyperRAB® S/D - Tetanus Immune Globulin (Human), marketed as HyperTET® S/D - Rho(D) Immune Globulin (Human), marketed as HyperRHO® S/D - Hepatitis B Immune Globulin (Human), marketed as HyperHEP B® S/D

Grifols also provides operational solutions for compounding areas in pharmacy and diagnostic instrumentation, reagents, software and related products for the clinical laboratory. Learn more about how Grifols can meet your hospital’s needs at www.grifols.com 1. Marketing Research Bureau data, June 2012

Printed in USA.

April 2013

CO24-0413

Up Front 3

Pharmacy Practice News • September 2013

surf

SEPTEMBER 2013

watch

Opioid Painkiller Overdoses Don’t Spare Women

The five most-viewed articles last month on pharmacypracticenews.com: 1. Pharmacists Feeling Pain Over AMA Resolution 2. FDA Warns of Rare but Serious Skin Reactions With Acetaminophen 3. Specialty Compounding Recalls All Sterile-Use Products 4. Acid-Suppressing Drugs Overprescribed in Infants 5. Big Ideas for Boosting Drug Safety Register for free at pharmacypracticenews.com to read these and other articles on the latest developments in hospital pharmacy.

raditionally considered a male problem, overdose deaths from opioid pain relievers (OPRs) have become a female problem as well. According to a Vital Signs report from the Centers for Disease Control and Prevention (CDC), between 1999 and 2010, the number of opioid painkiller overdoses climbed 415% for women compared with 265% for men. In all, 47,935 women died from OPR overdoses during the study period, versus 77,960 of men, according to the CDC report. A similar trend was seen in overdose deaths from all drugs: In 2010, the death rate from all medications in men was 1.55 times the rate among women—but this was down from 2.1 times in 1999.

‘Pharmacists are in a position to serve as whistleblowers for unsafe prescribing practices but need to balance this with ensuring that patients with legitimate needs continue to have access to care.’ —Michele Matthews, PharmD

heard here

‘Fabricated data are so insidious because they lead honest investigators

first

to pursue avenues of research that are not based

in fact and negatively impact patient care.’ —C. Michael White, PharmD

See article, page 22

“We saw that the gap between men and women was closing, and we felt like that was an important piece of information to share with both the public as well as health care providers,” Christopher M. Jones, PharmD, MPH, one of the authors of the report ((MMWR July 2, 2013; 62), told Pharmacy Practice News. “The bottom line here is that prescription opioid deaths among women have skyrocketed in the past decade,” Tom Frieden, CDC director, said at a press briefing. “Stopping the epidemic is everyone’s business and can be done.” Women aged 45 to 54 years were at highest risk for drug overdose death (21.8 per 100,000 population). “What’s interesting now is that we’re seeing more women experience an overdose within an age range that’s a little bit higher than what we’re typically used to seeing,” said Michele Matthews, PharmD, CPE, BCACP, an associate professor of pharmacy practice at Massachusetts College of Pharmacy and Health Sciences, in Boston, who was not associated with the study. The increase in OPR overdose deaths is consistent with a 300% increase in sales of OPRs over 11 years, according to the Vital Signs report. “We do know women are more likely to experience some of the more common forms of chronic pain and to experience that with more intensity and longer duration,” said Dr. Jones,

•

see OVERDOSES, page 13

EDITORIAL BOARD

ART/PRODUCTION STAFF

ADMINISTRATION

Michele McMahon Velle, MAX Graphics/Creative Director

Robert Adamson, PharmD, Livingston, NJ

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

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

Volume 40 • Number 9 • September 2013 • pharmacypracticenews.com

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

INTERNAL MEDICINE

EDITORIAL STAFF

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NUCLEAR PHARMACY

David Bronstein, Editorial Director davidb@mcmahonmed.com

BIOTECHNOLOGY

Jeffrey Norenberg, PharmD, Albuquerque, NM

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ONCOLOGY

CARDIOLOGY

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C. Michael White, PharmD, Storrs, s CT

Robert Ignoffo, PharmD, San Francisco, CA

CNS/PSYCHIATRY

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

Charles F. Caley, PharmD, Storrs, CT

Cindy O’Bryant, PharmD, Aurora, CO

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

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

Larry Ereshefsky, PharmD, San Antonio, T Texas

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

COMPLEMENTARY AND ALTERNATIVE MEDICINE

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com Kevin Horty, Don Pizzi, Adam Marcus, Cynthia Gordon, Contributing Editors James Prudden, Group Editorial Director Robin B. Weisberg, Manager, r Editorial Services Elizabeth Zhong, Associate Copy Chief

ORGAN TRANSPLANT PHARMACY

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References: 2013 Best in KLAS Awards: Medical Equipment & Infrastructure, SIGMA Spectrum, Best in KLAS for Smart Pumps – LVP, June 2013. ©2013 KLAS Enterprises, LLC. All rights reserved. www.KLASresearch.com

Rx Only. For safe and proper use of this device, refer to the complete instructions in the Operator’s Manual. Refer to manufacturers’ full Prescribing Information for Insulin Injection, USP.

Baxter and SIGMA Spectrum are trademarks of Baxter International Inc. KLAS is a registered trademark of KLAS Enterprises, LLC. Baxter Healthcare Corporation, Route 120 and Wilson Road, Round Lake, IL 60073 www.baxter.com 450725 07/13

Best in KLAS for Smart Pumps – LVP

SIGMA Spectrum Infusion System Three Years Running! 1,2,3

KLAS, an independent research ﬁrm, has again awarded the SIGMA Spectrum Infusion System with its “Best in KLAS” award for Smart Pumps – LVP as reported in the Best in KLAS Awards: Medical Equipment & Infrastructure Report. 1 2

Receiving the “Best in KLAS” award indicates a high level of customerr satisfaction with the SIGMA Spectrum Infusion System and its support services.

Medication delivery products from Baxter. Doing our part, so you can do yours. pharmacy workﬂow

drug delivery

nutrition

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6 Clinical

Pharmacy Practice News • September 2013

Educational Review

Assessing Interactions With

Cholesterol-Lowering Drugs

SERENA PU, PHARMD CANDIDATE University of Maryland School of Pharm macy Baltimore, Maryla and

TUAN HUYNH, PHARMD Pharmacy Manage er Target Pharmac cy Clinical Assistant Professorr University of Maryland School of Pharmacy Baltimore, Maryland

dverse drug effects account for up to 5% of hospital

admissions each year.1 Drug–drug interactions

(DDIs) are one type of adverse drug effects that are predictable

and readily avoidable with an understanding of the pharmacokinetics and pharmacodynamics of the involved drugs. Pharmacists are drug experts who can identify potential DDIs and recommend appropriate treatment alternatives to achieve therapeutic goals while minimizing possible interactions and side effects.

Dyslipidemia is one of the major contributors to coronary heart disease, myocardial infarction, and stroke. Dyslipidemia includes high levels of total cholesterol (TC), low-density lipoprotein (LDL) cholesterol and/or triglycerides (TGs), and/ or low levels of high-density lipoprotein (HDL) cholesterol.2 According to the Centers for Disease Control and Prevention’s 2012 Health Report, more than 14% of adults aged 20 years or older in the United States present with TC greater than 240 mg/dL.3 Approximately 60% to 70% of TC is composed of LDL. Therefore, the National Cholesterol Education Program’s Adult Treatment Panel III (ATP III) guidelines recommend optimal control of LDL cholesterol as the primary target of lipid-lowering therapy.4 In addition to lifestyle modifications, the use of cholesterol-lowering medications has increased in the past few decades for both men and women, with statins (5-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) having the greatest effect on reducing LDL levels.4,5 Patients with elevated cholesterol are likely to present with several comorbidities requiring multiple drug regimens, which raises the likelihood of having potential DDIs. This review explores commonly encountered DDIs and provides treatment modifications to minimize potential DDIs, specifically examining DDIs of

statins with medications that increase the risk for myopathy and DDIs that occur when cholesterol-lowering medications are used in combination.

Classes of Lipid-Lowering Drugs The 6 main classes of lipid-lowering agents on the market are statins, fibric acid derivatives, nicotinic acid (niacin), bile–acid sequestrants, ezetimibe (Zetia, Merck/Schering), and fish oil. Each class has a unique mechanism of action and effects on lipoproteins and TGs, and each is associated with various side effects. Statins are the most effective agents for reducing LDL; they also result in a slight decrease in TGs and a modest increase in HDL.4 Statins inhibit the rate-limiting step of cholesterol synthesis in the liver. In response to the decreased production of LDL, hepatic cells express more LDL receptors on the cell surface to capture circulating LDL in the blood, which further decreases plasma LDL.2 Statins generally are well tolerated, but potential side effects include hepatotoxicity and myopathy ranging from mild myalgia to severe rhabdomyolysis. Rhabdomyolysis, which can be a significant adverse effect due to the possible risk for kidney damage or failure, is more common in patients taking statins who are either predisposed to myopathy or on drugs that

affect the statin’s metabolism.4,6 Bile–acid sequestrants are positively charged polymers designed to bind to negatively charged bile acids from the small intestine.2 By interfering with the absorption of bile acids, bile–acid sequestrants ultimately decrease LDL levels in the blood. The main role of bile–acid sequestrants in dyslipidemia is to decrease LDL,4 but they also raise HDL levels. The main complaints of taking bile–acid sequestrants are related to gastrointestinal (GI) symptoms.2 Fibric and nicotinic acids are effective in reducing TGs by up to 50% and increasing HDL by as much as 20% to 35%.4 Fibric acid derivatives (gemfibrozil and fenofibrate) exert their function by stimulating peroxisome proliferatoractivated receptor-α (PPAR-α). The activation of PPAR-α increases lipolysis, inhibits apoprotein C-III production, and activates lipoprotein lipase to reduce TGs in the plasma. PPAR-α activity also increases HDL cholesterol synthesis.7 The common side effects are GI symptoms. Nicotinic acid, or niacin, is a water-soluble vitamin that comes in immediate, sustained, and extendedrelease forms. The major mechanism of action of niacin is to impede fatty acid mobilization from adipose tissues to the liver. Niacin causes various side effects from nausea to flushing.2,8

Clinical 7

Pharmacy Practice News • September 2013

Educational Review Additionally, both fibric acid derivatives and niacin—either used alone or with a statin—may cause myopathy and hepatotoxicity.8,9 Ezetimibe, a cholesterol-absorbing agent, hampers the absorption of cholesterol from the brush border of the small intestine to decrease the level of plasma cholesterol. It provides about a 15% to 20% reduction in LDL levels and is commonly used in conjunction with statin therapy.10 Ezetimibe mainly causes GI issues such as abdominal pain and diarrhea.11 There are many fish oil supplements available over the counter but only one prescription fish oil supplement (Lovaza, GlaxoSmithKline) approved by the FDA. Containing eicosapentaenoic acid and docosahexaenoic acid, Lovaza is used as an adjunct to diet to decrease TGs in patients with severe hypertriglyceridemia (>500 mg/dL). The mechanism of action is not entirely understood, but it is believed to inhibit liver enzymes involved in fatty acid metabolism, decrease lipogenesis, increase lipoprotein lipase activity, and inhibit TG synthesis. The primary side effects are indigestion, fishy taste, and loose stool.12

Myopathy and Its Clinical Presentation Myopathy, a global term to classify muscle disease, includes myalgia, myositis, and rhabdomyolysis.6 Myalgia is defined as muscle discomfort or weakness without an increase in creatine kinase (CK). Myositis generally presents with muscle symptoms and a mildly elevated CK level below 10 times the upper limit of normal (ULN), but sometimes it presents without symptoms.6 Rhabdomyolysis is a potentially life-threatening condition resulting from the breakdown of skeletal muscles and the leakage of intracellular constituents, such as myoglobin, into the blood circulation. These breakdown products are harmful to the kidneys and may cause acute kidney injury and other severe complications.13,14 Rhabdomyolysis frequently presents with muscle symptoms and markedly elevated CK (typically >10 times the ULN).6 Trauma, drugs, metabolic disorders, and infections can contribute to rhabdomyolysis. The classic triad of symptoms includes muscle pain, generalized weakness, and dark urine. Other symptoms of rhabdomyolysis are fever, nausea, vomiting, malaise, and coma.14

Agents Associated With Myopathy The lipid-lowering agents most commonly associated with myopathy are the statins. Theories of statin-induced myopathy have been proposed, but the definitive mechanism remains unclear and often the myopathy is dose-dependent.6,15 Myopathy is rare with statins alone, but is more common when a statin is coadministered with other medications that pharmacokinetically interfere with the statin’s metabolism and transportation or pharmacodynamically have similar side effects.13 Examples of DDIs associated with myopathy and that increase the risk for rhabdomyolysis involve the concurrent use of a statin with medications including amiodarone, calcium channel blockers (amlodipine, verapamil, and diltiazem), macrolide antibiotics (except for azithromycin), cyclosporine, azole antifungal agents, fibric acid derivatives, nicotinic acid, colchicine, and protease inhibitors.16-20 Most statins, except for pravastatin, are readily

Table 1. Statin Substrates and CYP Metabolizing Systems Substrates

3A4

Atorvastatin

✔

Fluvastatin

✔ (minor)

Lovastatin

✔

2C9

2C8

2C19

✔

2D6

✔ (minor)

Pravastatin Pitavastatin (Livalo, Lilly/Kowa)

✔

Rosuvastatin (Crestor, AstraZeneca)

✔

Simvastatin

✔

✔ (minor) ✔ (minor)

Based ased o on references e e e ces 15 5 and a d 18. 8

metabolized by the hepatic cytochrome P450 (CYP) enzyme system (Table 1).15,18 Consequently, the serum levels of statins are pharmacokinetically affected by coadministration of CYP inhibitors and inducers. Interference with statin transport via g-glycoproteins and organic anion transporting polypeptide also plays a role in increasing the plasma concentration and toxicity of statins.18 Additionally, medications that increase the risk for myopathy and rhabdomyolysis when used alone have an additive pharmacodynamic effect when taken with statins.15

Treatment and Prevention of Myopathy The ATP III guidelines recommend a baseline measurement of CK as well as a fasting lipid

panel and liver function test before initiation of statin therapy.4 Due to the possibility of asymptomatic myositis, a baseline CK can help guide clinicians on the course of therapy.6 Patients and practitioners also need to monitor for signs and symptoms of muscle problems once therapy has been initiated. If patients report muscle weakness, pain, and soreness, a CK value should be obtained.6 It is equally important to rule out other causes that may predispose patients to statin-induced myopathy, such as untreated hypothyroidism, vigorous exercise, and diminished hepatic and renal function.6,19 Older individuals (age >80 years) also should be monitored closely.19 Statin therapy or combination therapy Text continues on page 8

The Pharmacist’s Role in Treating Hyperlipidemia: A Case Study

S is a 55-year-old Asian woman who presents to the pharmacy asking for an over-the-counter medication to relieve her muscle pain and weakness. She states that she has been feeling an increase in muscle discomfort over the past 4 days. She was recently diagnosed with community-acquired pneumonia and her pulmonologist started her on clarithromycin. After obtaining her medication history, the pharmacist is concerned that the patient may be experiencing a potential DDI between clarithromycin and her other medications and consults her primary care physician.

Patient Profile: • Past medical history: dyslipidemia for 7 years, hypertension for 6 years, community-acquired pneumonia diagnosed 4 days ago • Social history: Denies alcohol and tobacco use • Family history: Noncontributory • Allergies: No known drug allergies • Vitals: weight, 55.33 kg; height, 165.1 cm; blood pressure, 130/76 mm Hg; pulse 85 beats/min • Current medications: clarithromycin 250 mg every 12 hours for 14 days, simvastatin 40 mg once daily at bedtime, fenofibrate 145 mg once daily, amlodipine 10 mg once daily, and hydrochlorothiazide 25 mg once daily

Pharmacist Assessment and Recommendation: • The patient is experiencing muscle pain and weakness, which is likely due, in part, to the DDI between simvastatin and clarithromycin. Clarithromycin is a strong CYP3A4 inhibitor and will increase the plasma level of simvastatin and increases the risk for myopathy.28 Clarithromycin also may increase concentration levels of amlodipine. A switch to doxycycline 100 mg orally twice daily for her pneumonia is recommended. • There is a DDI between simvastatin and amlodipine that increases the risk for the development of myopathy. Concomitant use increases the concentration of simvastatin. Consider decreasing simvastatin dose to 20 mg once daily.29 • There is a DDI between fenofibrate and statins. Concomitant use increases the patient’s risk for myopathy and hepatotoxicity. Consider ordering labs for CK and liver function tests to compare with baseline. If CK is 3 to 10 times the ULN, monitor weekly for signs and symptoms of worsening muscle symptoms.38 If CK is greater than 10 times the ULN and/or liver transaminase levels are persistently >3 times the ULN, then discontinue fenofibrate and simvastatin.4 The decision of whether to reinitiate the therapy can be discussed after the patient is stable.6

8 Clinical

Pharmacy Practice News • September 2013

Educational Review Table 2. Dose Adjustments for Statin DDI–Related Myopathy Calcium Channel Blockers

Macrolidesa Azolesb

Gemfibrozil

Fenofibrate

Colchicine

Protease inhibitors

Niacin

Cyclosporine Dd

X/Dh

Pitavastatin

Pravastatin

Amiodarone

Atorvastatin Fluvastatin Lovastatin

Rosuvastatin Simvastatin

Mf Mg

Mf Dq

X=Avoid concomitant use; D=Dose modification; M=Monitor therapy

Combination of cyclosporine and fluvastatin will increase the serum level of fluvastatin; the fluvastatin dose should be ≤20 mg.23

Includes clarithromycin and erythromycin but not azithromycin, which is less likely to interact with a statin.16 b

Atorvastatin dose should be ≤20 mg daily when it is used with clarithromycin.

Atorvastatin dose should be <10 mg daily when it is used with cyclosporine.21

Fluconazole will increase serum concentration of fluvastatin; the fluvastatin dose should be ≤20 mg daily.23

Includes fluconazole, itraconazole, ketoconazole, posaconazole, and voriconazole. 21

Lovastatin dose should be ≤40 mg daily when it is used with amiodarone.24 Lovastatin dose should be ≤20 mg daily when it is used with diltiazem or verapamil.24

Concomitant use of erythromycin and pitavastatin greatly increases the serum level of pitavastatin; pitavastatin dose should be ≤1 mg when it is used with erythromycin.25

Itraconazole will increase the serum level of atorvastatin; atorvastatin dose should be ≤20 mg daily when it is used with itraconazole.21 f

The risk for myopathy increases when statins are used with fenofibrate or niacin ≥1 g daily; these combinations should be used with caution.21,23-28 g

Increasing incidences of myopathy, including rhabdomyolysis, were reported when colchicine was co-administered with atorvastatin, fluvastatin, lovastatin, pravastatin, or simvastatin; monitor for signs and symptoms of myopathy.21,23,24,26,28

Pravastatin dose should be ≤40 mg daily when it is used with clarithromycin.26

Pravastatin dose should be ≤20 mg daily when it is used with cyclosporine.26

Rosuvastatin dose should be <5 mg daily when it is used with cyclosporine.27

Rosuvastatin dose should be <10 mg daily when it is used with atazanavir±ritonavir or lopinavir/ritonavir.27

Concomitant use of amiodarone and simvastatin increases the serum concentration of simvastatin and side effects; simvastatin dose should be <20 mg daily when it is used with amiodarone.28

Avoid using atorvastatin with telaprevir and tipranavir/ritonavir; use lowest dose of atorvastatin when it is used with lopinavir/ritonavir; use <20 mg if it is used with darunavir/ritonavir, fosaprenavir±ritonavir, or saquinavir/ritonavir; use use <40 40 mg if it is used with nelfinavir.21

Simvastatin dose should be ≤20 mg daily when it is used with amlodipine and <10 mg daily when it is used with diltiazem or verapamil..28,29

Based on references 16 and and 21 to 29.

Text continued from page 7

(either a statin plus fibrate or niacin) should stop immediately if CK is more than 10 times the ULN.6 According to the ACC/AHA/NHLBI clinical advisory, weekly monitoring is indicated in patients experiencing muscle discomfort with no or moderate elevation of CK (ie, between 3 and 10 times the ULN) until the patient is stable without further worsening.6 If rhabdoymyolysis develops, the main goal of therapy is to prevent renal dysfunction and failure. Suspected offending agents should be discontinued promptly, and fluid resuscitation should be initiated to maintain adequate hydration. Other necessary measures may be taken, depending on patient’s condition and accompanying complications.20 Recognizing clinically significant DDIs is key to preventing the occurrence of rhabdomyolysis due to drug-related causes. The severity of the interaction directs the treatment options— contraindication, dose adjustment, or cautious monitoring. Table 2 summarizes common statinrelated DDIs that potentiate the development of myopathy and rhabdomyolysis and provides recommendations on therapeutic modification for each combination.21-29

DDIs Among Lipid-Lowering Agents If statin monotherapy fails to achieve cholesterol goals, then combination therapy is indicated.6 Adding another cholesterol-lowering medication to statin therapy can result in further reductions in LDL and TGs, as well as a further increase in HDL and better control of non–HDL cholesterol.6 Despite the positive benefits from a combination therapy, safety needs to be considered. Table 3 summarizes the possible DDIs

Table 3. Therapy Modifications for DDIs With Cholesterol-Lowering Agents Statins

Gemfibrozil X

Fenofibrate a

Niacin

Bile-acid Sequestrants

Ezetimibe

Gemfibrozil

Fenofibrate

Niacin

Bile-acid sequestrants

Ezetimibe

Lovaza

Db Db

Fish oils X=Avoid concomitant use; D=Dose modification; M=Monitor therapy The risk for myopathy increases when statins are used with fenofibrate or niacin ≥1 g daily; the combination therapy should be used with caution.21,23-28 a

Take 1 hour before or 4 to 6 hours after a bile-acid sequestrant.7,8,11,34-37

Fibrates are generally not recommended with ezetimibe due to an increased risk for cholelithiasis; a gallbladder study is indicated and an alternative lipid-lowering regimen should be considered if cholelithiasis is suspected.11 Based on referencess 7, 8, 11, 21, 23 23-28, 3 28, and 34 34-37. 37.

related to combination therapy of cholesterollowering agents with corresponding suggestion for therapeutic modification.

Statins With Fibric Acid Derivatives or Niacin The combination of gemfibrozil and a statin carries a high risk for rhabdomyolysis and generally should be avoided.9 Gemfibrozil not only confers a risk for myopathy when used alone, but it also has an additive pharmacodynamic effect and pharmacokinetically inhibits the hepatic

glucuronidation of statins, increasing the risk for myopathy and rhabdomyolysis.30,31 Due to this safety concern, pharmacists should recommend a switch to a statin plus fenofibrate for patients taking a statin and gemfibrozil.9 However, the use of a fenofibrate with a statin still requires frequent monitoring for the signs and symptoms of muscle discomfort because fenofibrate alone confers its own risk for myopathy.9 The combination of a statin and niacin is commonly used in patients with high LDL, high TGs, and/or low Text continues on page 10

For patients with invasive fungal infections who are refractory to, or intolerant of conventional amphotericin B therapy

ABELCET saves time

*Abelcet is supplied in a ready-to-use vial and does not require reconstitution thereby saving drug preparation time. 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. Contact your Abelcet national account manager to learn about Abelcet. 1

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. 2

**For additional information, please see full prescribing information at abelcet.com.

abelcet.com** To contact an Abelcet National Account Manager please call 1-800-447-0169, select option 1 and enter 572. 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. ÂŠ 2013 Sigma-Tau Pharmaceuticals, Inc.

ABL-172P-0813

10 Clinical

Pharmacy Practice News • September 2013

Educational Review Text continued from page 8 2

HDL. Niacin has the potential side effect of myopathy and use with a statin may increase the risk. The risk for myopathy associated with a statin and niacin is relatively small, and coadministration of nicotinic acid with a statin appears to result in less rhabdomyolysis compared with a statin coadministered with a fibrate.6 A daily dose of less than 1 g of niacin usually is suggested when it is used with a statin.8 Both fibric acid derivatives and

niacin alone have the potential side effect of liver abnormalities and dysfunction. The use of either of these agents with a statin may increase the risk for hepatotoxicity. Although the exact mechanism for liver damage is unknown, baseline and periodic monitoring of liver function enzymes, especially levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), should be obtained.8 Therapy should be reevaluated and may require reduction or discontinuation if hepatotoxicity

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).

is suggested (AST or ALT is at least 3 times the ULN).2,8,32,33

Bile–Acid Sequestrants Versus Other Lipid-Lowering Drugs Bile–acid sequestrants inhibit reabsorption of bile acid back to the liver and enhance conversion of hepatic cholesterol into bile acid to further deplete systemic cholesterol.34-36 Due to their binding ability, bile–acid sequestrants induce a potential DDI by hindering the absorption of concomitant

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.

I-101-41-US-N

Manufactured by Sigma-Tau PharmaSource, Inc., Indianapolis, IN 46268. Distributed by Sigma-Tau Pharmaceuticals, Inc., Gaithersburg, MD 20878.

medications such as fenofibrate, gemfibrozil, niacin, and ezetimibe. Thus, the effectiveness of lipid-lowering agents may be affected when they are taken at the same time as a bile–acid sequestrant. Therefore, pharmaceutical manufacturers suggest taking other drugs 1 hour before, or at least 4 hours after, bile– acid sequestrants.7,8,11,34-37

Ezetimibe Versus Other Lipid-Lowering Drugs Ezetimibe interrupts intestinal cholesterol absorption to decrease LDL cholesterol and may be used as adjunctive therapy for cholesterol control.2,11 It does not affect the absorption of TGs, fatty acid, and fat-soluble vitamins. In a randomized controlled trial, ezetimibe added to statin therapy reduced the LDL cholesterol level by an extra 26%.11 The combination was well tolerated, but patients taking ezetimibe with a statin had a slightly higher incidence of hepatotoxicity than patients taking a statin alone. As a result, patients who concurrently use ezetimibe and a statin may require close monitoring of their hepatic function.11 Several cases of cholelithiasis from the combination of a fibrate and ezetimibe have been reported.11 Fibrates alone increase cholesterol excretion into bile, which may cause cholelithiasis.7 The data on gallstones resulting from administration of ezetimibe are inconsistent. Gallbladder studies are indicated for patients who are suspected to have cholelithiasis due to the combination of ezetimibe and a fibrate, and an alternative cholesterol-lowering therapy should be considered for such patients.11

Fish Oils Versus Other Lipid-Lowering Drugs Fish oils are used as an adjunct to other cholesterol-lowering agents to lower TGs and possibly increase HDL-cholesterol. Although fish oils may reduce LDL, in some individuals LDL levels may increase and periodic monitoring may be required. Adverse effects of fish oils include nausea, dyspepsia, and a fishy aftertaste. No noticeable DDIs have been reported between the use of fish oils and other lipid-lowering agents; therefore, they are is considered safe to use with other lipid-lowering agents.2,12

Summary Due to the effectiveness for reducing LDL level and long-term benefits in decreasing coronary heart diseases, cardiovascular risks, and total mortality, statins remain the drug of choice for treating dyslipidemia.4 Because most statins are

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Pharmacy Practice News • September 2013

Educational Review effects on low-density lipoproteincholesterol reduction. J Clin Lipidol. 2012;6(2):180-191. 11. Zetia (ezetimibe) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; February 2013. http://www.merck.com/ product/usa/pi_circulars/z/zetia/zetia_ pi.pdf. Accessed July 31, 2013. 12. Lovaza [package Insert]. Research Triangle Park, NC: GlaxoSmithKline; 2012. https:// www.gsksource.com/gskprm/htdocs/ documents/LOVAZA-PI-PIL.PDF. Accessed July 31, 2013. 13. Fallah A, Deep M, Smallwood D, Hughes P. Life-threatening rhabdomyolysis following the interaction of two commonly prescribed medications. Australas Med J.

2013;6(3):112-114. 14. Giannoglou G, Chatzizisis YS, Misirli G. The syndrome of rhabdomyolysis: pathophysiology and diagnosis. Eur J Intern Med. 2007;18(2):90-100. 15. Williams D, Feely J. Pharmacokineticpharmacodynamic drug interactions with HMG-CoA reductase inhibitors. Clin Pharmacokinet. 2002;41(5):343-370. 16. Westphal JF. Macrolide-induced clinically relevant drug interactions with cytochrome P-450A (CYP) 3A4: an update focused on clarithromycin, azithromycin and dirithromycin. Br J Clin Pharmacol. 2000;50(4):285-295. 17. Patel AM, Shariff S, Bailey DG, et al. Statin toxicity from macrolide antibiotic

DURING WARFARINRELATED BLEEDS…

coprescription: a population-based study. Ann Intern Med. 2013;158(12):869-876. 18. Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80(6):565-581. 19. Sathasivam S, Lecky B. Statin induced myopathy. BMJ. 2008;337:a2286. 20. Sauret JM, Marinides G, Wang GK. Rhabdomyolysis. Am Fam Physician. 2002;65(5):907-912. 21. Lipitor (atorvastatin calcium) [package insert]. New York, NY: Pﬁzer Inc.; October 2012. http://labeling.pﬁzer.com/ ShowLabeling.aspx?id=587. Accessed August 1, 2013. Text continues on page 12

N NOW APP APPROVED Kcentra

mainly eliminated via the hepatic CYP system, agents that are metabolized by the same route should be used cautiously in patients taking statins. Additionally, patients taking drugs with similar side-effect profiles to statins should be monitored carefully for a potential additive effect when they are used concomitantly. Moreover, several DDIs are observed from combined use of cholesterol-lowering medications. As illustrated by the patient case, pharmacists, with their specialized knowledge in pharmacokinetics and pharmacodynamics, play an important role in the detection and prevention of DDIs related to lipid-lowering therapy.6,38 Pharmacists should discuss appropriate treatment modifications with physicians when clinically significant interactions are recognized. By acting proactively, pharmacists can minimize adverse side effects and DDIs, optimize therapeutic regimens, and provide better patient care.

References 1. Juurlink DN, Mamdani M, Kopp A, Laupacis A, Redelmeier DA. Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA. 2003:289:(13): 1652-1658. 2. Joseph TD, Robert LT, Gary GY, et al. Pharmacotherapy: A Pathophysiology Approach. 7th ed. New York, NY: McGrawHill; 2008. 3. Centers for Disease Control and Prevention. Health, United States, 2011 with special feature on socioeconomic status and health. CDC. http://www.cdc.gov/nchs/data/hus/ hus11.pdf#071. Accessed July 31, 2013. 4. National Heart, Lung, and Blood Institute. Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). NHLBI. http://www. nhlbi.nih.gov/guidelines/cholesterol/ atp3full.pdf. Accessed July 31, 2013. 5. Kuklina EV, Carroll MD, Shaw KM, Hirsch R. Trends in high LDL cholesterol, cholesterollowering medication use, and dietary saturated-fat intake: United States, 19762010. http://www.cdc.gov/nchs/data/ databriefs/db117.pdf. Accessed July 31, 2013. 6. Pasternak RC, Smith SC Jr, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI Clinical Advisory on the Use and Safety of Statins. Stroke. 2002;33(9):2337-2341. 7. Tricor (fenoﬁbrate) [package insert]. North Chicago, IL: AbbVie Inc.; February 2013. http://www.rxabbvie.com/pdf/tricorpi.pdf. Accessed July 31, 2013. 8. Niaspan (niacin extended-release) [package insert]. North Chicago, IL: AbbVie Inc.; March 2013. http://www. rxabbvie.com/pdf/niaspan.pdf. Accessed July 31, 2013. 9. Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with ﬁbrate therapy. Am J Cardiol. 2007;99(6a):3c-18c. 10. Toth PP, Ballantyne CM, Davidson MH, et al. Changes in prescription patterns before and after reporting of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression trial (ENHANCE) results and expected

bin othrom eversal r P r o t R ac irst 4-F ent Warfarin F e h t Urg a™— Kcentr CC) for g P n F i c 4 ( u e Introd centrat n o C x e Compl 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

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Educational Review Text continued from page 11

22. US Food and Drug Administration. FDA drug safety communication: interactions between certain HIV or hepatitis C drugs and cholesterol-lowering statin drugs can increase the risk of muscle injury. http://www.fda.gov/Drugs/DrugSafety/ ucm293877.htm. Published March 01, 2012. Accessed August 1, 2013. 23. Lescol (ﬂuvastatin sodium) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; October 2012. http://www.pharma.us.novartis.com/ cs/www.pharma.us.novartis.com/product/ pi/pdf/Lescol.pdf. Accessed August 1, 2013. 24. Mecavor (lovastatin) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc;

October 2012. http://www.merck.com/ product/usa/pi_circulars/m/mevacor/ mevacor_pi.pdf. Accessed August 1, 2013.

http://www1.astrazeneca-us.com/pi/crestor. pdf. Accessed August 1, 2013.

25. Livalo (pitavastatin) [package insert]. Montgomery, AL: Kowa Pharmaceuticals America, Inc.; May 2013. http://www. kowapharma.com/documents/LIVALO_PI_ CURRENT.pdf. Accessed May 30, 2013. 26. Pravachol (pravastatin sodium) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; October 2012. http:// packageinserts.bms.com/pi/pi_pravachol. pdf. Accessed August 1, 2013. 27. Crestor (rosuvastatin calcium) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; December 2012.

28. Zocor (simvastatin) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; October 2012. http://www.merck.com/ product/usa/pi_circulars/z/zocor/zocor_ pi.pdf. Accessed. August 1, 2013. 29. US Food and Drug Administration. FDA drug safety communication: new restrictions, contraindications, and dose limitations for Zocor (simvastatin) to reduce the risk of muscle injury. http:// www.fda.gov/Drugs/DrugSafety/ ucm256581.htm. Accessed August 1, 2013. 30. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenoﬁbrate + statin

versus gemfibrozil + any statin. Am J Cardiol. 2005;95(1):120-122. 31. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation. 2004;109(23 suppl 1):III50-III57. 32. National Kidney Foundation. 2006 Updates. Clinical Practice Guidelines and Recommendations. Hemodialysis Adequacy, Peritoneal Dialysis Adequacy, Vascular Access. http://www.kidney.org/ professionals/kdoqi/pdf/12-50-0210_JAG_ DCP_Guidelines-VA_Oct06_SectionC_ofC. pdf. Accessed August 1, 2013. 33. Korth CE, Backes JM. Hepatotoxic effects of lipid-altering agents. US Pharmacist. 2012;37(9):HS17-HS20. 34. Colestid (colestipol) [package insert]. New York, NY: Pfizer Inc.; June 2006. http://labeling.pfizer.com/ShowLabeling. aspx?id=593. Accessed August 6, 2013. 35. Questran (cholestyramine) [package insert]. Spring Valley, NY: Par Pharmaceutical Companies, Inc.; April 2012. http:// www.parpharm.com/generics/images/ pdf/09336_po.pdf. Accessed August 1, 2013. 36. Welchol (colesevelam hydrochloride) [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc.; 2000. http://www. accessdata.fda.gov/drugsatfda_docs/ label/2006/021176s014lbl.pdf. Accessed August 1, 2013.

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. B 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. B 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 IKcentra dosing should be individualized based on the patient’s baseline International Normalized Ratio (INR) value, and body weight. IAdminister Vitamin K concurrently to patients receiving Kcentra to maintain factor levels once the effects of Kcentra have diminished. BRepeat dosing with Kcentra is not supported by clinical data and is not recommended. IAdminister 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-------------------------IKcentra 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: I 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. I Disseminated intravascular coagulation. I Known heparin-induced thrombocytopenia. Kcentra contains heparin. --------------------------------WARNINGS AND PRECAUTIONS-----------------------------I Hypersensitivity reactions may occur. If necessary, discontinue administration and institute appropriate treatment. I 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. IKcentra 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--------------------------------------IThe most common adverse reactions (ARs) (frequency *2.8%) observed in subjects receiving Kcentra were headache, nausea/vomiting, arthralgia, and hypotension. IThe most serious ARs were thromboembolic events including stroke, pulmonary embolism, and deep vein thrombosis. To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-915-

37. Lopid (gemfibrozil) [package insert]. New York, NY: Pfizer, Inc.; September 2010. http://www.pfizer.com/files/products/uspi_ lopid.pdf. Accessed August 1, 2013. 38. Reamy BV. Hyperlipidemia Management for Primary Care: An Evidence-Based Approach. New York, NY: Springer Science+Business Media; 2008.

Ms. Pu and Dr. Huynh reported no relevant ﬁnancial conﬂicts of interest.

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Clinical 13

Pharmacy Practice News • September 2013

Pain Medicine

OVERDOSES continued from page 3

who is the team lead of the Prescription Drug Overdose Team, Division of Unintentional Injury Prevention, National Center for Injury Prevention and Control, CDC, Atlanta. “We know that some women are more likely to be prescribed higher doses of opioids.” Dr. Jones noted that “the majority of the overdose deaths are unintentional. A smaller fraction were intentional, where someone was trying to commit suicide.” Fatal opioid overdoses “nearly always occur at night,” explained Jane C. Ballantyne, MD, FRCA, a professor in the Department of Anesthesiology and Pain Medicine at the University of Washington School of Medicine, in Seattle, who was not involved in the report. “I think they occur because people get really desperate. They take the nighttime dose and they’re lying there and they’re still in pain, so they eventually get up and take more than they’re supposed to take. And they do that two or three times. And they finally get off to sleep, but then it catches up and then they never wake up.”

to their patients. … Ultimately it comes down to getting as much information as possible and [talking] with the patient to determine if an opioid is the right medication for that individual.” Health-system pharmacists also can play a key role in preventing medication mishaps—especially if they have access to a prescription drug monitoring program, Dr. Jones noted. Such practitioners, he said, “can see what may be going on with patients, if they’re getting multiple drugs from multiple providers (which is a known risk factor for overdose), and then

they can share that information [with the prescribing clinician].” Dr. Matthews said education of pharmacists in pain management and opioid issues “has to start as early as possible.” She added, “I practice within a primary care clinic to support physicians who admittedly do not receive extensive knowledge of pain management and addiction medicine during their training. I assist with risk management and decision making that can identify patients at risk for misuse, abuse, addiction and other opioid-related adverse events.”

Dr. Matthews added, “Pharmacists are in a position to serve as whistleblowers for unsafe prescribing practices, but need to balance this with ensuring that patients with legitimate needs continue to have access to care.” —George Ochoa Drs. Ballantyne, Jones and Matthews reported no relevant ﬁnancial conﬂicts of interest.

Acetaminophen alert, page 20

EXPOSURE TO HAZARDOUS DRUGS THREATENS

THE SAFETY OF HEALTHCARE WORKERS

‘We know that some women are more likely to be prescribed higher doses of opioids.’ —Christopher M. Jones, PharmD, MPH Commenting further on the Vital Signs report, Dr. Ballantyne said, “The article deals with what I think we didn’t quite understand, and that’s that the overuse of analgesics is a female problem as much as it is a male problem.” Although it is only a single study, “it sets off alarm bells,” she said. She added, “It’s an epidemiological study and epidemiological studies have their own weaknesses, mainly that you can’t exclude confounding factors.”

SAFEGUARDS EXIST TO HELP PREVENT EXPOSURE TO HAZARDOUS DRUGS—BUT ARE THEY ENOUGH?

Clinicians Can Make an Impact Physicians and pharmacists can take steps to reduce opioid overdoses. “There are a lot of common pain diagnoses where the track record for opiates is very poor and so we shouldn’t be prescribing for those diagnoses,” Dr. Ballantyne said. “There are a lot of patients whose risks are so high we shouldn’t be prescribing for those patients.” Opioids can be appropriate for palliation, she said, but not for increasing functionality. “We could probably only say 10% of the patients currently treated with opiates are appropriately treated, and the other 90% are not.” Asked how physicians can reduce OPR overdoses, Dr. Jones said, “The most important step they can take is talking

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14 Clinical

Pharmacy Practice News • September 2013

Practice Pearl

Improving Health Literacy and Medication Adherence Johanna Sierra, BS, PharmD Candidate

Table 1. Key Communication Strategies

Nova Southeastern University College of Pharmacy Fort Lauderdale, Florida

Strategies

Comments

Warm greeting

Greet patients with a smile and a welcoming attitude.

Vaiyapuri Subramaniam, PharmD, MS

Eye contact

Make appropriate eye contact throughout the interaction.

Associate Chief Consultant Pharmacy Benefits Management Services Department of Veterans Affairs Washington, DC Clinical Affiliate Professor Nova Southeastern University College of Pharmacy Fort Lauderdale, Florida

illions of Americans suffer from adverse health outcomes each year because of barriers to medication adherence.1 This national burden of poor medication adherence in the United States is, in part, due to low literacy and reading skills and, more specifically, low health literacy. Poor health literacy is most pronounced among patients with lower socioeconomic status and those with chronic medical conditions, such as type 2 diabetes mellitus and hypertension.2 Schillinger et al compared health literacy levels in type 2 diabetic patients and found that nearly 80% of participants with a high school education or less developed poorly controlled diabetes and complications related to higher rates of nonadherence to medications, medical treatments and misunderstanding of lifestyle modifications.3 While health literacy has been recognized widely as a strong predictor of medication adherence, the health care system continues to have significant gaps in the way health information is written and the patient’s ability to understand and act on it. Addressing low health literacy can be expected to result in major financial savings in the health care industry,4 and pharmacists are in a key position to have a positive influence in this area. Recognizing that the strategies that work for one patient might not yield results in another, they need to provide personalized care for each patient. As pharmacists interact with patients, they can implement some basic methods for improving communication. They should practice speaking slowly in plain nonmedical language, use familiar terms and integrate the patient’s culture, and limit the amount of information presented to a maximum of 3 key points. Pharmacists should avoid vague or relative terms that leave room for interpretation, and instead should give patients specific percentages for frequencies of adverse events to reinforce how rare some of these can be. Patients need to become familiar with the phrase “common side

Plain, nonUse common words when speaking to patients. medical language Take note of what words they use to describe their illness and use them in your conversation. Slow down

Speak clearly and at a moderate pace.

Limit content

Prioritize what needs to be discussed and limit information to 3 to 5 key points.

Repeat key points

Be specific and concrete in your conversation and repeat key points.

Graphics

Draw pictures, use illustrations, or demonstrate with 3-D model.

Patient participation

Encourage patients to ask questions and be involved in the conversation during visits and to be proactive with their health care.

Teach-back

Confirm that patients understand what they need to know and do by asking them to re-teach directions.

effects” instead of “adverse events.” It also is necessary to confirm at the point of care that the patient understands specific dosing quantities and times

to take each of his or her medications. Although the label may state, for example, “take one tablet three times daily,” it is important to make sure the patient

knows he or she actually needs to take the drug at evenly spaced intervals. Thus, a pharmacist could recommend, for example, that the patient take one tablet at 8 am, another at 4 pm, and the last one before bedtime.

Communication Strategies Patients often need to remember a great deal of information after a visit with their health care provider to use their medications correctly and appropriately manage their chronic diseases. Clear communication strategies help patients become more involved in their care plans, increase positive outcomes, and encourage them to ask questions and be proactive with their health care (Table 1).5 A proven way to assess and reinforce the information you have shared with your patient is to use the “teach-back” method.6 This is a simple verbal tool that will help close a communication gap between the pharmacist and the patient. This repetitive form of communication gives the pharmacist an evaluation of the patient’s recall and understanding while allowing the pharmacist to clarify the points that the patient does not understand or is forgetting.

Table 2. Examples of Common Drugs Dispensed for Alternative Indications Common Indications

Possible Alternative Indications

β-Blockers (eg, atenolol, propranolol, nadolol)

Angina, hypertension

Migraine prophylaxis

• Warn patients about possible impaired cognition and dizziness due to decreases in BP, but focus counseling on migraine management. • Advise patients to keep a migraine journal to identify triggers, keep track of frequency and severity. • Contraindications such as asthma, depression, and peripheral vascular disease often limit use (complete medical history needed). • Advise patients with diabetes to carefully monitor blood glucose because drugs can mask hypoglycemia.

Tricyclic antidepressants (eg, amitriptyline)

Depression

Chronic pain, insomnia, migraine prophylaxis

• Use with caution in patients with heart disease and epilepsy. • Possible sedation; recommend bedtime administration and avoidance of concomitant alcohol. • Advise patients that symptom improvements may not be seen for a few weeks.

Clonidine

Hypertension

Attention deficit/ hyperactivity disorder

• Warn patients about possible dizziness due to decreases in BP. • Advise patients against sudden discontinuation of drug because rebound hypertension may occur. • Warn patients not to drink alcohol or use other CNS depressants while taking this drug.

Bupropion

Depression

Smoking cessation

• Advise patients about possible changes in behavior or appetite. • Patients should start treatment 1 week before they stop smoking. • Insomnia may be minimized by avoiding bedtime dosing. • Recommend smoking cessation classes along with treatment and provide appropriate resources for best outcome.

Sildenafil citrate

Erectile dysfunction

Pulmonary hypertension

• Disregard side effects that occur in men (priapism) when counseling female patients. • Drug may cause epistaxis, headache, dyspepsia, or possible insomnia. • Patients should not take this medication if they are using nitrates.

Drug Name

BP, blood pressure; CNS, central nervous system Based on reference 7.

Relevant Counseling Points

Clinical 15

Pharmacy Practice News • September 2013

Practice Pearl Using the teach-back method, after explaining a new concept or counseling about a new medication, the pharmacist asks open-ended questions such as “What are you going to do when you get home?” or “I want to be sure that I explained your medication correctly. Can you tell me how you are going to take this medicine?” The pharmacist also can conclude with specific questions such as “We covered a lot today about your diabetes, and I want to make sure that I explained things clearly. So let’s review what we discussed. What are 3 strategies that will help you control your diabetes?” or “What are 2 possible side effects you should be on the lookout for after starting this new medication?” Over time, this tool can help the pharmacist identify explanations and communication strategies that are most commonly understood by patients for future use.

Patient Education Materials Pharmacists can promote public health by using their knowledge and skills to develop patient education programs on safe and effective medication use. Often, pharmacists supplement their verbal consultation with written information. It is important to make sure that these patient education materials are easy to read and understand. Medication labels and instruction leaflets often are printed in a small-sized type, making them difficult to read, especially for geriatric patients. In addition to having complicated medication regimens, patients, especially the elderly, may commonly have problems resulting from impairments

in cognition, comprehension, recall of information on medications, and vision. Improving these educational materials can lead to better medication adherence.

Personalized Health Sheets To minimize confusion and improve health literacy for patients, pharmacists should help develop personalized written health information sheets targeted to the patient’s gender, age, and illness(es). Various other examples, along with general counseling points to focus on, are listed in Table 2. Pharmacists should not assume that the patient is taking a medication for the most common indication. Instead, approach patients by asking, “What did the doctor tell you this medication was for?” By asking this simple question, not only will the patient be involved immediately in the conversation but will be encouraged by the pharmacist’s open communication to take a more active role in his or her health care. Additionally, the pharmacist will have the information needed to effectively counsel and guide the patient through the prescribed treatment by focusing on the relevant counseling points instead of superfluous information that does not apply because of the patient’s gender, age, or illness(es). Medications often are prescribed for a specific health condition and yet can have multiple indications that are not relevant to the patient. Making the information sheets as specific as possible can help minimize confusion. For example, an older man who is pre-

scribed gabapentin for neuropathic pain should not receive information that explains the serious risks of using this medication when pregnant or that the drug is used for the management of epilepsy. This might lead the patient to become alarmed that the pharmacy provided the wrong medication or that the doctor prescribed the incorrect treatment. This is an easy way to lose credibility and the trust that a pharmacist needs to have with patients to foster medication adherence. These sheets also should reflect the fact that people have a preference for picture-based rather than word-based information. In the United States and around the world, there is compelling evidence that patients are not taking their prescribed medications correctly and that they lack the knowledge to properly navigate the health care system. Health illiteracy is being viewed increasingly as a patient safety concern and a prime source of medication-related errors. The ramifications of failure to follow prescribed medication instructions and to navigate the health management system affect every aspect of health care. According to a study released in June 2013, by the IMS Institute for Healthcare Informatics, nonadherent behaviors have been linked to significantly higher avoidable health care costs, emergency room readmissions, and patient mortality rates.8,9 Pharmacists are in a key position to help promote health literacy and reduce nonadherence to improve patient outcomes and reduce health care costs.

We Want Your Pearls Do you have an interesting practice pearl you’d like to share? If so, send it to smtilyou@mcmahonmed.com. Pearls should: • Focus on a clinical or operational problem at your institution, with tips (“tricks of the trade”) on how to manage the problem via an innovative system or strategy • Offer insights that are not widely known, understood or published • Explain why the pearl should be implemented on a widespread basis • Not exceed 1,000 words

Readers whose Practice Pearls are accepted for publication will be paid a $100 honorarium.

References 1. Pignone M, DeWalt DA, Sheridan S, Berkman N, Lohr KN. Interventions to improve health outcomes for patients with low literacy: a systematic review. J Gen Intern Med. 2005;20(2):185-192. 2. Keller DL, Wright J, Pace HA. Impact of health literacy on health outcomes in ambulatory care patients: a systematic review. Ann Pharmacother. 2008;42(9):1272-1281. 3. Schillinger D, Grumbach K, Piette J, et al. Association of health literacy with diabetes outcomes. JAMA. 2002;288(4):475-482. 4. Vernon JA, Trujillo A, Rosenbaum S, DeBuono B. Low health literacy: implications for national health policy. 2003. http://sphhs. gwu.edu/departments/healthpolicy/CHPR/ downloads/LowhealthLiteracyReport10_4_07. pdf. Accessed August 6, 2013. 5. DeWalt DA, Callahan LF, Hawk VH, Broucksou KA, Hink A. Health literacy universal precautions toolkit. AHRQ Publication No. 10-0046EF. www.ahrq.gov/qual/literacy/healthliteracytoolkit.pdf. Accessed July 30, 2013. 6. Schillinger D, Piette J, Grumbach K, et al. Closing the loop: physician communication with diabetic patients who have low health literacy. Arch Intern Med. 2003;163(1):83-90. 7.

Clinical Pharmacology website. http://www.clinicalpharmacology.com. Accessed June 23, 2013.

8. Howard DH, Sentell T, Gazmararian JA. Impact of health literacy on socioeconomic and racial differences in health in an elderly population. J Gen Intern Med. 2006;21(8):857-861. 9. Aitken M, Valkova S. Avoidable costs in U.S. healthcare: the $200 billion opportunity from using medicines more responsibly. IMS Institute for Healthcare Informatics; June 2013. This article was written by the authors in their private capacity, and the opinions expressed are those of the authors and do not represent the views of the Department of Veterans Affairs (VA). No ofﬁcial support or endorsement by the VA is intended or should be inferred.

16 Clinical

Pharmacy Practice News • September 2013

ED Pharmacy

Treat the Patient, Not the Score, for Best ER Analgesia Minneapolis—Contrary to common belief, the best way to determine if a patient in the emergency department (ED) needs analgesics is simply to ask if he or she wants more pain medication, rather than using pain scores, according to an emergency medicine pharmacist who led an educational session at the American Society of Health-System Pharmacists 2013 Summer Meeting. Scores on the standard 11-point Numeric Pain Scale can be factored into the decision, but “I don’t think it is something that you should rely on entirely. You can get the score, but it shouldn’t determine whether you treat,” said Asad Patanwala, PharmD, an associate professor at the University of Arizona College of Pharmacy, in Tucson. What does count is whether patients say yes or no when asked if they would like pain medication, he said. A recent study of nonelderly ED patients with acute severe pain revealed a significant drop in the need for additional pain relief at 60 minutes among those treated with the patient-driven 1+1 protocol (1 mg of IV hydromorphone followed by a second 1 mg dose 15 minutes later) compared with those who received physician-driven doses of IV opioids (92.3% vs. 76.6%; P<0.05) (Ann Emerg Med d 2011;58:352-359). Based on these findings, Dr. Patanwala encouraged ED pharmacists to recommend a patient-driven approach to pain management in the ED at their institutions. “It’s more intuitive just to ask this simple question,” he said in an interview. Furthermore, the standard 11-point scale may not be as reliable a method because patients may be more likely to give the pain score they believe the clinician wants to hear to get pain medication. Pain scores vary based on history and previous experience and some patients report a high score even if they really don’t want medication or a low score when pain relief actually would be necessary. Nicole M. Acquisto, PharmD, BCPS, an emergency medicine specialist at the University of Rochester Medical Center, in Rochester, N.Y., said pain management in the ED at her institution is patient-driven, and that the system works well. Pain control is discussed at the initial evaluation. If needed, the patient is given an initial dose of medication; the physician writes a standing as-needed order for medication; and additional doses are administered on nurse evaluation and patient request. The problem with a physician-driven approach, she said, is “the provider may evaluate the patient’s pain and there may be a delay in entering a single pain medication order because the provider

is taking care of several patients. Also, after the order is entered, the nurse may be taking care of several patients as well. There can be additional delays in the time to acknowledge that order and administer the medication, which ultimately creates a significant delay in the time it takes for patients to receive adequate pain relief,” she said. Dr. Patanwala encouraged pharmacists to support timelier administration of analgesics in the ED, where pain intensity is high but pain medication appears to be underused. The results of a prospective, multicenter study of 842 ED patients (median pain score of 8/10) showed that only 60%

most trauma patients, that’s all we use initially,” he said. Recent research also is calling into question the common ED practice of basing opioid dosages solely on patient weight, he said. A study by Dr. Patanwala and his colleagues at the University of Arizona Health Center of 50 opioidnaive patients showed that morphine dosing based on weight was not necessary to achieve pain relief. Patients received a fixed single dose of 4 mg of morphine regardless of weight on presentation in the ED. Pain was assessed at baseline and at 15 and 30 minutes. Patient weight was not significantly associated with the level of patients’

‘The more the pharmacist is at the bedside and involved in decisions, the more likely patients with severe pain are to receive analgesics in a timely manner.’ —Asad Patanwala, PharmD

of patients received pain medication, and the median time to receive that medication was 90 minutes, he noted. Among the patients who did not receive analgesics, 42% wanted them, but only 31% voiced their requests ((J Pain 2007;8:460-466). According to Dr. Patanwala, the optimal pain management strategy in the ED is one of titration based on three factors—time to achieve analgesia, time to reach peak analgesic effect and duration of effect. These factors are underappreciated or misunderstood in many EDs, he said. “For example, there is a misconception out there that once you give someone morphine, they have instant pain relief. That’s not true. The onset could take several minutes, rather than seconds, and the peak effect isn’t for 15 minutes.” For this reason, at his institution, a level 1 trauma center, Dr. Patanwala and his colleagues use fentanyl instead of morphine for severe pain when rapid onset is required. “In

responses to morphine on an 11-point verbal numeric scale ((J Opioid Manage 2012;8:51-55). “The first thing clinicians often look at is the size of the patient, and based on that one variable, they start recommending larger or smaller doses of morphine. Our thinking is that a lot of different factors can predict someone’s response. We don’t know what all of those factors are, but contrary to common wisdom, it’s not just weight,” Dr. Patanwala said. A smaller person with a history of chronic pain may have a higher tolerance to opioids and not achieve sufficient relief with a smaller dose, whereas an opioid-naive obese person with obstructive sleep apnea (OSA) could experience respiratory depression with a larger dose. Dr. Patanwala recommended a non– weight-based titration strategy in the ED. “Start everyone at a standard dose, such as intravenous morphine 4 mg, and then titrate them in a timely man-

ner. Titrate based on patient request, not pain scores alone.” However, he urged caution with elderly patients and patients with OSA or pulmonary disease. “This method may not apply to these patients because they were excluded from the study,” he said. Dr. Patanwala discussed the challenge of identifying drug-seeking behavior in the ED. “You can make your best guess, but the bottom line is that there is no guarantee that someone is or isn’t drug seeking,” he said. “You have to rely on what they say. It’s a difficult situation.” Drug-seeking behaviors can include reporting a pain score of 10 out of 10 and complaints of back pain and headache, but looking for any one of these behaviors does not reliably identify a drugseeking patient because these behaviors also are extremely common among non–drug-seeking patients in the ED. At his institution, Dr. Patanwala and his colleagues use a state database of controlled drug prescriptions to help determine whether a patient may be “doctor shopping.” They also use the database to verify medication dosages for ED patients because patients often don’t remember the correct dosages. The same strategy of giving lower doses of propofol for sedation to elderly patients in the operating room also holds true in the ED, according to recent research by Dr. Patanwala and his colleagues. Their retrospective study found that patients aged 65 years and older required significantly less propofol for induction of sedation than patients aged 18 to 40. They also required significantly less propofol for the entire procedure than all of the other age groups ((P<0.001). Mean induction doses were 1.4, 1 and 0.9 mg/kg and total doses were 2, 1.7 and 1.2 mg/kg for patients aged 18 to 40, 41 to 64 and 65 and older, respectively ((J Emerg Med 2013;44:823-828). Pharmacists can play an important role in optimizing pain management in the ED considering these issues. A study conducted by Dr. Patanwala and his colleagues, but not yet published, showed a reduction in time for the administration of analgesia and sedation in trauma patients when a pharmacist was present. “There is a role for pharmacists on many levels in terms of quality and bedside care in the ED,” he said. “The more the pharmacist is at the bedside and involved in decisions, the more likely patients with severe pain are to receive analgesics in a timely manner.” —Susan Birk Drs. Patanwala and Acquisto reported no relevant ﬁnancial conﬂicts of interest.

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10 mL single dose vial

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Important Safety Information The 500 mcg/mL strength product should be diluted prior to use in an appropriate solution. Clonidine hydrochloride injection is not recommended for obstetrical, postpartum, or peri-operative pain management. The risk of hemodynamic instability, especially hypotension and bradycardia, from epidural clonidine may be unacceptable in these patients. However, in a rare obstetrical, post-partum or perioperative patient, potential benefits may outweigh the possible risks. Clonidine hydrochloride injection is contraindicated in patients with a history of sensitization or allergic reactions to clonidine. Epidural administration is contraindicated in the presence of an injection site infection, in patients on anticoagulant therapy, and in those with a bleeding diathesis. Administration off clonidine hydrochloride above the C4 dermatome is contraindicated since there are no adequate safety data to support such use. Because severe hypotension may follow the administration of clonidine, it should be used with caution in all patients. It is not recommended in most patients with severe cardiovascular disease or in those who are otherwise hemodynamically unstable. Vital signs should be monitored frequently, especially during the first few days of epidural clonidine therapy. Sudden cessation of clonidine treatment, regardless of the route of administration has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor, accompanied or followed by a rapid rise in blood pressure. Adverse reactions seen during continuous epidural clonidine infusion are dose-dependent and typical for a compound of this pharmacologic class. The adverse events most frequently reported in the pivotal controlled clinical trial of continuous epidural clonidine administration consisted of hypotension, decreased heart rate, rebound hypertension, dry mouth, nausea, confusion, dizziness, somnolence, and fever. Hypotension is the adverse event that most frequently requires treatment.

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Clonidine Hydrochloride Injection Rx Only The 500 mcg/mL strength product should be diluted prior to use in an appropriate solution. NOTE: Clonidine hydrochloride injection (epidural clonidine) is not recommended for obstetrcal, postpartum, or perioperative pain management. The risk of hemodynamic instability, especially hypotension and bradycardia, from epidural clonidine may be unacceptable in these patients. However, in a obstetrical postpartum or perioperative patient, potential beneſts may outweigh the possible risks. INDICATIONS AND USAGE Clonidine hydrochloride is indicated in combination with opiates for the treatment of severe pain in cancer patients that is not adequately relieved by opioid analgesics alone. Epidural clonidine is more likely to be effective in patients with neuropathic pain than somatic or visceral pain. DRUG DESCRIPTION Clonidine Hydrochloride Injection is a centrally-acting analgesic solution for use in continuous epidural infusion devices. Each mL of the 100 mcg/mL (0.1 mg/mL) concentration contains clonidine hydrochloride 100 mcg and sodium chloride 9 mg in water for injection. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. Each 10 mL vial contains clonidine hydrochloride 1 mg (1000 mcg). Each mL of the 500 mcg/mL (0.5 mg/mL) concentration contains clonidine hydrochloride 500 mcg and sodium chloride 9 mg in water for injection. Hydrochloric acid and/or sodium hydroxide may have been added for pH adjustment. Each 10 mL vial contains clonidine hydrochloride 5 mg (5000 mcg). CLINICAL PHARMACOLOGY Mechanism of Action Epidurally administered clonidine produces dose-dependent analgesia not antagonized by opiate antagonists. The analgesia is limited to the body regions innervated by the spinal segments where analgesic concentrations of clonidine are present. Clonidine is thought to produce analgesia at presynaptic and postjunctional alpha-2-adrenoceptors in the spinal cord by preventing pain signal transmission to the brain. Special Populations The pharmacokinetics of epidurally administered clonidine has not been studied in the pediatric population or in patients with renal or hepatic disease. INDICATIONS Clonidine Hydrochloride Injection is indicated in combination with opiates for the treatment of severe pain in cancer patients that is not adequately relieved by opioid analgesics alone. Epidural clonidine is more likely to be effective in patients with neuropathic pain than somatic or visceral pain. The safety of this drug product has only been established in a highly selected group of cancer patients, and only after Ct an adequate trial of opioid analgesia. Other use is of unproven safety and is not recommended. In a rare patient, the potential beneſts may outweigh the known risks. CONTRAINDICATIONS Clonidine Hydrochloride Injection is contraindicated in patients with a history of sensitization or allergic reactions to clonidine. Epidural administration is contraindicated in the presence of an injection site infection, in patients on anticoagulant therapy, and in those with a bleeding diathesis. Administration of clonidine hydrochloride above the C4 dermatome is contraindicated since there are no adequate safety data to support such use. (See WARNINGS).

Information for Patients Patients should be instructed about the risks of rebound hypertension and warned not to discontinue clonidine except under the supervision of a physician. Patients should notify their physician immediately if clonidine administration is inadvertently interrupted for any reason. Patients who engage in potentially hazardous activities, such as operating machinery or driving, should be advised of the potential sedative and hypotensive effects of epidural clonidine. They should also be informed that sedative effects may be increased by CNSdepressing drugs such as alcohol and barbiturates, and that hypotensive effects may be increased by opiates. Drug Interactions Clonidine may potentiate the CNS-depressive effect of alcohol, barbiturates or other sedating drugs. Narcotic analgesics may potentiate the hypotensive effects of clonidine. Tricyclic antidepressants may antagonize the hypotensive effects of clonidine. The effects of tricyclic antidepressants on clonidine’s analgesic actions are not known.Beta-blockers may exacerbate the hypertensive response seen with clonidine withdrawal. Also, due to the potential for additive effects such as bradycardia and AV block, caution is warranted in patients receiving clonidine with agents known to affect sinus node function or AV nodal conduction, e.g., digitalis, calcium channel blockers, and beta-blockers.Epidural clonidine may prolong the duration of pharmacologic effects of epidural local anesthetics, including both sensory and motor blockade. ADVERSE REACTIONS Adverse reactions seen during continuous epidural clonidine infusion are dose-dependent and typical for a compound of this pharmacologic class. The adverse events most frequently reported in the pivotal controlled clinical trial of continuous epidural clonidine administration consisted of hypotension, postural hypotension, decreased heart rate , rebound hypertension, dry mouth, nausea, confusion, dizziness, somnolence, and fever. Hypotension is the adverse event that most frequently requires treatment. The hypotension is usually responsive to intravenous ƀuids and, if necessary, appropriate parenterally-administered pressor agents. Hypotension was observed more frequently in women and in lower weight patients, but no dose-related response was established. The following adverse reactions have also been reported with the use of any dosage form of clonidine. In many cases patients were receiving concomitant medication and a causal relationship has not been established: Body as a Whole: Weakness, 10%; fatigue, 4%; headache and withdrawal syndrome, each 1%. Also reported were pallor, a weakly positive Coomb’s test, and increased sensitivity to alcohol. Cardiovascular: Palpitations and tachycardia, and bradycardia, each 0.5%. Syncope, Raynaud’s phenomenon, congestive heart failure, and electrocardiographic abnormalities (i.e., sinus node arrest, functional bradycardia, high degree AV block) have been reported rarely. Rare cases of sinus bradycardia and atrioventricular block have been reported, both with and without the use of concomitant digitalis. Central Nervous System: Nervousness and agitation, 3%; mental depression, 1%; insomnia, 0.5%. Cerebrovascular accidents, other behavioral changes, vivid dreams or nightmares, restiessness, and delirium have been reported rarely. Dermatological: Rash, 1%; pruritus, 0.7%; hives, angioneurotic edema and urticaria, 0.5%; alopecia, 0.2%. Gastrointestinal: Anorexia and malaise, each 1%; mild transient abnormalities in liver function tests, 1%; hepatitis, parotitis, ileus and pseudo obstruction, and abdominal pain, rarely. Genitourinary: Decreased sexual activity and libido, impotence, and libido, 3%; nocturia, about 1%; difſculty in micturition, about 0.2%; urinary retention, about 0.1%. Hematologic: Thrombocytopenia, rarely. Metabolic: Weight gain, 0.1%; gynecomastia, 1%; transient elevation of glucose or serum phosphatase, rarely. Musculoskeletal: Muscle or joint pain, about 0.6%; leg cramps, 0.3%. Oro-otolaryngeal: Dryness of the nasal mucosa was rarely reported. Ophthalmological: Dryness of the eyes, burning of the eyes and blurred vision were rarely reported.

WARNINGS Use in Postoperative or Obstetrical Analgesia Clonidine hydrochloride (epidural clonidine) is not recommended for obstetrical, post-partum, or perioperative pain management. The risk of hemodynamic instability, especially hypotension and bradycardia, from epidural clonidine may be unacceptable in these patients. Hypotension Because severe hypotension may follow the administration of clonidine, it should be used with caution in all patients. It is not recommended in most patients with severe cardiovascular disease or in those who are otherwise hemodynamically unstable. Withdrawal Sudden cessation of clonidine treatment, regardless of the route of administration, has, in some cases, resulted in symptoms such as nervousness, agitation, headache, and tremor, accompanied or followed by a rapid rise in blood pressure. The likelihood of such reactions appears to be greater after administration of higher doses or with concomitant beta-blocker treatment. Special caution is therefore advised in these situations. Infections Infections related to implantable epidural catheters pose a serious risk. Evaluation of fever in a patient receiving epidural clonidine should include the possibility of a catheter-related infection such as meningitis or epidural abscess.

OVERDOSAGE Hypertension may develop early and may be followed by hypotension, bradycardia, respiratory depression, hypothermia, drowsiness, decreased or absent reƀexes, irritability, and miosis. With large oral overdoses, reversible cardiac conduction defects or arrhythmias, apnea, coma, and seizures have been reported. As little as 100 mcg of oral clonidine has produced signs of toxicity in pediatric patients.

PRECAUTIONS Cardiac Effects Epidural clonidine frequently causes decreases in heart rate. Symptomatic bradycardia can be treated with atropine. Rarely, atrioventricular block greater than ſrst degree has been reported. Clonidine does not alter the hemodynamic response to exercise, but may mask the increase in heart rate associated with hypovolemia. Respiratory Depression and Sedation Clonidine administration may result in sedation through the activation of alpha-adrenoceptors in the brainstem. High doses of clonidine cause sedation and ventilatory abnormalities that are usually mild. Tolerance to these effects can develop with chronic administration. These effects have been reported with bolus doses that are signiſcantly larger than the infusion rate recommended for treating cancer pain. Depression Depression has been seen in a small percentage of patients treated with oral or transdermal clonidine. Depression commonly occurs in cancer patients and may be exacerbated by treatment with clonidine. Patients, especially those with a known history of affective disorders, should be monitored for the signs and symptoms of depression. Pain of Visceral or Somatic Origin In the clinical investigations, at doses tested, clonidine hydrochloride was most effective in well-localized, “neuropathic” pain that was characterized as electrical, burning, or shooting in nature, and which was localized to a dermatomal or peripheral nerve distribution. Clonidine hydrochloride may be less effective, or possibly ineffective in the treatment of pain that is diffuse, poorly localized, or visceral in origin.

HOW SUPPLIED Clonidine Hydrochloride Injection 100 zg/mL solution in 10 mL vials, packaged individually. Clonidine Hydrochloride Injection 500 zg/mL solution in 10 mL vials, packaged individually.

DOSAGE AND ADMINISTRATION The recommended starting dose of Clonidine Hydrochloride Injection for continuous epidural infusion is 30 zg/ hr. Although dosage may be titrated up or down depending on pain relief and occurrence of adverse events, experience with dosage rates above 40 zg/hr is limited. Familiarization with the continuous epidural infusion device is essential. Patients receiving epidural clonidine from a continuous infusion device should be closely monitored for the ſrst few days to assess their repsonse. The 500 zg/mL (0.5 mg/mL) strength product must be diluted prior to use in 0.9% Sodium Chloride Injection, 7.S.P., to a ſnal concentration of 100 zg/mL. Renal Impairment Dosage should be adjusted according to the degree of renal impairment, and patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

STORAGE Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

BS0730 Iss. 8/2013 AMERICAN REGENT, INC. SHIRLEY, NY 11967

Clinical 19

Pharmacy Practice News • September 2013

Pain Medicine

Algorithm Helps Cut Opiate Use for ED Headaches E

mergency and pain physicians from the Cleveland Clinic, in the process of refining an algorithm for headache management in the emergency department (ED), reported that it has resulted in an 82% reduction in both treatment with opioids or narcotics in the ED and discharge with prescriptions for these types of medications. The researchers also hope to reduce the amount of imaging, number of consults and number of admissions related to headache, all while continuing to maintain or increase patients’ pain relief. “We were astonished at how much we were able to diminish the use of opiates,” said lead investigator Cynthia Bamford, MD, after she and her colleagues presented the details of the algorithm implementation in poster form at the 2013 International Headache Congress, held recently in Boston. “The director of the emergency department really worked hard with his team

to get them to utilize this algorithm, and to educate them about opiate use— and it really made a difference.” The initial version of the algorithm was tested in the ED of Lakewood Hospital, in Lakewood, Ohio. According to the investigators, it is complex, with lists of “red flags” such as fever and chills, “yellow flags” such as recurrent ED visits without appropriate follow-up care, and detailed criteria for migraine without aura and cluster headache (Figure). Nonetheless, the ED physicians were able to significantly reduce opiate use after implementation of the algorithm in February 2013. Two-thirds of patients were treated with opiates or narcotics between October 2012 and January 2013, compared with only 12% in the post-implementation period of February to April 2013. Furthermore, the percentage of patients discharged with prescriptions for opiates or nar-

cotics fell from 44% to 8%. The percentage of patients undergoing imaging remained relatively constant, at 48% pre- and 54% postimplementation, as did the number of patients for whom consults were called (8% and 6%, respectively), and admissions (8% in both periods). Pain relief did not suffer during the drop in opiate use, with 63% of pre-implementation patients experiencing greater than 50% pain relief and 68% having this amount of pain relief after the ED doctor implemented the algorithm. Three other metrics the team measured—time from arrival at the hospital to discharge, time from evaluation to treatment, and time from treatment to discharge—also remained constant. Based on the ED doctors’ feedback on the algorithm, Dr. Bamford and her colleagues removed unnecessary elements and created one that has three simple

steps to treatment. Each step is used in sequence if the previous one does not result in halving of the patient’s pain within two hours. Brad Uren, MD, a clinical assistant professor, Department of Emergency Medicine, University of Michigan, Ann Arbor, and the president of the Michigan College of Emergency Physicians, who was not involved in the study, said further validation of the algorithm will show whether it will hold up in various ED settings. “This proposed treatment algorithm and others like it are useful adjuncts to the treatment of headaches in the emergency department,” he said. “Narcotic misuse is becoming a great concern in this country, and evidence-based treatment protocols that represent safe, appropriate and timely patient care are of great interest.” —Rosemary Frei, MSc

Figure. Draft algorithm for Emergency Department management of headache. CAD, coronary artery disease; DHE, dihydroergotamine; ED, emergency department; HTN, hypertension; IVP, intravenous push; OARRS, Ohio Automated Rx Reporting System; PCP, primary care provider

20 Clinical

Pharmacy Practice News • September 2013

Pain Medicine

Acetaminophen Linked to Serious Skin Reactions A

cetaminophen carries the risk for rare but serious and potentially fatal skin reactions, the FDA warned on Aug. 1. The risk is present both in prescription and over-the-counter (OTC) products containing the pain reliever and fever reducer, whether it is the single active ingredient or is combined with other medications. The skin reactions include StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN), both lifethreatening, as well as acute generalized exanthematous pustulosis (AGEP), which is usually not life-threatening, the FDA said in documents that included warnings for consumers and health care professionals. In AGEP, the skin reddens and gives rise to up to hundreds of pustules. SJS and TEN begin with flulike symptoms, followed by rash, blisters and detachment of the skin’s upper surface. Health care professionals should advise patients using an acetaminophen-containing product to stop using it at the first sign of a skin rash or reaction and seek immediate medical attention. “This new information is not intended to worry consumers or health care professionals, nor is it meant to encourage them to choose other medications,” Sharon Hertz, MD, the deputy director of the FDA’s Division of Anesthesia, Analgesia, and Addiction, said in a statement. “However, it is extremely important that people recognize and react quickly to the initial symptoms of these rare but serious side effects, which are potentially fatal.” Other drugs used to treat pain and reduce fever, including nonsteroidal anti-inflammatory drugs (NSAIDs), also carry the risk for serious skin reactions, the FDA noted. These drugs include aspirin, ibuprofen, naproxen and ketoprofen. A serious skin reaction can occur in people who have previously taken acetaminophen without incident. The FDA said it is requiring the addition of a warning about serious skin reactions to the labels of prescription medications containing acetaminophen, and will work with the manufacturers of OTC products that contain acetaminophen to add a warning to their labels. According to the FDA, evidence of the reported risk comes primarily from three published case reports in which patients were rechallenged with acetaminophen and had the serious skin reaction recur. Two of the papers were published more than a decade ago ((Ann Pharmacother 2000;34:3234; Acta Derm Venereol 1998;78:222223). The most recent was published in 2010 ((Allergol Immunopathol [Madr]

‘[The FDA is] looking at all aspects of acetaminophen safety.’ —Lisa Kubaska, PharmD 2010;38:99-100). Additional sup-porting data come from other casee reports that did not involve positiive rechallenge, as well as the FDA Adverse Event Reporting System database, the agency noted.

A History of Regulation This is not the first action the FDA has taken to address safety issues associated with acetaminophen-containing products. In April 2009, the agency issued a ruling requiring manufacturers of OTC acetaminophen and NSAID products to revise their labeling to include warnings about potential safety risks, including internal bleeding and liver damage, in patients taking the drugs. Additionally, the FDA mandated that acetaminophen labeling include a warning that patients talk to their doctor about the risks posed by taking the painkiller in conjunction with warfarin, which can increase the risk for bleeding. Two months after the OTC labeling rule was issued, the FDA convened an advisory committee meeting to discuss further steps the agency could take to promote the safer use of acetaminophen, with many of the proposals targeted at prescription formulations. For example, the advisory panel voted overwhelmingly (36 to 1) to recommend that a black box warning regarding liver injury be added to labeling for prescription medications containing acetaminophen and other painkillers, including hydrocodone (Vicodin, Abbott Laboratories), oxycodone (Percocet, Endo Pharmaceuticals) and codeine (Tylenol, McNeil). During the deliberations, one of the panel members cited data showing that approximately 10% of all fatal acetaminophen overdoses occur in patients taking such combination products.

The overdoses Th d ttypically i ll occur b because patients often do not realize they are taking multiple products (in many cases, an OTC and a prescription product) that contain acetaminophen, the panelist noted. The advisory panel recommended several additional safety steps, including lowering the maximum single adult dose from 1,000 mg to 650 mg, and making 500-mg acetaminophen pills obtainable by prescription only—an effort by the panel to effectively put dose limits on OTC formulations. And in its most controversial decision, the panel voted by a very slim margin (20 to 17) to ban all prescription combination products containing acetaminophen. In 2011, the FDA responded to the advisory panel recommendations, but adopted only some of the panel’s suggestions. The agency said, for example, that it would now require a black box warning highlighting the painkiller’s potential for causing severe liver failure and allergic reactions. It also announced that it would place a 325-mg dosage limit on prescription products containing acetaminophen—a ruling that primarily affected combination opioid/acetaminophen formulations. But the FDA chose not to place any dosage restrictions on OTC acetaminophen, and it passed on the polarizing panel recommendation to ban all acetaminophen combination products.

Public Citizen’s Stance Public Citizen, a national nonprofit health advocacy group, has long championed that the FDA be more aggressive in its oversight of acetaminophen. In a Jan. 13, 2011 statement posted on its website, the group’s director, Sidney

Stevens-Johnson syndrome (left) and toxic epidermal necrolysis (right) are rare but potentially lethal side effects of over-the-counter acetaminophen.

Wolfe, MD, criticized the FDA’s decision to place dosage limits only on prescription acetaminophen. “It is inexcusably poor judgment” for the agency not to have lowered acetaminophen doses in OTC formulations, which are “a major source of acetaminophen consumption and, consequently, acetaminophen toxicity,” Dr. Wolfe said. Indeed, in 2008, more than 370 million bottles and packets of acetaminophen—nearly 24.6 billion doses—were sold in the United States, Dr. Wolfe noted, citing FDA data. “Nearly 80% of this entire market is [represented by] OTC consumption,” he said. Public Citizen’s response to the most recent acetaminophen FDA action was considerably less combative. In a statement provided to Pharmacy Practice News on Aug. 7, the group chose to focus on how patients should react to the new labeling changes in a safe manner. The group said it “does not advise consumers taking acetaminophen to switch to another pain reliever unless they experience an adverse reaction. This is because other drugs used to treat fever and pain/body aches [e.g., NSAIDs, ibuprofen, naproxen, etc.] also carry the risk of causing serious skin reactions, as described in the warning sections of their labeling.” The statement also sought to ease any fears that the severe skin reactions cited in the new labeling are a common occurrence. “The [FDA] has not been able to determine how frequently serious skin reactions occur with acetaminophen, but it estimates that these events are very rare.” Public Citizen did not comment on whether it had any plans for reiterating its earlier calls for more aggressive oversight of OTC acetaminophen.

FDA Responds As for the FDA, when asked whether the skin reactions cited in the new acetaminophen labeling will result in the agency taking another look at dosing limits on OTC formulations, agency spokesperson Lisa Kubaska, PharmD, responded that its Division of Nonprescription Regulation Development “is aware of this safety issue; we are assessing the data and working on a new proposal to improve the safe use of acetaminophen drug products.” Asked to provide further details of the proposal, Dr. Kubaska told Pharmacy Practice News that no such details are available. “However, we are looking at all aspects of acetaminophen safety.”

—George Ochoa, with additional reporting by David Bronstein

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22 Clinical

Pharmacy Practice News • September 2013

Cardiology

DATA FRAUD continued from page 1

studies of perioperative β-blocker use in 10,529 patients, and found that β-blockers caused a “statistically and clinically significant increase in mortality.” Analyzing six of the studies, the team found that β-blockers reduced the risk for non-fatal myocardial infarction (MI) (relative risk [RR], 0.73; P=0.001) but increased the risk for stroke (RR, 1.73; P=0.05) and hypotension (RR, 1.51; P<0.00001). Meanwhile, U.S. and European cardiology guidelines released in 2009 recommend this therapy, and the study authors say it’s high time for an update. Those guidelines were based largely on the series of DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) studies that reported various cardiac benefits from the use of perioperative β-blockers. DECREASE I found that perioperative bisoprolol reduced short- and long-term cardiac death and MI; a follow-up DECREASE IV found that bisoprolol also significantly reduced 30-day cardiac death and MI in intermediate-risk patients. Then, in 2011, the studies’ principal investigator, Don Poldermans, MD, PhD, was fired from Erasmus Medical Center in Rotterdam, after an investigation found him guilty of scientific misconduct, including failure to obtain patient consent and logging results that did not match patient medical records. A medical center investigation found that the events in DECREASE IV did not match patients’ medical records, and at least one of the DECREASE trials reported almost entirely fictitious data, according to Darrel P. Francis, MD, a professor of cardiology at Imperial College’s National Heart and Lung Institute and the senior author of the new study. Dr. Poldermans promptly resigned from the European Society of Cardiology’s (ESC) Committee for Practice Guidelines. But because the papers have not been retracted from medical journals, the guidelines have remained, leaving clinicians confused about what to do. “I used to feel so reassured recommending perioperative β-blockade,” Dr. Francis said. “It seemed a fantastic solution to a difficult problem.” But now Dr. Francis recommends the therapy mainly for patients with a high risk of MI who must undergo surgery. He suggested that other clinicians review the paper and guidelines to make an informed decision.

Earlier Signs of Trouble The benefits of perioperative β-blocker therapy have been questioned in previous studies, such as the PeriOperative ISchemic Evaluation (POISE) trial and another meta-analysis by researchers at Brigham and Women’s Hospital,

in Boston, both published in the Lancet in 2008 (371:1839-1847; 1962-1976). But it was the POISE study—included in the current study’s analysis—that served as perhaps the strongest initial salvo against β-blocker perioperative therapy. The study compared extendedrelease metoprolol with placebo in 8,351 patients with atherosclerosis or at risk for the condition. Patients were given the drug between two and four hours before surgery and took it for 30 days after their operations. As expected, fewer patients who received metoprolol had an MI during the study period (4.2% vs. 5.7%; P=0.0017). However, those patients given the β-blocker were significantly more likely to have a stroke (41 vs. 19; P=0.0053) or to die (129 vs. 97; P=0.0317) during the 30 days of follow-up. The bottom line, according to the researchers: For every 1,000 patients given metoprolol for non-cardiac surgery, 15 would avoid an MI but five would have a stroke and eight would die. In addition, although β-blocker therapy would prevent some cases of atrial fibrillation and cardiac revascularization, it would lead to nearly 100 cases of clinically relevant hypotension and bradycardia for every 1,000 people who received the drug. (For more details on POISE, see Pharmacy Practice News, July 2008; bit.ly/170y42U, as well as the sidebar below.) POISE co-principal investigator Homer Yang, MD, a professor and the former chair of anesthesiology at the University of Ottawa, in Canada, said the new study findings are consistent with POISE. “Even in our paper, we stated that people need to be careful with patients and not use β-blockers as ‘holy water’ for everyone,” he told

Pharmacy Practice News. Dr. Yang said that he still recommends ß-blockers in the perioperative setting, “but not in the low-risk patient population—that’s where the risk–benefit ratio comes in. “We have always taken a balanced approach,” he added. “We don’t want to [characterize] β-blockers as evil or permanently condemned. Medicine just isn’t like that.”

‘We have always taken a balanced approach. We don’t want to [characterize] β-blockers as evil or permanently condemned. Medicine just isn’t like that.’ —Homer Yang, MD POISE used “industrial dosages of β-blockers that most of us would never use,” said Kim Eagle, MD, the A. Walter Hewlett Professor of Internal Medicine and the director of the Cardiovascular Center at the University of Michigan, in Ann Arbor, but the current study “does call into question how much value versus harm” they offer. Dr. Yang replied that the seemingly high (100 mg) doses of slow-release, once-daily metoprolol metabolize in the body similar to thricedaily lower doses (25 mg) of immediaterelease metoprolol. The current metaanalysis also explained that, stating “the POISE trial was therefore not high-dose.”

A Balanced Approach Other physicians also continue to use β-blockers for perioperative purposes but are doing so more judiciously. Dr. Eagle said β-blockers are indicated “for patients with established coronary artery disease and ischemia based on symptoms

or non-invasive testing, for whom no contraindications exist, and where the dose is carefully titrated so as to avoid undue bradycardia and or hypotension. They would be especially indicated for patients having major vascular surgery.” If they are used, they should be started at low doses “and never pushed to the expense of low blood pressure. We have to be circumspect in how we dose the medicines because they can cause harm.” W. Scott Beattie, MD, PhD, the R. Fraser Elliott Chair in Cardiac Anesthesia at the University Health Network in Toronto, Ontario, Canada, said the current findings are similar to previous meta-analyses. “Lost in the ‘controversy’ is that β-blockers do exactly what we thought they would—reduce perioperative MI,” he said. “We need to ask: If the risk of heart attack, the leading cause of postoperative mortality, is lowered, why are more patients dying?” The POISE data, Dr. Beattie noted, identified poten-

The Pharmacist’s Perspective

ne of the strongest cases against perioperative β-blocker therapy was made by the PeriOperative ISchemic Evaluation (POISE) trial (Lancet 2008;371:1839-1847). At the time the POISE data were published, C. Michael White, PharmD, the director of the University of Connecticut/Hartford Hospital Evidence-based Practice Center, helped put the findings in perspective for Pharmacy Practice News. He stressed that any decisions regarding blocker therapy must be made in the context of the new evidence. “The data from that trial apply only to non-cardiac surgery; they do not apply to cardiothoracic procedures,” he said. “So your coronary artery bypass and heart-valve surgery patients still need to get C. Michael β-blockers for prophylaxis.” White, PharmD Dr. White also cautioned against withdrawing β-blockers from patients who have already been prescribed the drugs due to known risk factors. If such patients are on β-blockers, “DO NOT stop them perioperatively or postoperatively, based on the POISE data or any other trial results,” he said. “The data suggest that ß-blocker withdrawal is worse than [the risks associated with] β-blocker continuation.” If anyone has doubts about matching the right patients to β-blocker therapy, Dr. White suggested looking at the specifics of the POISE results. “You’ll see that the benefits of β-blockers were concentrated in patients with vascular surgery, with no significant benefit in orthopedic patients and no benefits in intraperitoneal surgery. So given the potential for harm, why would anyone recommend this therapy in [the latter] patients?” Asked to comment on the 2013 meta-analysis, Dr. White first noted that he was most struck by the fact that the DECREASE (Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography) data may have been fabricated. “The DECREASE trials were showing genuinely positive results that I thought might have been explained by their gentle dosing [regimens],” Dr. White said. “If it turns out that the trial data were indeed fabricated, then this future research avenue seems a much less likely one to pursue.” When the DECREASE data are taken out of the equation for assessing perioperative β-blockers, he added, “the trend toward increased mortality becomes significant with the remaining trials. Fabricated data are so insidious because they lead honest investigators to pursue avenues of research that are not based in fact and negatively impact patient care.” —David Bronstein

Clinical 23

Pharmacy Practice News • September 2013

Diabetes Management

Look for Patterns To Optimize Insulin Therapy Minneapolis—As the practice of pharmacy expands, more health-system pharmacists are assuming responsibility for optimizing diabetes and cardiovascular (CV) care for patients with type 2 diabetes, particularly those on insulin therapy, according to a diabetes clinical pharmacist speaking at the American Society of Health-System Pharmacists 2013 Summer Meeting. This growing role in chronic disease management offers an excellent practice opportunity for the profession as well as a valuable service for primary care physicians (PCPs), said Eric Ip, PharmD, BCPS, CSCS, CDE, a diabetes clinical pharmacist at Kaiser Permanente Mountain View Clinics, in Mountain View, Calif., and an associate professor of pharmacy practice at Touro University California College of Pharmacy, in Vallejo. “Primary care physicians really appreciate pharmacists taking on this role to improve patient care,” Dr. Ip told Pharmacy Practice News. Under a collaborative practice agreement with 16 PCPs at Kaiser Permanente Mountain View, Dr. Ip has full autonomy and prescribing authority for diabetes and CV medications. Most of his referrals are patients with high CV risk and poor glycemic control. He sees the patients in his clinic for approximately three to 12 months before referring them back to their PCPs for followup care once their glycemic control is stable and they have achieved goals for glycated hemoglobin (A1cc), low-density lipoprotein cholesterol (LDL-C) and blood pressure (BP). In addition to managing diabetes and CV care, Dr. Ip also prescribes and administers vaccines

tial safety issues that may be contributing to that excess mortality, including anemia, blood transfusion, emergent surgery and pre-existing cerebrovascular disease. “It is important for us to figure out how to use these drugs safely. Irrespective of starting β-blockers anew, as was done in these studies, 20% to 40% of surgical patients are chronically taking β-blockers. Recent evidence suggests that these patients also have [an] increased number of strokes.” Dr. Yang and others are trying to tease out which patients might benefit—or be harmed—the most from perioperative β-blocker therapy. One hypothesis is that patients treated during emergency surgery might not benefit as much as those with scheduled surgeries. “Emergency surgery has always been known to be a higher-risk setting,” Dr. Yang said. “In a subgroup analysis [of POISE]

‘If the patient has tried moderating carbohydrate intake at dinner and in the evening but still has elevated [glucose] readings at bedtime, then it is reasonable to consider adding a rapid-acting insulin before dinner.’ —Eric Ip, PharmD, BCPS, CSCS, CDE (pneumococcal, influenza, hepatitis B), performs comprehensive annual foot examinations and refers patients for appropriate preventive care (e.g., mammography, cervical and colon cancer screenings, and annual retinal exams). Pharmacist involvement in initiating and adjusting insulin regimens for patients with type 2 diabetes is likely to increase because so many patients are poorly controlled, predicted Dr. Ip. It is estimated that more than 60% of patients with diabetes do not meet their glycemic goals and that only 12% achieve the American Diabetes Association (ADA) standards of an A1c less than 7%, BP less than 130/80 mm Hg (raised to 140/80 mm Hg in 2013) and LDL-C less than 100 mg/dL. Poorly controlled diabetes and CV markers increase the risk for myocardial infarction, stroke, peripheral vascular disease, retinopathy, nephropathy and neuropathy, and are a leading cause of blindness, nontraumatic amputation and kidney failure. In many cases, a therapeutic regimen that includes insulin can help patients achieve better glucose control and prevent or reduce the likelihood of complications, he noted, adding that the 2012 ADA/European Association for the Study of Diabetes (EASD) Management

… the survival curves of patients getting metoprolol versus controls in emergency surgery do not separate as nicely as the elective cases.” He also speculated that “emergent cases possibly are already bleeding more or already have more hypotension, which was identified in our POISE study as risk factors for worse outcomes. Additionally, β-blockers reduce the reserve in cardiac

of Hyperglycemia in Type 2 Diabetes Position Statement recommends adding insulin therapy as an option for patients who do not achieve good control with metformin ((Diabetes Care 2012;35:13641379). Other options that may be added to metformin include sulfonylureas, a thiazolidinedione (e.g., pioglitazone), dipeptidyl peptidase 4 inhibitors (e.g., sitagliptin [Januvia, Merck], saxagliptin [Onglyza, Bristol-Myers Squibb]), and injectable glucagon-like peptide-1 receptor agonists. Studies have shown that approximately 60% of patients can achieve an A1c less than 7% with a basal insulin regimen, which tends to be effective, easy to titrate and well tolerated, Dr. Ip said, noting that if basal insulin or a three-drug combination fails to achieve glucose control, guidelines recommend the use of insulin in multiple daily doses. Dr. Ip described a clinical case to illustrate use of the ADA/EASD consensus algorithm for initiating therapy with basal insulin. The patient, a 51-year-old man with type 2 diabetes (A1c, 9.5%), hypertension and hyperlipidemia, who was taking metformin 1,000 mg twice daily and glipizide 10 mg twice daily (both roughly the maximum effective dose) and had a morning fasting blood glucose of 190 to 220 mg/dL.

output responses, and so those risk factors in emergency surgery may be exacerbated by the use of β-blockers. That’s a hypothesis—we can’t prove it yet.” Thus, more clinical trials focusing on β-blocker safety are “urgently required,” Dr. Yang added. One early clue has already emerged: a study that he presented at the Canadian Anesthesiologists’ Society meeting this summer showed no

Of the next-line agents, neutral protamine Hagedorn (NPH) insulin at bedtime would most likely help the patient attain his glycemic goal of less than 7%, according to Dr. Ip. But, he said, “before adding the medication, you always want to think about efficacy. How much is the medication that you’re going to add on going to lower the patient’s blood sugars as well as A1c? You also want to think about safety profile and patient preference. Are there any contraindications to the medication or side effects that may hinder patient adherence?” The 2009 ADA/ EASD Position Statement recommends starting NPH at 10 units or 0.2 units/ kg at bedtime, said Dr. Ip. “Or you can use some of the long-acting insulins, like detemir or glargine. The dosing is the same—10 units or 0.2 units/kg—but it can be administered at bedtime or in the morning. Consider using a lower starting dose if the patient is elderly, has a low body weight or has poor renal function.” To titrate up the insulin, the patient can self-increase the dose by two units

•

see PATTERNS, page 24

significant difference between the two groups of patients. He said he is still analyzing those data. The American College of Cardiology, the American Heart Association and the ESC are all in the process of completing updated guidelines for perioperative cardiac management, according to a statement on ESC’s website. “In the interim, our current joint position is that the initiation of β-blockers in patients who will undergo non-cardiac surgery should not be considered routine, but should be considered carefully by each patient’s treating physician on a case-by-case basis.” —Karen Blum, with additional reporting by Adam Marcus None of the sources reported any relevant conﬂicts of interest.

24 Clinical

Pharmacy Practice News • September 2013

Diabetes Management

PATTERNS continued from page 23

every three days until morning fasting blood glucose reaches the desired range of 70 to 130 mg/dL, he said. Dr. Ip discussed several case scenarios with different blood glucose readings. If a patient has his or her highest blood glucose at bedtime, for example, “you want to think about the cause of the high readings. Which meal is it? You would assume it’s dinner, but maybe it’s snacking after dinner,” he said. “If the patient has tried

moderating carbohydrate intake at dinner and in the evening but still has elevated [glucose] readings at bedtime, then it is reasonable to consider adding a rapidacting insulin before dinner.” He stressed the need to explore all of the potential causes of high readings, including excessive carbohydrate intake, decreased physical activity, an insulin dose that is too low, infections, other medications (e.g., corticosteroids) or even an expired vial of insulin. Many patients forget to use a new insulin vial every 28 to 30 days, he said.

He also emphasized the importance of always checking with patients to see whether they are experiencing hypoglycemia before increasing their insulin dose. “Is it because the insulin dose is too high, the patient ate too few carbohydrates, skipped a meal, became more physically active or drank hard liquor?” he said. A patient with an elevated morning fasting blood glucose reading may either require a higher dose of insulin or be rebounding from an overnight low, a phenomenon of posthypoglycemic hyperglycemia known as the

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Somogyi effect. “If the high [glucose] reading is because of an overnight low, increasing the dose will only worsen the situation. You would want to lower the dose in that scenario. Once you get rid of the hypoglycemia, that rebound high glucose should disappear,” he said. The goal in adjusting insulin doses is to determine patterns and assess which insulins are affecting readings, said Dr. Ip. For example, the solution for consistently low morning blood glucose could be a lower dose of bedtime basal insulin, and the solution for consistently high morning glucose could be a higher dose of basal insulin at bedtime or dinner. The recently approved sodium glucose cotransporter 2 inhibitor canagliflozin (Invokana, Janssen), a novel agent that promotes the secretion of glucose in the urine, shows some potential as a possible alternative agent after metformin in the treatment of type 2 diabetes, according to Dr. Ip. The drug’s advantages are that it can cause modest weight loss and lower systolic BP, but it produces only modest reductions in A1c, and “we still need more long-term efficacy and safety data,” he said. “Pretty much any time there’s a diabetes drug with a new mechanism of action I get excited, but what we need is more information on safety,” agreed Michelle Zingone Farland, PharmD, BCPS, CDE, an associate professor of clinical pharmacy at the University of Tennessee Health Science Center College of Pharmacy, in Knoxville. One of the safety concerns is the potential for an increased risk for stroke, but current data are inconclusive, she said in an interview. Another safety concern is the increased potential for urinary tract infections (UTIs) due to the secretion of sugar in the urine, which can create a potential breeding ground for bacteria. “How frequently are these UTIs going to be occurring? Is there really an increased risk for stroke? If we’re able to answer those two big questions, we might see it used more frequently,” she said. Like Dr. Ip, Dr. Farland has the authority to initiate and adjust insulin and CV therapy for patients with type 2 diabetes at her institution, “but the relationship with the physicians is slightly different in that we have shared appointments— we’ll both see patients in the same day and make treatment decisions together,” she noted. Dr. Ip said he hopes more clinical pharmacists will have the opportunity to have such expanded practice responsibilities, including prescriptive authority, as the profession strives for “provider status” in the coming years. —Susan Birk

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Policy 25

Pharmacy Practice News • September 2013

Compounding

FDA Reasserts Concerns About NuVision Sterile Products

he FDA continued to advise health care providers not to use sterile products from NuVision Pharmacy of Dallas, because the sterility of the products is not assured, according to an Aug. 16 FDA news release. This alert followed an April recall by NuVision of methylcobalamin injection and lyophilized injection products due to a lack of sterility assurance, and a May 18 FDA announcement of expanded concerns about a lack of sterility assurance of all NuVision’s sterile drug products. “The FDA received adverse event reports of fever, flu-like symptoms, and soreness at the injection site associated with the methylcobalamin injection product” that was recalled, said the Aug. 16 news release. NuVision has repeatedly declined FDA requests for a more widespread recall of the company’s sterile products, according to the agency; the FDA said it lacks the authority to require such a recall. Most recently, on July 26, the FDA issued a letter to NuVision outlining poor sterile production practices observed during an FDA inspection of NuVision’s Dallas facility. Among the agency’s findings: • The firm’s facility design “was inadequate for the processing of aseptically filled, injectable products.” HEPA filters, for example, “covered less than one-half of the area in which sterile drugs are aseptically manipulated.” • The ISO area where the HEPA filters were located “consisted of a table with inadequate protection to safeguard the sterile product from influx of lowerquality air from the immediately adjacent ISO 7 clean room.” Without an adequate physical barrier, the FDA’s letter noted, the compounding area was vulnerable to microbial contamination from the activities of personnel in or near the work area. • The company lacked any proof that the aseptic work area “was supplied with a clean unidirectional air of sufficient velocity to protect sterile components from microbial contamination during aseptic processing.” The letter, from Melinda K. Plaisier, the acting associate commissioner for regulatory affairs at the FDA, requested an immediate “recall of all lots of all sterile products produced at NuVision that are within expiry,” and warned, “if a drug product marketed as sterile contains microbial contamination, patients could be at risk for serious infections, which may be life-threatening.” NuVision responded by refusing the requested recall, according to the Aug. 16 news release. On NuVision’s website, the company stated that it is not recalling all sterile injectables, and that all its sterile injectables are tested for sterility by a

Adverse event reports of fever, flu-like symptoms, and soreness at methylcobalamin injection site trigger agency action. third-party laboratory before dispensing. The website also reports that NuVision is a compounding pharmacy, not a manufacturer. “We are in compliance with USP [Chapter] <795> and [Chapter] <797> which are the standards of law for

compounding pharmacy. The FDA has been inspecting compounding pharmacies based on a different set of standards for manufacturers called FDA 210 and 211. … The current state laws do not require compounding pharmacies to fol-

low the standards for manufacturing.” The FDA advises health care professionals to check their medical supplies for NuVision sterile products, quarantine any such products, and not administer them to patients. —George Ochoa

More compounding news, pages 26, 28

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26 Policy

Pharmacy Practice News • September 2013

Compounding

QI PLAN continued from page 1

to USP <797>.” But Mr. Kastango said the general attitude had been, “‘I really don’t have to worry because this is just about compounding pharmacies and not hospital pharmacies.’ There’s not an overarching sense of urgency in the hospital segment.” That has to change, Mr. Kastango said. “Based on the consulting that I do,” he said, “even people who are doing a good job have significant gaps in compliance that can have a [major] impact on the quality of medications they’re making for their patients.” An Institute for Safe Medication Practices survey earlier this year supports Mr. Kastango’s contention that hospital pharmacies are lagging (Pharmacy ( Practice News 2013;40:1, 29-32; bit.ly/1bWXmjI). The survey showed that three of four (74%) respondents felt contamination could be a risk for their facilities, and 13% said contamination actually had occurred during the past year.

Cedairs-Sinai Initiative Cedars-Sinai Medical Center, in Los Angeles, has taken these compounding risks to heart. The hospital has carried out a major reevaluation and revision of its sterile compounding quality plan, according to Rita Shane, PharmD, FASHP, the director of pharmacy services at the center. Dr. Shane said the review was prompted not only by the desire to update and improve the pharmacy’s long-serving compounding quality assurance plan but also by new California compounding safety rules, considered to be among the nation’s strictest. The initiative was launched several months before the meningitis crisis erupted last September, said Katherine Palmer, PharmD, the sterile products area supervisor at Cedars-Sinai, but its timing seemed to grow in importance as more and more infections and deaths from injections of contaminated methylprednisolone distributed by the New England Compounding Center (NECC) were reported. “Compounding is on everyone’s radar right now,” said Dr. Shane, who with Dr. Palmer and pharmacy manager Bruce Vinson, PharmD, reported on Cedars-Sinai’s revised quality assurance plan at the June 2013 Medication Safety Collaborative meeting, held in conjunction with the American Society of Health-System Pharmacists Summer Meeting. One new innovation in the medical center’s plan is an online dashboard, an easy-to-grasp Excel tool that helps pharmacy monitor and report progress in meeting USP Chapter <797> goals as well as state requirements for environmental control, personnel performance, medication storage and other factors.

‘[Hospitals] need to understand that the events that happened at NECC can happen in their pharmacies, and they need to be vigilant.’ —Eric Kastango, RPh, MBA, FASHP

The dashboard, Dr. Shane said, “serves as a kind of tickler or prompt to make sure that everything is being evaluated on a timely basis.” Before the dashboard was introduced, compounding activities were monitored and documented in an assortment of notebooks, Dr. Shane said. Now, with the template in place, the new system “has enabled us to organize our quality assurance activities and include the frequency for each component to facilitate tracking of our monitoring [efforts].” All of the components of the dash-

board are essentially in compliance with USP Chapter <797> standards, Dr. Shane said, but a few specifically address California rules, such as the need to validate the time spent observing staff prepare sterile medications. “This is USP <797> plus,” she said.

Are Hospitals Ready For Random Inspections? California hospital pharmacies now are required to file self-assessment reports on compounding quality only every two years. But Dr. Shane said that she expected the California board to add hospital

pharmacies to the list of random inspection sites. She said that a state inspector who was evaluating a new Cedars-Sinai outpatient cancer center last fall took a look at the pharmacy’s revised compounding quality plan and “felt that it did support what they expected organizations to be doing.” The Cedars-Sinai pharmacy staff is not standing still when it comes to improving compounding quality. They are anticipating the imminent arrival of a new microbial air sampler, a much more efficient and accurate tool than the agar paddles now in use. The new device will allow pharmacy to measure the biological burden around hoods and clean rooms more frequently than the twice-yearly intervals recommended by USP Chapter <797>. “The machine will enable us to simulate what the certifiers are able to test when they’re here,” Dr. Palmer said. What lessons can other hospital pharmacies take from the fungal meningitis crisis? Mr. Kastango said, “They need to understand that the events that happened at NECC can happen in their pharmacies, and they need to be vigilant,” even if they are not required to be inspected under federal or state rules. “From a strategic and tactical position,” he added, “people need to get their house in order and understand where they are relative to compliance with <797>. The chapter has been out for nine years now, and this stuff matters.” —Bruce and Joan Buckley

Who Is Taking the Compounding Crisis Seriously?

om Van Hassel, RPh, the pharmacy director at Yuma Regional Medical Center, in Yuma, Ariz., is no stranger to the crisis of confidence in compounding triggered by the NECC debacle. For the past several months, he has been working in his capacity as the president of the Arizona State Board of Pharmacy to draft new guidelines intended to make the practice safer for patients and hospitals. Given the intensive level of activity those efforts require, does Mr. Van Hassel take issue with Mr. Kastango’s claim that there is a lack of urgency among some elements in pharmacy to fix what’s broken in the admixture arena? “I actually agree with Eric on this—there does need to be a lot more effort than I am seeing, at least in health systems,” he told Pharmacy Practice News. “And remember, there’s no one right solution: some facilities will decide to bring compounding in-house to boost safety, which is fine—iff they do it right and can guarantee USP [Chapter] <797> compliance. Other facilities will decide to continue to outsource, which is also OK—but again, only if they do it correctly, by thoroughly vetting vendors to ensure the companies take good manufacturing practices and patient safety seriously. “The problem is I don’t see a groundswell of hospitals stepping up and implementing these important quality improvement strategies.” Help may be at hand from recent actions taken by the National Association of Boards of Pharmacy (NABP), which

recently decided that USP Chapter <797> has to be the common nationwide source for guidance on compounding policies and procedures. Mr. Van Hassel said he has been working with his own state chapter to make that happen, even though it’s something of a departure from previous policy. “We used to pick and choose the parts of <797> that we thought would work for hospitals in our state,” he said. “Frankly, we did that because we felt <797> and the related USP materials on beyond-use-dating and other safety issues were way too complicated to follow. But after the NABP meeting, we saw that kind of cherry-picking may have led to some confusion and an uneven playing field among the states in terms of safe compounding expertise and compliance. So we are working hard to redraft our guidelines and get everyone on the same page.” Mr. Van Hassel said he hopes the current pharmacy compounding bill (see related story, page 28) doesn’t work at cross purposes to the proactive steps boards of pharmacy are taking to boost compounding safety. If the Senate version of the bill gets passed, he noted, the section that excludes health systems from some of its provisions could impede action. “Some hospitals may be looking at that exclusion and feeling as though they will get a pass,” he said. “Well, even if the Senate version does get signed into law, nobody gets a pass from USP Chapter <797> when it comes to in-house compounding. And we all need to handle outsourcing of compounding in a responsible fashion. That’s an important safety message that can’t be lost.” —David Bronstein

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28 Policy

Pharmacy Practice News • September 2013

Compounding

Recalls Continue, but Compounding Legislation Stalls

compounding pharmacy in Texas recalled all of its sterile products in August after 15 patients in two hospitals developed bacterial bloodstream infections linked to calcium gluconate infusions made and distributed by the compounder. The voluntary action by Cedar Park, Texas-based Specialty Compounding was the latest of at least four recent national recalls involving pharmacy com-

‘The hope is that [Congress] will have some sort of deal in place by the time [it] returns.’ —Joseph M. Hill pounders or distributors of compounding products. Although relatively minor in comparison to last fall’s fungal meningitis crisis that left more than 60 people dead and in excess of 700 sickened

in 15 states, the newest incidents have increased pressure on Congress to pass legislation giving the FDA the authority to oversee pharmacies that make and distribute bulk-quantity sterile products

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Volu ume 40 • Number 4 • April 2013

Printer-friendly versions available online

in this issue CLINICAL

3 12

Safety, quality pearls: collaboration a key to successs. E-alerts boost venous thromboembolism prevention.

TECHNOLOGY

16 23

Health IT pearls: telepharmacy, smarter IV pumps and more. When the carousel stops: a plan for drug dispensing.

POLICY

IOM urges trackand-trace system for protecting drug supply

OPERATIONS & MGMT

The case against overuse of proton pump inhibitors.

EDUCATIONAL REVIEW

Medication Errors: A Year in Review See insert after page 8.

REPORT Teﬂaro® (ceftaroline fosamil) for the Treatment of Acute Bacterial Skin and Skin Structure Infections Caused by Designated Susceptible Bacteria See insert after page 16.

OIG Says REMS Program Falling Short Of Goals

fter four years, the effectiveness of the FDA’s mandatory Risk Evaluation and Mitigation Strategies (REMS) program remains open to question because drug companies have failed to comply with key reporting requirements and the agency lacks adequate enforcement authority to take action against them, according to a report by the Department of Health and Human Services’ Office of Inspector General (OIG). Nearly one-fourth of the drug companies with medications in the REMS program were found to be in violation of legislatively approved timetables for data reporting, according to the OIG report. Furthermore, less than 15% of the companies had met all of the safety goals stipulated in their products’ REMS. As for the FDA, the agency has reviewed only one of 32 drugs whose REMS contain “elements to assure safe use” (ETASU)—usually reserved

•

ospital pharmacists face several ral challenges in h helping l i manage antibiotic-resistant, gram-negative superbugs that produce carbapen nemases. One of the most worrisome is carba-penemase-producing Klebsiella pneumoniae (KPC). A report in the March issue off Infection Control and Hospital Epiidemiology (2013;34:259-268) foun nd that the proportion of K. pneumon niae cases resistant to carbapenems increa creaased d from 0.1% in 2001 to 4.5% in 2010 0. ““That is huge,” said Robert Rapp, PhaarmD, a professor of pharmacy and sur-gery emeritus at the University of Kentucky Medical Center in Lexington, who is one of manyy pharmacists concerned about KPC C. Those concerns were compound ded by a Centers for Disease Control aand Prevention’s report on the rising prrevalence of carbapenem-resistant en nterobacteriaceae (CRE). According to the h report, in the last decade, hospitals have seen a fourfold increase in CRE, with most of the increase attrib-utable to Klebsiella species (MMWR ( 2013;62:1-6).

•

see REMS, page 24

Addiction Cited As Powerful Diversion Driver

ontrolled substance diversion is a major challenge for hospitals across the country. The problem is being fueled, in part, by the power of addiction: It is estimated that 10% to 15% of health professionals will develop serious substance abuse/addiction problems during their career (Crit Care Med 2007;35:S106-S116). Experts warned during a recent webinar

•

In Ranking of Superbugs, Klebsiella Takes the Lead

see CHALLENGE, page 20

see SUPERBUGS, pag ge 6

Shifting the Main Focus off Acid id Suppression to the Critically Ill Las Vegas—A San Antonio health care system markedly reduced unnecessary use of proton pump inhibitors (PPIs) for stress ulcer prophylaxis (SUP) in the ICU and ended up saving $80,000 annually. At a Boston-area hospital, researchers determined that reducing inappropriate PPI use among general medicine patients could lead to yearly cost avoidance in the neighborhood of $1 million. Both initiatives, presented at the Decem-

ber 2012 Midyear Clinical Meeting of the American Society of Health-System Pharmacists (ASHP), were undertaken to address persistent inappropriate use of PPIs, which has been linked to higher hospital costs and an increased risk for Clostridium difficile infections (sidebar, page 30). “Many of our general medicine patients were on PPIs or H2-receptor agonists constantly, and

•

see STRESS ULCERS, page 30

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See page 19.

See page 27.

without specific patient prescriptions, and often across state lines. In May, the Senate Health, Education, Labor and Pensions (HELP) Committee approved legislation combining its version of an FDA compounding oversight bill (S. 959) with a separate measure that would allow the agency to track and trace prescription drugs through the entire supply chain from manufacturers to end users (S. 957). The Senate left for its August recess without taking action on the bill. The House, on the other hand, had already passed its version of “track-and-trace” legislation (H.R. 1919) in June. Although the Senate and House were both officially out of action through Sept. 9, Joseph M. Hill, the director of Federal Legislative Affairs at the American Society of Health-System Pharmacists (ASHP), told Pharmacy Practice News in August that “conventional wisdom suggests” both bodies “are negotiating right now, and the hope is that they will have some sort of deal in place by the time Congress returns.” Mr. Hill said “the most likely scenario” was that the Senate would vote to pass S. 959 on the floor and send the bill to a conference committee to work out differences with the House legislation. “If the talks are productive,” he added, “we could see this as a done deal” by October or November. He cautioned, however, that “all this is subject to change at a moment’s notice.” The Senate version has the strong support of ASHP. However, in an article posted in the association’s July 30 online magazine Intersections, Paul W. Abramowitz, PharmD, ScD (Hon.), FASHP, CEO, warned that “strong opposition” to the bill was forming “because certain interests want to protect the status quo, which we believe could be at the expense of protecting patients from another compounding tragedy.” He added that “special interests” also were “threatening to severely limit how pharmacists in hospitals and health systems serve and protect patients.” Dr. Abramowitz explained that one key provision in the Senate bill directly concerns the interests of hospital compounding pharmacies. It would exempt hospitals from having to register with the FDA as a compounding manufacturer because they prepare a portion of their sterile medications in advance based on anticipated patient needs rather than specific prescriber orders. “Without this important exemption,” he wrote, “many hospitals would not be able to prepare compounded preparations and send them to their wholly owned outpatient clinics, surgery centers, smaller inpatient facilities and

Policy 29

Pharmacy Practice News • September 2013

Compounding office practices.”

FDA Dragging Its Feet? As the compounding legislation awaited further developments, Public Citizen, the Washington, D.C.-based public health advocacy group, sought to keep safety and regulatory oversight top-ofmind by issuing a critique of how the FDA handled the Specialty Compounding recall. At press time, the group charged that the FDA knew of potentially unsafe drug production practices at the Texas compounder as early as March 2013, when the agency found manufacturing issues during an inspection of the facility. And yet Specialty NEW PRODUCTS Amneal’s Five New Oral Solids

mneal Pharmaceuticals has launched five new oral solid products. They include: • Potassium chloride extended-release capsules, available in 10 mEq K (750 mg) strength in 100, 500 and 1,000 count. Amneal’s generic version of the medication is AB-rated and therapeutically equivalent to the reference-listed drug for Micro-K®10 ExtenCaps® (registered trademarks of Nesher Pharmaceuticals [USA] LLC), the company noted. • Sildenafil tablets, available in 20-mg strength in 90 count. The Amneal generic is AB-rated and therapeutically equivalent to Revatio® (a registered trademark of Pfizer Inc.). • Nevirapine tablets, USP, available in 200 mg strength in 60 count. Amneal’s generic is AB-rated and therapeutically equivalent to Viramune® (a registered trademark of Boehringer Ingelheim Pharmaceuticals, Inc.). • Metaxalone tablets, available in 800mg strength in 100 count. The Amneal generic is AB-rated and therapeutically equivalent to Skelaxin® (a registered trademark of King Pharmaceuticals Research and Development, Inc.). • Warfarin sodium tablets, available in 1-, 2-, 2.5-, 3-, 4-, 5-, 6-, 7.5-, and 10-mg strengths in 100 count. Amneal’s generic is AB-rated and therapeutically equivalent to Coumadin® (a registered trademark of Bristol-Myers Squibb Pharma Company). All five products are now shipping and available through wholesalers, distributors, and directly to the trade, according to the company.

Generic Temozolomide Launch

eva Pharmaceutical Industries Ltd. and Perrigo Company announced the launch of the generic equivalent to Temodar® (temozolomide). Temozolomide is the generic equivalent to Temodar® (Merck) and is indicated for the treatment of adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as maintenance treatment and for refractory anaplastic astrocytoma patients who have experienced disease progression on a drug regimen containing nitrosourea and procarbazine. “The launch of this product provides a quality alternative, making cancer therapy more cost-effective for patients who suffer from this devastating cancer,” the companies stated in a joint press release. Joseph C. Papa, Perrigo’s chairman, president and CEO, said, “This first-to-file launch with our partner Teva is another example of our focus to manufacture complex APIs [active pharmaceutical ingredients]. We are pleased to offer this important product to patients in the United States.”

Compounding didn’t issue its voluntary product recall until Aug. 9, Public Citizen pointed out. “The FDA knew there was a serious problem here, but didn’t use its existing legal authority to take prompt, aggressive action against the company,” Michael Carome, the director of Public Citizen’s Health Research Group, stated in the press release. That delay, he said, “exposed patients to unnecessary risk and might have contributed to 15 people being infected. What’s the purpose of inspecting a facility if you’re not going

to take appropriate action when you find conditions that pose a safety threat to patients?” The FDA was not immediately available to comment on the Public Citizen charges. In addition to August’s Specialty Compounding recall, there have been at least three other recent recalls involving sterile compounded products: • Earlier in August, Nexus Pharmaceuticals of Vernon Hills, Ill., voluntarily recalled two lots of benztropine mesylate, after visible particles were

discovered in product vials. According to the company, the product was manufactured by Allergy Laboratories and distributed by Nexus. • In July, Beacon Hill Medical Pharmacy of Michigan recalled 46 products after the FDA raised questions about their sterility. • Also in July, Fresenius Kabi USA recalled four lots of benztropine mesylate injection, also due to the potential presence of glass particles in the vials. —Bruce and Joan Buckley

30 Operations & Management

Pharmacy Practice News • September 2013

JC Compliance

Getting Ready for Joint Commission Surveys Medication management updates for 2013 Minneapolis—Joint Commission surveys are a fact of life for health care facilities. Whether a hospital is gearing up for a planned audit or wants to stay vigilant in case of an unannounced visit, survey tips from Joint Commission representatives can provide welcome insight to help health care facilities meet the latest standards.

In a presentation during the American Society of Health-System Pharmacists Summer Meeting, Jeannell Mansur, RPh, PharmD, FASHP, the practice leader for medication safety at Joint Commission Resources, and Pat Adamski, RN, MS, MBA, FACHE, the director of standards interpretation at The Joint Commission, reviewed some trouble-

some survey issues for hospitals related to the medication management (MM) standards, and offered some strategies to help improve compliance. “One of the most important standards of the medication order chapter,” Dr. Mansur said, is MM.05.01.01, which requires pharmacist review of all orders for medications to be dispensed

in the hospital. “This is a critical safety net,” she stressed. Some “red flags for surveyors in this area” were related to automated dispensing cabinets (ADCs) and therapeutic duplication. The surveyors look closely at which ADCs are not profiled, as well as at the override process, she said, adding, “We need a best practice on how to review overrides.” Often a pharmacist will review the override, but he or she may not know the nuances of the clinical situation, so nurses may need to be involved in such a review. Element of performance (EP) 7 within that standard, which sets the requirements for reviewing therapeutic duplication, also raised concerns. Specifically, Dr. Mansur pointed out that pharmacists need to make sure the hospital is “not developing order sets that provide options without specific direction” and that allow users to choose multiple duplicate options.

‘We need a best practice on how to review overrides.’ —Jeannell Mansur, RPh, PharmD, FASHP Failure to meet the requirements of MM.05.01.09, regarding labeling of medications, is another area of concern for the Joint Commission. Dr. Mansur said this labeling requirement applies throughout the hospital anywhere drugs can be dispensed, unless they will be given immediately to a patient. She noted further that the label must be fairly comprehensive, including the name, strength, amount if not apparent from the container, expiration date/ time, date prepared, and diluent for compounded IV drugs. Points related to this labeling standard were raised at Kimball Medical Center’s recent Intracycle Monitoring Process (formerly the Periodic Performance Review). Sandra Richardson, PharmD, the director of pharmacy at the Lakewood, N.J., affiliate of Barnabas Health, told Pharmacy Practice News that the elements of this standard were reviewed in detail to ensure that the standard would be met during an actual survey. Labeling problems can be common in areas such as radiology, endoscopy, same-day surgery, etc., that have no direct pharmacy oversight, she said, recommending that pharmacists “be aware of departments outside of pharmacy that handle medications, evaluate all of these outpatient areas, and see what their process is for dispensing and handling medications.” A perpetual MM hot button for

•

see SURVEYS, page 38

Operations & Management 31

Pharmacy Practice News â&#x20AC;˘ September 2013

Reimbursement Matters

Kudos to CMS for Untangling the Billing Unit Web U

sing incorrect billing units for drugs in payment claims to Medicare and Medicaid has escalated to the point that this is one of the key findings during examinations of our billing systems by recovery audit contractors (RACs). So here are a few tips to stay clear of trouble. First, know that very expensive medications are a natural target for RAC audits. There have been so many issues with inappropriate and incorrect billing of rituximab and bevacizumab, for example, that in a recent publication of Medicare Learning Networkâ&#x20AC;&#x2122;s MLN Matters (http://go.cms.gov/19oAlIR / R), these two drugs were used as examples of exactly how to use billing units correctly (Table). As the publication details, there are several key issues to keep in mind. As a starting point, the article noted, be sure to focus on the overall goalâ&#x20AC;&#x201D;to convert the actual dose of a drug ordered for the patient into the number of billing units to be submitted for payment to Medicare or Medicaid. During that process, youâ&#x20AC;&#x2122;ll need to ensure that youâ&#x20AC;&#x2122;re using the assigned billing unit for the product. Sounds simple enough, right? After all, itâ&#x20AC;&#x2122;s just basic arithmetic! So how and where do things go awry? Here are a few potential source for miscalculations: y Your hospitalâ&#x20AC;&#x2122;s billing department is doing the calculations manually, either because there is no computer system in the outpatient areas or, for whatever reason, the system canâ&#x20AC;&#x2122;t be programmed to do the calculations. Or the person(s) doing the calculations are not skilled in performing the conversions. y Rather than using automated â&#x20AC;&#x153;crosswalkâ&#x20AC;? software to do these calculations before the information is sent to the billing system, order entry is being manipulated to accommodate billing units. These order-entry manipulations can lead to medication errors and other problems

if the billing units rather than the dose appear on any clinical documents. y Multiple entries for the same product are being made in the charge description master and/or drug dictionary or pharmacy drug master, or there is a mismatch between the two, as well as inconsistencies in how billing units are assigned to each of these products. y There are multiple ways of acquiring the drug (automated cabinets, infusion center pharmacy, etc.), as well as different computer systems in outpatient clinics vs. the emergency room vs. pharmacy department, etc., resulting in a potential mismatch in the description of a product and its corresponding billing unit. y Thereâ&#x20AC;&#x2122;s no defined strategy for timely input of codes changes, billing unit changes or other updates.

e-Library a Crucial Tool To avoid these types of problems, build an e-library for your pharmacy department that contains timely information on ever-changing reimbursement codes and policies. This will help you untangle the complex web of billing for medications. Hereâ&#x20AC;&#x2122;s a list of tips and resources that you can use to build your e-library: 1. Know your local Medicare Part A or Part B Administrative Contractor (A/B MAC) and how to contact them. There are subtle differences between carriers, so donâ&#x20AC;&#x2122;t depend on a recommendation from a colleague covered by a different MAC. Toll-free MAC numbers can be found at go.cms.gov/13TkopG. 2. Know where to find the list of medications that have National Coverage Determinations (NCDs) and what these are. Use the link at go.cms.gov/13Tl2n9. For example, the NCD for bevacizumab is Document ID: 110.17. A search can be done by drug name or document number. For regional variations in payment poli-

Table. Key Points To Remember When Billing For Rituximab and Bevacizumab

cies, known as local coverage determinations (LCDs), check your MACâ&#x20AC;&#x2122;s website. 3. Look at the long description in Healthcare Common Procedure Coding System (HCPCS) tables to be clear about how to describe a product; the truncated short description may not be sufficient. Find the alphanumeric HCPCS code listings at go.cms.gov/13f6r79. 4. Know what the reimbursement rates for the product are going to be and confirm that the billing units youâ&#x20AC;&#x2122;re using are correct. Use the Medicare Part B Drug Average Sales Price tables that are updated quarterly. There are three tables with each update, one of which lists all the NDC numbers associated with a particular HCPCS code as well as the maximum number of billing units for that product. Visit go.cms.gov/16LuwS1. 5. Past issues of MLN Matters should occupy an important place in your e-library, in part because CMS payment decisions may continue for several years and just be updated for reference purposes. If you missed any of the MLN Matters articles as of June 2007, search the archives at 1.usa.gov/16GyUjg. For some illustrative examples, check out

â&#x20AC;&#x153;Reimbursement Mattersâ&#x20AC;? is a tool for maintaining your health systemâ&#x20AC;&#x2122;s fiscal health. Please email the author at bkirschen@aol.com with suggestions on reimbursement issues that you would like to see covered.

Bonnie Kirschenbaum, MS, FASHP

updates for colorectal cancer chemotherapy at go.cms.gov/13vvqhj; updates for rituximab and carboplatin are at go.cms.gov/19ea7W0. 6. Get started or refresh your understanding of reimbursement with Medicare Reference Manuals: go.cms. gov/13TmUMF and go.cms.gov/144crKH. Someone on your staff may already be on the distribution list for these materials. But, who is that mystery person and does that information get to you in a timely fashion? Since itâ&#x20AC;&#x2122;s your pharmacy budget thatâ&#x20AC;&#x2122;s taking the hit for mistakes that are made, be proactive, get on the distribution mailing lists and have information sent to you directly! â&#x2013;

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Rituximab â&#x20AC;˘ J9310 is defined in the HCPCS manual as: Injection, rituximab, 100 mg â&#x20AC;˘ One (1) unit represents 100 mg of rituximab ordered/administered per patient â&#x20AC;˘ Rituximab should be billed based on units, not the total number of mg -For example, if the quantity administered is 200 mg and the description of the drug code is 100 mg, the units billed should be two (2). Bevacizumab

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32 Operations & Management

Pharmacy Practice News • September 2013

Drug Shortages

SHORTAGES continued from page 1

pharmacist at Johns Hopkins Hospital, in Baltimore. “It’s certainly taken a big chunk of my time over the past three years.” Indeed, many of the systems changes his team makes each day are related to shortages. “I was talking with my boss about the effort we spend to keep our information systems up to date on shortages,” Mr. Burometto said. “That’s when we decided to look back over a year and put some numbers together.”

‘It’s helpful to see published results like this on how to more efficiently manage shortages in the real world. It gives organizations ideas they can copy at their own institutions.’ —Erin Fox, PharmD There were 50 reported drug shortages that required computer systems to be modified, according to a study he presented at the meeting (24-M). Most of the changes involved adding pop-ups and other messaging tools to alert prescribers about short-supply medications. All told,

the staff made 128 systems changes in nine different categories. “I knew we made quite a few system changes,” Mr. Burometto said. “But I didn’t realize it was that many.” The messaging updates ranged from a simple alert stating that a drug was in

short supply, to alerts that actually prevented certain short-supply items from being ordered. “The messages direct prescribers on how to proceed, and when appropriate, suggest alternative medications,” Mr. Burometto explained. “We used to put a note on the item, but physicians would just order it anyway.” In some cases, very extensive programming changes were needed, he noted. “For example, we had to rewrite some of the logic for how total parenteral nutrition orders are processed, because so many of the options available for the additives are in short supply.” Mr. Burometto added that all but six of the 50 shortages required a faster turnaround on software updates than usual. (The normal turnaround time is 14 days.) Some of the shortages were so severe that they required an immediate systems change. Dr. Fox said Mr. Burometto’s informatics research is spot on. “The IT [Information Technology] Department is crucial in managing a shortage. Hospitals have become very automated, with various machinery to track meds. It’s great to have informatics pharmacists on staff who understand the urgency of making changes to the systems.”

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A second study (32-M) presented at ASHP described how Novant Health, a 13-facility hospital system in North Carolina, South Carolina and Virginia, developed a strategy for monitoring and quickly responding to drug shortages. Atiya A. McNeal, PharmD, the pharmacy supervisor at Novant’s Forsyth Medical Center, in Winston-Salem, said her team’s approach has resulted in fewer instances of running out of medications and has reduced the system’s reliance on outside compounding and the use of secondary drug wholesalers. Dr. McNeal outlined how her system works. “There’s a facility-based weekly meeting to assess upcoming shortages, to implement clinical and operational changes, and to develop a back-up plan in case we can’t get a drug and need to think of an alternative,” she noted. This is followed by a weekly corporate conference call with the procurement teams of each facility to coordinate stock. Finally, a weekly communication is sent with shortage information to staff. “It’s time-intensive,” she conceded. “We spend an average of eight hours a week dealing with drug shortages.” All shortage information is maintained in a medication database. “We take counts of our meds every week. For example, there are 187 items currently on our shortage list, ranging from cyclomydrila eye drops to potassium phosphate injections.” “We decided to do the study after we ran out of meds a couple of times,” Dr.

Operations & Management 33

Pharmacy Practice News • September 2013

Drug Shortages 300

McNeal said. “Once when our suppliers couldn’t get tablets of 7.5-mg warfarin, we split 5-mg tablets in half. We had to change the order profile on each patient taking that drug. Of course, it happened at night when we were short staffed.” Dr. McNeal was shocked at the high number of medications affected by shortages: “I thought there might be 50 or so. But I was also pleasantly surprised by how well our plan worked to help alleviate problems.” The initiative “significantly decreased incidences of drugs being completely unavailable,” although hard data on that outcome were not tracked during the study, Dr. McNeal said, explaining that “this was an observational study rather than a quantitative analysis.” Additionally, she said the health system has been weaning itself off outsourcing these short-supply medications, but again, that outcome “was more of an observation” than a quantified study endpoint. That weaning effort, Dr. McNeal added, “started two years ago and we’re still doing it.” A final outcome had to do with staff attitudes toward drug shortages. Once the initiative was in place, Dr. McNeal noted, “there were much less people moaning and groaning that we’re out of something. This led to better staff engagement, better teamwork and improved monitoring of medication stocks.” Dr. Fox said the Novant Health experi-

Drug Shortages

267

250 211 195

200 166 149

150

129 120

100

2005

2006

50 0 2001

2002

2003

2004

2007

2008

2009

2010

2011

2012

Figure. Nationally reported medication shortages in the United States. University of Utah Drug Information Service

ence illustrates how a large system can make just a few improvements to its shortage management strategy and realize a significant difference. “It could nudge folks concerned about how much effort it takes, because it shows how you’re reaping the benefits in the end,” she said. “It proves the more proactive you are, the better you’ll manage a shortage.” —Dana Hawkins-Simons Drs. Fox and McNeal and Mr. Burometto reported no relevant ﬁnancial conﬂicts of interest.

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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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111932 07/13

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

38 Operations & Management

Pharmacy Practice News • September 2013

JC Compliance

SURVEYS continued from page 30

the Joint Commission relates to the storage and security of medications (MM.03.01.01). Dr. Mansur noted that this has been among the top areas on the noncompliance list for MM standards for hospitals for more than a decade. There are several problematic EPs within this standard, including EP 6, which requires that “the hospital prevent unauthorized individuals from obtaining medications ….” Dr.

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Mansur noted that “you can designate who should have access to medications, but you should make sure your practices and policies are consistent.” She also noted that it “is important that access be removed when individuals are no longer part of the organization.” Explaining that she has been on several surveys during which escorts who had changed positions within the facility still had access to ADCs or areas from their previous positions, she stressed, “You need to make sure that process is tight.” Another problematic EP within MM.03.01.01 is EP 2, requiring that “medications are stored according to manufacturer’s recommendations.” Some issues that Dr. Mansur raised are that warming solutions (e.g., for contrast agents) change beyond-use dating (BUD) because manufacturer dates are based on room temperature. At this point, the Joint Commission only accepts manufacturer dating for BUD, noted Dr. Mansur, but she added that she is hoping to “re-ignite” this issue “to have the Joint Commission define its position … in the near future” to, perhaps, allow pharmacies to adhere to requirements other than manufacturer requirements for storage of certain medications. There is also confusion surrounding EP 7, which requires all stored medications to be labeled with an expiration date, said Ms. Adamski. While the manufacturer’s expiration date is based on unopened product, once the vial cap is removed or punctured, the manufacturer expiration date is no longer valid and a revised expiration date is needed. This requires that multidose vials be relabeled with revised expiration dates. This leads to confusion regarding what date is meant when the product is relabeled. Dr. Richardson noted that “the pharmacy department is usually pretty well versed” in dealing with this properly, but she again recommended that facilities look outside the pharmacy at other personnel who might be handling these medications. “If nursing opens a vial, make sure they are dating it with the actual date that the product will expire once opened, which is usually 28 days unless specified by the manufacturer.”

Operations & Management 39

Pharmacy Practice News • September 2013

JC Compliance To assist health care providers with that dating, Ms. Adamski referred to a tool developed by Health Care Logistics that provides expiration dates based on the date the vial was opened (http:// gohcl.com/sites/default/files/pdf/ Multi-Dose-Vial-Chart.pdf ). One new EP within the MM standards for 2013 is MM.04.01.01 EP 15, which relates to standing orders/protocols and order sets. This EP is “putting some rigor into order sets,” Dr. Mansur said. “There is new language about these order sets requiring evidence and nationally recognized information,” she said, adding, “We really want to see some science in the development of those” order sets. The criteria of the new EP also include regular review of the protocols to ensure they continue to be appropriate and relevant for the institution. Another area addressed during the session was confusion surrounding the Sentinel Event Alert (SEA) on the safe use of opioids in hospitals that was published in August 2012 (http://www. jointcommission.org/assets/ 1/ 18/ SEA_49_opioids_8_2_12_final.pdf ). Ms. Adamski stressed that there are several misconceptions about the pain management standard. She said that the Joint Commission does “not require that patients be brought to a pain-free status,” but rather that efforts be made to manage pain. It calls for a comprehensive assessment of the patient and a plan of care. Second, Ms. Adamski also noted that there is no requirement that narcotics or any medication be given to manage pain. She said that medication might be appropriate but that alternative nonpharmacologic therapies and treatment of any underlying diseases also should be considered. Dr. Mansur noted a significant number of opioid-related adverse drug events (ADEs) continue to be reported to the Joint Commission. “There are a lot of dosing errors that are creating harm to our patients,” she said, also pointing to inadequate monitoring, inconsistent conversions and drug interactions as problem areas. Noting that “the solutions that hospitals have in place are not robust enough,” she referred pharmacists to the SEA’s nine evidence-based actions—covering areas including processes, technology, education and training, and tools—that are designed to help prevent opioidrelated ADEs. More specifically, she said that the SEA recommends screening patients for respiratory depression risk, taking a thorough medication history, and using extra caution when treating opioid-naive patients. “The SEA,” she said, “gives you a blueprint to put a strategy in place.” Dr. Richardson suggested that facilities take a close look at the SEA and evaluate their processes. It is critical

‘If nursing opens a vial, make sure they are dating it with the actual date that the product will expire once opened.’ —Sandra Richardson, PharmD that not only pharmacists but also the front-line staff (nurses, physicians) “know what the process is.” This holds true for areas outside the SEA, she noted, pointing out how the Joint Commission surveyor who conducted her recent Intracycle Monitor-

ing Process was “interested in talking to the staff” to ensure they knew the procedures that the facility had put in place to address the various standards and that they are applying those procedures. Dr. Richardson said she takes on the arduous task of “going through the

MM standards each year to see if she meets each element and that it is documented.” That way she knows her target areas for creating new processes to address the standards. But because the Joint Commission is looking beyond the “what” to the “how,” facilities need to show surveyors how those new processes actually work. “They are not only asking questions to see that you have a process,” she said, “but also about how it is implemented.”

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40 Operations & Management

Pharmacy Practice News • September 2013

Crisis Management

THE UNTHINKABLE continued from page 1

“A plan must describe a well-defined process that you can rely on in times of extraordinary stress,” added Elizabeth Ennis, MD, the chief medical officer of Baptist Health System in Birmingham, Ala., who also spoke at the session. “Without one, you decrease your ability to assess the crisis, intervene and resolve it.” A standing crisis management team under the direction of the organization’s chief executive is also an integral com-

‘Truthfulness in disclosure to all affected people is crucial, including patients, families and employees.’ —Elizabeth Ennis, MD ponent, Mr. Federico continued. Ideally, the team can assemble immediately in response to a serious clinical event and members have clearly delineated responsibilities. Team members may include the hospital’s chief medical officer, chief nursing officer, chief public relations officer, legal counsel, an ethicist, a patient

representative and a pastoral care counselor, according to an IHI white paper co-authored by Mr. Federico, “Respectful Management of Serious Clinical Adverse Events” ((bit.ly/14VRdVL). The IHI recommends that, during a crisis, the team check in daily—multiple times if necessary; maintain highly

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disciplined documentation; listen carefully and be prepared to hear things it doesn’t want to hear; expect an inquiry from external accrediting and regulatory agencies; and embrace speed and flexibility. To assess a response plan’s viability, Mr. Federico advised that the team walk through the steps the organization will take for a variety of crisis situations—hypothetical or based on actual events elsewhere. The process provides instant feedback on the hospital’s level of preparation and gaps that need filling. The effectiveness of a crisis response often hinges on putting the well-being of patients and their families first, not the hospital’s image. That means ensuring that the patient is safe or, in the event of a patient’s death, that that family members receive whatever support they need, that they’re heard and that their questions are answered candidly. According to the IHI, a sensitive and open response to a crisis, coupled with deliberate measures to prevent a recurrence, can build good will and enhance a hospital’s standing in the community, even at a time fraught with the potential to cause serious and lasting damage to its reputation. Studies also have shown that such an approach reduces the chances that litigation will be brought against the hospital: As honesty and full disclosure about a serious medical or medication error increase, the risk for a lawsuit decreases ((Front Health Serv Manage 2012;28:13-28).

A Nightmare Scenario

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

In March 2011, the nightmare scenario struck the Baptist Health System—an organization that prided itself on its safety record—when 12 patients at two of its four hospitals in Alabama were infected with Serratia marcescens. Six of the infected patients died. Three more deaths occurred at three other Alabama hospitals. The source of the infection was traced to contaminated batches of total parenteral nutrition (TPN) produced by Meds IV Pharmacy, a Birmingham compounder. The toll could have been much higher had not an infection preventionist at Shelby Baptist Hospital noticed an unusually high number of S. marcescens bacteremia present over just four days. All infected patients had been receiving TPN. Dr. Ennis learned about the events while vacationing in Alaska and returned immediately to join the crisis response in full swing. Before her return, the hospital notified the compounding pharmacy, which contacted all facilities that purchased its TPN solutions. Dr. Ennis asked the pharmacy to sequester all products from the supplier, which included several agents in addition to the TPN solution. “At that point, we still didn’t know where the break in sterility had occurred, and we had to assume that anything from the

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42 Operations & Management

Pharmacy Practice News • September 2013

Crisis Management

THE UNTHINKABLE continued from page 40

compounder could be contaminated,” she said. A joint federal–state investigation found that a faulty filtration process at the compounding pharmacy allowed S. marcescens in tap water to pass into batches of amino acids that were incorporated into the TPN solution. Baptist Health’s crisis response dictated that all relevant individuals within the system be kept current on all developments. “Our CEO was engaged and we kept in constant communication with all of our facilities,” she added. “There are also mechanisms for communication within a single facility, with our board of directors, and with all clinicians involved in a serious adverse event.” In this particular crisis, Dr. Ennis and the system’s chief nursing officer spoke often with patients and family members, she noted.

About 200 U.S. hospitals currently use the Artemis drug dosing and tracking system (above), which employs a variety of visual clues, bar codes and textual prompts to bolster medication safety.

as professional counseling and reassurance that a bad system, not a bad person, caused the crisis.

Focusing on Error Prevention The ability to respond to a crisis quickly and effectively is invaluable. Far more

‘We tend to forget that [hospital staff] are secondary victims and they also carry the burden of an [adverse] event.’ —Frank Federico, RPh Baptist Health learned several valuable lessons as a result of working through the TPN contamination crisis, Dr. Ennis stressed. First and foremost, “Be honest and honorable and it will sustain you through a disaster like this,” she advised. “Be diligent in notifying everyone who needs to know what’s happening, such as the CDC [Centers for Disease Control and Prevention], the state board of pharmacy, hospitals outside of your system—anyone who’s relevant. That can take many, many phone calls, but it has to be done. Truthfulness in disclosure to all affected people is crucial, including patients, families and employees.”

Patients Not the Only Victims Dr. Ennis underscored the importance of addressing the needs of a staffer who unwittingly has a hand in an error that causes patient harm. For exampe, if your facility experiences a TPN error similar to what occurred at Baptist Health, she said, “you can’t forget about the nurse who administered the [infusion].” Indeed, employees often are overlooked in the wake of a crisis. “Patients and family come first, but it’s equally important to ensure that hospital staff are also safe and well cared for,” the IHI’s Mr. Federico said. “We tend to forget that they are secondary victims and they carry the burden of an event.” Staff connected to the events leading to a crisis may feel guilt, anguish and depression and struggle to do their work. That’s a recipe for additional mistakes, and hospitals would do well to offer those who need it support, such

desirable, of course, is to avert crises. That requires a “focus on essential factors and designing systems that prevent errors in the first place,” Mr. Federico said. One prime area where pharmacists can make a difference, he noted, is reducing the number of drugs taken unnecessarily, especially by elderly patients. By one estimate, more than 40% of Americans aged 65 years or older use five or more different medications weekly ((Arch Intern Med 2004;164:1957-1959). Older patients tend to be more sensitive to drug side effects. It’s not uncommon, Mr. Federico said, to hear of elderly patients whose symptoms of dementia and confusion disappeared after they stopped taking certain medications. “Pharmacists can recognize polypharmacy, which I define as ‘more drugs than a patient can handle,’ and point out to prescribers inappropriate medications that are being prescribed.” They also can consider which medications for chronic diseases that, although appropriate for younger patients, will not benefit an older population, he said, adding that the Beers Criteria for Inappropriate Medication Use in Older Adults is a valuable guide for making treatment decisions, Mr. Federico added. Because drugs are the most common intervention in health care, they are frequently a component in errors. Mr. Federico argued that focusing on pharmacists in such cases is misguided because medication errors are hospitall problems, not pharmacy problems, and, therefore, require a hospital-wide response. “Pharmacists can play a vital role when the

medication management system goes wrong, and they’re well placed to take a lead in finding solutions, but they must be supported by a multidisciplinary team,” he said.

A Mathematical Approach To Preventing Drug Errors James Broselow, MD, an emergency room physician and chief medical officer of eBroselow, LLC, has taken a different angle of attack against medication errors, endeavoring to “take the math” out of medicine. Dr. Broselow is the latest recipient of the Institute for Safe Medication Practices Lifetime Achievement Award. He is best known for developing the Broselow Tape, which greatly reduces the need for practitioners to make treatment calculations (e.g., drug doses, equipment size and defibrillator voltage) while they are contending with the intense pressure of pediatric emergencies. A similar arithmetical quandary underlies many medication errors, Dr. Broselow noted during the ASHP session. Computations are constantly in play when drugs are manipulated in the hospital: diluting IV agents, dose conversions, metric conversions, reconstituting powders, figuring a dose based on patient weight, to name a few. According to one study, 80% of 10-fold dosing errors go unrecognized, and more than one-third of drug dilutions are done improperly ((J Patient Saff 2009;5:79-85). “I don’t think we realize how much time and effort is spent on math,” he said. And whereas computerized prescriber order entry helps reduce prescribing errors, it doesn’t address mistakes related to drug preparation and administration. Dr. Broselow asserted that such failures are responsible for 40% of medication errors. So he developed a web-based system, called Artemis, which is designed to reduce that number, particularly in acute care settings. Artemis merges the parameters of the physician’s order with a bar-code scan of the drug vial to produce standardized and precise information about how to mix and administer the medication. Administration guidelines, pump settings and warnings also are dis-

played further along in the medication management process when a clinician scans the bar code applied to the final preparation. “The goal is to standardize and automate the entire process,” explained Dr. Broselow. “After all, alerts are helpful, but it’s best not to make the mistake in the first place.” Artemis is available commercially (bit.ly/14lX30a) and is being used in more than 200 hospitals, primarily in the United States, Dr. Broselow noted via email. He declined to give specific information regarding pricing, but said the system would be “inexpensive for a hospital; it usually doesn’t need to be a budgeted item.” Natasha Nicol, PharmD, the director of medication safety for Cardinal Health, which organized and moderated the seminar, said Dr. Broselow’s system “removes many complex calculations needed to prepare compounded drugs, and it removes the need for people to remember things. We need more solutions like that.” Among Dr. Nicol’s goals was to make the audience recognize the astounding complexity of many health care processes and understand that many of the processes are broken. Flaws in our health networks are inevitable because every component, every system and subsystem, is designed and implemented by fallible humans, “but we continue to be too complacent about how things work in health care,” she said. “We continue to accept the situation because we were trained that this is the way things are. That attitude has to change. Sometimes, we make it so complex and so difficult to do the right thing that it’s really a wonder we get anything at all done correctly. I hope the seminar opened people’s eyes and expanded their imaginations so they see that these systems can be simpler, and by simplifying them, we make them safer.” —Steve Frandzel Drs. Ennis and Nicol and Mr. Federico reported no relevant ﬁnancial conﬂicts of interest. Dr. Broselow is the founder of eBroselow, which markets the Artemis drug dosing and tracking system.

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. 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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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Concomitant Medication: $GYLVH SDWLHQWV WR LQIRUP WKHLU SK\VLFLDQ LI WKH\ DUH WDNLQJ RU SODQ WR WDNH DQ\ SUHVFULSWLRQ RU RYHU WKH U counter drugs since there is a potential for interactions.Strong and Moderate CYP 3A inhibitors and P-gp inhibitors: $GYLVH SDWLHQWV WR LQIRUP WKHLU SK\VLFLDQ LI WKH\ XVH VWURQJ H J NHWRFRQD]ROH LWUDFRQD]ROH FODULWKURP\FLQ WHOLWKURP\FLQ QHOÂ¿QDYLU VDTXLQDYLU LQGLQDYLU ULWRQDYLU RU PRGHUDWH &<3 $ LQKLELWRUV H J DSUHSLWDQW HU\WKURP\FLQ GLOWLD]HP YHUDSDPLO Ã&#x20AC;XFRQD]RO RU 3 JS LQKLELWRUV (e.g., cyclosporine) [see Dosage and Administration (2.3), Contraindications (4.4), Warnings and Precautions (5.5) and Drug Interactions (7.1)]. 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

Compatibility of

Commonly Used IV Drugs LISA CAYO, PHARMD Clinical Pharmacy Coordinator Garden City Hospital Garden City, Michigan

he number of available IV medications continues to expand. Many institutions have observed an increase in patient acuity and a rise in the number of medications

administered to each patient. This increases the likelihood that multiple IV medications will need to be administered concurrently.

These factors contribute to the escalating complexity of IV drug administration and have resulted in an ever-increasing number of possible incompatibilities. The potential for serious and life-threatening adverse drug events exists when incompatible medications are infused together. Therefore, it is important to verify drug compatibility prior to coadministration. A clear and concise compatibility chart can be a useful tool in helping to deliver safe, high-quality IV therapy to patients. A chance of incompatibility exists whenever any

medication is combined or added to an IV fluid. It is important to recognize that compatibility is not just a function of the drugs themselves, but also can be dependent on a variety of factors including the concentration, temperature, storage vehicle, infusion solution, order of mixing, and administration technique. Compatibility differences even have been reported for different brands of the same drug. Three types of incompatibilities are commonly discussed: physical, chemical, and therapeutic. Physical Text continues on page 8

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

P H A R M AC Y P R AC T I C E N E WS â&#x20AC;˘ S E P T E M B E R 2 0 1 3

Amiodarone

N C

Ampicillin

C N N

Ampicillin-sulbactam

Anidulafungin

C C C C C

Argatroban

C C N C C C

Atracurium

C C C N N C C

Azithromycin

C N

Dextrose 5% in water

Dexmedetomidine

Dexamethasone

N C

Daptomycin

Cisatracurium

Clindamycin

Ciprofloxacin

Ceftriaxone

Ceftizoxime

Ceftazidime

C C C C C C

Ceftaroline

Cefoxitin

Cefotaxime

C C C N C

Cefazolin

Cefepime

Caspofungin

Calcium gluconate

Bumetanide

Bivalirudin

(Acyclovir through Dextrose 5% in water)

Aztreonam

Azithromycin

C C C C

Amikacin

Atracurium

Argatroban

Anidulafungin

Ampicillin

Amiodarone

C N C

Ampicillin-sulbactam

Acyclovir

Amikacin

Acyclovir

Table. Compatibility of Selected IV Drugs

C C C Acyclovir

C N N C C C N C C C C C C H C C C C C C N C C C C C C Amikacin

N I

C N C

C C C C C C N C N Amiodarone

N N N N N N N N N N S

C C N C N C N N

N C N N N N N N

C N C

Ampicillin

N N C N C A Ampicillin-sulbactam

C C C C C C C C C C C C N C C C C C C N C C C Anidulafungin C C C C C C C C

C C N C C C C C C C C C C Argatroban

C C C C C C C N C C N

C C C C C

C C C N C C C C C Atracurium

N C C C N C C N C C N C N N C N C C C C Azithromycin

Aztreonam

Bivalirudin

C C

C N N N C C C N

Bumetanide

C C C N N C C C C C C

C C C N N N N C

N C C N C N C N N

C C C C C C C C N C C C C C C C C C C Aztreonam

C C C C C C C

C C

C C C C N C C C C C C C C C C Bivalirudin

C C C C C C C C C C N C C C C C C Bumetanide

Calcium gluconate

C C C N N C C C C C C C

Caspofungin

N C C

Cefazolin

C C N N N C C C C C C C C

Cefepime

N C C C C C

Cefotaxime

C C N N N C C C N C C C C

Cefoxitin

C C N N N C C C C C C C C

C N C

Ceftaroline

C C C N N N N N C N N C C

N N N N

Ceftazidime

C C

C N

Ceftizoxime

C C C N N C C C C C C C C C C N

Ceftriaxone

C C C N N C C C N C C C

Ciprofloxacin

Cisatracurium

N C C N N C C N C C C C C C N N N N C N N C C

Clindamycin

C C C

Daptomycin

Dexamethasone

C C N N N C C C C C C C

Dexmedetomidine

C C C C C C C C C C C C C C C C C C N C C C C C C C C

D5W

C C N

Diltiazem

N C C N N C C C C C C C C C C

Diphenhydramine

N C N

N C C C C N C C C C

Dobutamine

C C

N C C C C C N N N C

Dopamine

C C

N C C C C C C C C C

Doripenem

C C C N N C N N C N N C C C N N N N C N N N C N N C C N C Doripenem

Doxycycline

C C C

Enalaprilat

C C N N N C C C C C C C C

Epinephrine

C C N N C C C C C C C C C C N C C N C C C N C C C C C C Epinephrine

Eptifibatide

C N C C C C C C C C C C N C C C C N C C C C C C C C N N Eptifibatide

Esmolol

C C N N C C C C C C C C C C N C C N C C C N C C C

Famotidine

C C C N N C C C N C C C C C N

C C C N C

H N N C C

N N C C

N C N

C C C C C C C C

C C

N C C C C I

A C C C

C C Calcium gluconate

C C

C N C C C N N C C C C C Cefazolin

N N N N N N N

C N

A C C C C C C C C

I I

C C C C C C C C C I

Caspofungin

N C C C C C Cefepime

C N N C C C C C Cefotaxime

N C

C N N C C C C C Cefoxitin

N N N C C C N C N C Ceftaroline C C C N C C C C C Ceftazidime

N C

C N N C C C C C Ceftizoxime N C

C C C C Ceftriaxone

N N C C N N

C C C C C C C

C C C C C C C C

C C Ciprofloxacin

C C C C C Cisatracurium C

C C C C Clindamycin

C C C C N C C C C C C C C C C C C N C C C C C C I

C N C C N C C

C C C N C C N A C N

S N C C C N C C C C

C C

C C C

C C C C C C C C C C C

Daptomycin

C C Dexamethasone C Dexmedetomidine

C C

D5W

C C C C C C C C C C C C C Diltiazem

C C C C

C C Diphenhydramine

N N C

C C C C

C C Dobutamine

N C C C C C C C C C C C C C Dopamine

N C

C N C C C

C C Doxycycline

C C C C C C N C C C C C C Enalaprilat

C C Esmolol

C N C C N N N C C C C C C Famotidine

KEY A = Physically compatible for at least 2 hours

H = Physically compatible for at least 1 hour

C = Physically compatible

I = Incompatible

D = Physically compatible in dextrose 5% in water

N = Information on compatibility is not available or not adequate

E = Physically compatible for at least 5 minutes

R = Physically compatible for 24 hours under refrigeration

G = Physically compatible in glass bottle only

S = Physically compatible in 0.9% sodium chloride

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

Dextrose 5% in water

Dexmedetomidine

Dexamethasone

Daptomycin

Clindamycin

Cisatracurium

Ciprofloxacin

Ceftriaxone

Ceftizoxime

Ceftazidime

Ceftaroline

Cefoxitin

Cefotaxime

Cefepime

(Acyclovir through Dextrose 5% in water)

Cefazolin

Caspofungin

Calcium gluconate

Bumetanide

Bivalirudin

Aztreonam

Azithromycin

Atracurium

Argatroban

Anidulafungin

Ampicillin-sulbactam

Ampicillin

Amiodarone

Amikacin

Acyclovir

Table. Compatibility of Selected IV Drugs

Fentanyl

C C N N N C C C N C C C C C C N C C C C C C N C C C C C C Fentanyl

Fluconazole

C C C

Furosemide

C C N S N C C

Gentamicin

N C C

Heparin

S N C C N C C C C C

Hydrocortisone

C C N N

Hydromorphone

C C N N C C C C C C C C C C N C C C C C C C C C C C C C C Hydromorphone

Imipenem-cilastatin

C C

Insulin, regular

C N C N N C C N N C C C C C C H C

Labetalol

C C N N C C C C C C C C C N N

Levofloxacin

Linezolid

C C C C C C C C C C C C C C C C C C N C C N C C C C C C C Linezolid

Lorazepam

C C C

Magnesium sulfate

C C N N N

C C C C C C N C N

C C N C C

Mannitol

C C N C N C C C C C C C C C C

C C C C C C N C C C C C N Mannitol

Meropenem

N N N N N C C N C N C N N C N N N N N N N N N N N C C C

Methylprednisolone

C C C N

Metoclopramide

N C N N N C C C C C C C C C C

Metronidazole

C C C C C C C C C

Micafungin

N N

C C

N C C C C C C C N C C C N C C N C N C C N C C C C Fluconazole I

N C C C C

C C C C C C C C

C C Gentamicin

N C C C C C Heparin

C C C C C C C N C C C C C C C C C

C C C C C C Hydrocortisone

C C C C I

N C C

C N

C C C C N C C C C C C Levofloxacin

C C

N N N C

C C Labetalol

C C I

C C C C

C C C

Meropenem

C C C C C C C C C C C C C Metoclopramide

C C N Metronidazole

N N N N C Micafungin

C C C

N C C N N C C C N C C C C C C N C C C C C C N C C C C C C Morphine sulfate I

C C Magnesium sulfate

N C C C C N Methylprednisolone

C C C N C C C C C C C C C C C

C C N C C C

Morphine sulfate

C C N Imipenem-cilastatin

Midazolam

C C

C C C

C C C C N N C C C C C Insulin, regular

C C C N C C C C C C C C C C C C C C N Lorazepam

C C C C C C C I

N N N N N N N N C C N N N N N N N N N N I

C C C C C N C C C C C

N C C C C C Furosemide

C C C C C C C C

N N C C C N N C C N C C C C C N C C

N C C C N C C C C C N N N C C N C N C C C C

C C C C N C

Nicardipine

Nitroglycerin

C C C N N C C C C C C C C C C N C C N C C C N C C

C C C C C C N C C N N C N C C N C I

I I

C C Midazolam C C Nicardipine

C C G Nitroglycerin

Nitroprussidea

Norepinephrine

N C N N N C C C N C C C C C C N C C C C C C C C C C C C C Norepinephrine

Octreotide

C C C C C C C C C C C C C C C C C C N C C C C C C C C C C Octreotide

C N N N C C N C C C C C

C N C C N

C C C C C C C C C C

C C N N C C C C C Nitroprussidea

Ondansetron

C N

Palonosetron

C C C C C C C C C C C C C C C C C N C C C C C C C C C C Palonosetron

Pantoprazoleb

N N N C C C C

Penicillin G

C C C C N N N C N C N C C N C N C C N C C C N N C N C N C Penicillin G

Phenylephrine

Phenytoin

Piperacillin-tazobactam

N N C C N N C C C C

N C N N N N N N

N C C C C C Piperacillin-tazobactam

Potassium chloride

C C C N N C C C N C C C C C C C C C C C C C C C C C C C C Potassium chloride

N C N N N

C C C N C N C C C C C C C Ondansetron I

N C N C C

C Pantoprazoleb

C C N N C C C C C C C C C C N C C N C C C N C C C C C C Phenylephrine I

Phenytoin

N N N

N N C N C C Potassium phosphate

N C N N N N N C N C C N C N C C C N C C

N C N C C C Propofol

Ringerâ&#x20AC;&#x2122;s, lactated

C C N N R N C

C C N C C C C N C C C C C

Sodium bicarbonate

C C

C C C C

Sodium chloride 0.9%

C C N C C C C C C C C C C C C C C C C C C C C C C C C C C Sodium chloride 0.9%

C C

C C N N C C C C C C C C C C

C C C C

N C C C C C Sodium bicarbonate

C C N C C Ringerâ&#x20AC;&#x2122;s, lactated

Tacrolimus

Tigecycline

C C

Tobramycin

C C C N N C C C N C C C C C N N C C C C C

C C N C

TMP-SMX

N N

Vancomycin

C C C N N C C C C N

Vasopressin

C C C N N C C C C C C C C C C C C C C C C C C C C C C C N Vasopressin

I N

N N N N

C N C N C N N

Propofol

Potassium phosphate

N N

C C N C C C C C C C C C N Tacrolimus

C C N C C C C C C C C C C C C N C C C C C C C C C C Tigecycline I

C C N C N C I

C C Tobramycin

C N TMP-SMX

C C C N N N N N N N N N C C

N C C Vancomycin

Vecuronium

C C C C C C N C C C C C C C

Voriconazole

C C C C C C C N C C C C C C C

C C C C C C C C C C C C C Voriconazole

C N C C C C N C C C C C Vecuronium

Protect from light. b Testing was performed with ethylenediaminetetra-acetic acid (EDTA)-free formulation.

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

Metoclopramide

Methylprednisolone

Magnesium sulfate

C C C C N C N Acyclovir

Meropenem

Mannitol

Lorazepam

Linezolid

C C C C C C C C C C C C C C C

Levofloxacin

N N

Amikacin

Labetalol

Insulin, regular

Imipenem-cilastatin

Hydromorphone

Hydrocortisone sod. succ.

C C C C N C C C C C

Acyclovir

Heparin

Gentamicin

Furosemide

Famotidine

Fluconazole

Esmolol

Fentanyl

Eptifibatide

C C C

(Diltiazem through Metoclopramide)

Epinephrine

Doripenem

Enalaprilat

Dopamine

Doxycycline

Dobutamine

Diphenhydramine

Diltiazem

Table. Compatibility of Selected IV Drugs

C C C N C C C C C C N C C Amikacin N N

Amiodarone

C N C C C C N C N C C N C N C

Ampicillin

N N C N N N

S N N N N N C C

Ampicillin-sulbactam

N N N N N

N N C N N N N N N N

Anidulafungin

C C C C C C C C C C C C C C C C C C C C C C C C

Argatroban

C C C C N C C C C C C C C C C C C C C C C C C C C C C C C Argatroban

Atracurium

C C C C N C C C C C C C C

Azithromycin

C C C C C C C C C C N N C N N C C C N N C N C C C C C C C Azithromycin

Aztreonam

C N C C N C C C C C C C C C C C C C N C C C C

Bivalirudin

C C N C N C C C C C C C C C C C C C C C C C C C C C C C C Bivalirudin

Bumetanide

C C N C C C C C C C C C C C C C C C C C C C C C C C N C C Bumetanide

C C

C C N N N C N Amiodarone

C N N N C C

N C N N N Ampicillin

N N N I

N Ampicillin-sulbactam

C C C C Anidulafungin

C N C C C N C C C C C C N C C Atracurium I

C C N C C Aztreonam

Calcium gluconate

C C N C C C C C C C C C N C C C N C N C C C C C N C N

C Calcium gluconate

Caspofungin

C C C C C C

C Caspofungin

Cefazolin

C C C C N C C C N C C N C C N

Cefepime

N N N N

Cefotaxime

C N C C C C C C C N C N C C C C C

Cefoxitin

C N

Ceftaroline

C C N C C N C N N N C C C C C C C C N C

N C N

C C C C C C C N C C C I

C C N C N C C Cefazolin

N C C N C C C C H N C C C

C C C C N C C C C C C C C

N C

Cefepime

N C C C C N

C Cefotaxime

C Cefoxitin

C N C N C N C C Ceftaroline

C C C C N

Ceftazidime

N C N

C C C C C C N C N C C C C C C C C C C C N C C Ceftazidime

Ceftizoxime

C C C C N

C C C C N C C C C C C C C C C C C C C C N C C Ceftizoxime

Ceftriaxone

Ciprofloxacin

C C C C C N N N C N N N C

Cisatracurium

C C C C N C C C C C C C C N C N C C C N N C C C C C N N C Cisatracurium

Clindamycin

C C C C N C C C C C C C N C C C C C C C N C C C C C N C C Clindamycin

Daptomycin

C C C C C C C C C C C C C C C C C C

Dexamethasone

Dexmedetomidine

C C C C N C C C N C C C C C C C C C C C C C C C C C C C C Dexmedetomidine

D5W

C C C C C C C C N C C C C C C C C C N C C C C N C N

Diltiazem

C N C C C C

C N C C C C C N C N C N C C C

C C

C C C

C C C C

C N C

C N C C Ceftriaxone

C N N N N C C

N N

C Ciprofloxacin

C C C C C C C C C C Daptomycin

C C C C C

C C C

C C C C Dexamethasone I

N C D5W

C C C C C C C C C C C C

C N N C C N C C C C C C C N C Diltiazem

C C C C C C C C C C C

C N N C C

Diphenhydramine

Dobutamine

C C

Dopamine

C C C

Doripenem

C C C C

Doxycycline

C C C C N

Enalaprilat

C C C C C C

Epinephrine

C C C C N C C

Eptifibatide

C C C C N C C C

Esmolol

C C C C C C C C C

Famotidine

C C C C C C C C C C

C C C C C C C C C C N C N

C C C C C C C

C Diphenhydramine

C N N C C C C N C C C C Dobutamine

C C C C C C C C C N C C C C C N C C C C C C C C C Dopamine N C N N C C C C C C C C C N C C C C C C C N C C Doripenem C C C C C C C

C C C C C C C C C N

C Doxycycline

C C C C C C C C C C C C C C C C C C C C C C Enalaprilat C C C C C C C C C C C N C C C C C C N C C Epinephrine C C C C

C C C C C N C C C C C C C C C Eptifibatide

C C C

C C N C C C C C C C C C N N C Esmolol

C C N C C C C C N C C C C C C N C C Famotidine

KEY A = Physically compatible for at least 2 hours

H = Physically compatible for at least 1 hour

C = Physically compatible

I = Incompatible

D = Physically compatible in dextrose 5% in water

N = Information on compatibility is not available or not adequate

E = Physically compatible for at least 5 minutes

R = Physically compatible for 24 hours under refrigeration

G = Physically compatible in glass bottle only

S = Physically compatible in 0.9% sodium chloride

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

Fentanyl

C C C C C C C C C C C

Fluconazole

C C C C C C C C C C C C

Furosemide

Gentamicin

C C C C C C C C C C C C C

Heparin

N N N C C

C C C C C C C C

Hydrocortisone

N N

C C C N C C C C N N

Hydromorphone

C C C C C C C C C C C C C C C C C

Imipenem-cilastatin

C C N C N C C C C C C C N C C C C C

Insulin, regular

Labetalol

C C C C C C C C C C C C C N C N

Levofloxacin

C C C C C C C C C C C C C

C C C N C

Linezolid

C C C C C C C C C C C C C C C C C C C C C C

Lorazepam

C C C C C C C C C C C C C C C C C C

Magnesium sulfate

C C N C C C C C C C C C C N C C N C C C C N C C

Mannitol

C C C C C C C C C C C C C C C C C C

N N C

C C

Metoclopramide

Methylprednisolone

Meropenem

Mannitol

Magnesium sulfate

Lorazepam

Linezolid

Levofloxacin

Labetalol

Insulin, regular

Imipenem-cilastatin

Hydromorphone

Hydrocortisone sod. succ.

Heparin

(Diltiazem through Metoclopramide)

Gentamicin

Furosemide

Fluconazole

Fentanyl

Famotidine

Esmolol

Eptifibatide

Epinephrine

Enalaprilat

Doxycycline

Doripenem

Dopamine

Dobutamine

Diphenhydramine

Diltiazem

Table. Compatibility of Selected IV Drugs

C C C C C C C C C C C C C C N C C Fentanyl N C C C C N C C C C C C C C C C Fluconazole

N C N

C C C C N N

I I

N C C C N C C C

C C N C C C N Furosemide

C C C C C N C Heparin

C C C N C N N C Hydrocortisone

C C C C C C C C C C C Hydromorphone C C C C

N N C C C N N C N C C N N C C C C I

N C C N C C C C C C C C C Gentamicin

C C

I I

N C C Imipenem-cilastatin

N C C C C C C C Insulin, regular C C C C C N C C Labetalol C N N C N C C Levofloxacin C C C C C C Linezolid

C C N C

C C C C C Lorazepam C C

C C C C C C

C Magnesium sulfate

C C Mannitol

Meropenem

C C C C N N C N C N N N C C C C N C N C N N C C C

Methylprednisolone

C N

Metoclopramide

C C C C C C C C C C C C C N C C C C C C C C C C C C C C

Metronidazole

C C C C C C C C C C C C C C C C C C C C C C C C C C C C C Metronidazole

C C C

C C C N C C C C C N N C C C C C C C

C C N N

C C N N N C N C N C N

Metoclopramide

Morphine sulfate

C C C C C C C C C C C C C N C N C C C N C C C C C C C C C Morphine sulfate

Nicardipine

C C C C N C C C C C C C C

Nitroglycerin

C C C C N C C C C C C C C N C C C C C C C

C C C C N C C Nitroglycerin

Nitroprussidea

C C C C N C C Nitroprussidea

Norepinephrine

C C C C C C C C N C C C C N C C C C C N C N C C C C C C C Norepinephrine

Octreotide

C C C C N C C C C C C C C C C C C C C C C C C C C C C C C Octreotide

Ondansetron

C C C C C C C C C C C C C

Palonosetron

C C C C N

N C C N N N N Micafungin

C C N C N N C C C C C C N N C Midazolam C N C C

N C C C N C C

N C N C C C C C C C C C C C C C N C C

C Methylprednisolone

C C N C C C C C C C C C C

N C Meropenem

Midazolam

Micafungin

C C C C C N C C C

C C C C C C C C C C C C

C C Nicardipine

C C N N C Ondansetron

C C C C C C C C N C Palonosetron

Pantoprazoleb

N C C N N N

Penicillin G

C C

C N

Phenylephrine

C C C C C C C C C C C C C N C C C C C

C C C C C C N C C Phenylephrine

Phenytoin

Piperacillin-tazobactam I

C N

C C C C

C C C N C C C N

C C C C N C C Piperacillin-tazobactam

Potassium chloride

N N N N N C N

N N

N Pantoprazoleb

C C N C C C C C C C C C C C N C N N C C N C C Penicillin G I

N N I

Phenytoin

C C C C C C C C C C C C C C C C C C N C C C C C C C N N C Potassium chloride

Potassium phosphate

C N

N C N C C C N N N N N N C N N C N C

Propofol

N C N N

C C N N C C C C C

Ringerâ&#x20AC;&#x2122;s, lactated

N C C C N N N C N C C C C C C N C C

N C N C N C N

N C Ringerâ&#x20AC;&#x2122;s, lactated

Sodium bicarbonate

C N C C C C C

C C Sodium bicarbonate

C C C C C C

C C C C C C C C C

N N N N C Potassium phosphate

N C N C N

Propofol

Sodium chloride 0.9% C C C C C C C C N C C C C C C C C C R N C C C N C N R C C Sodium chloride 0.9% Tacrolimus

C C C C C C C C N C C C C N C C C C C C C C C C C C C C C Tacrolimus

Tigecycline

C C C C C N C C C C C C C C C C C C C C C C C C C C C N C Tigecycline

Tobramycin

C C C C C C C C C C C C C C C

TMP-SMX

Vancomycin

C C C C C C C C C C C C C

N C N C C C C C C C C N C Vancomycin

Vasopressin

C C C C N C C C N C C C C N C C C C C N C C C C C C C C C Vasopressin

Vecuronium

C C C C N C C C C C C C C

Voriconazole

C C C C C C C C N C C C C C C C C N C C C C C C C C C C C Voriconazole

C N

N C C N C C C C C C N C C Tobramycin C

C C C C

N C N C N

C C C C C C C C

TMP-SMX

C Vecuronium

Protect from light. b Testing was performed with ethylenediaminetetra-acetic acid (EDTA)-free formulation.

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

C C C N

N N N C N

C N C N

N N C C Ampicillin

Ampicillin-sulbactam

C N

N N N C

C C N N

N N N N R N C N C N

N N C C Ampicillin-sulbactam

Anidulafungin

C N C C C C C C C C C C N C

C C

Argatroban

C N C C C C C C C C C C N C

C C C N C C C C C C C C C C C Argatroban

Atracurium

C N C C C C N C C C C

C C

N C N N

Azithromycin

C N

C C N C C C C N C

N N C N C C C C C N C C C C C Azithromycin

C C C C C

N N I

I I

TMP-SMX

Pantoprazoleb

C C C C C C

C Acyclovir

C C C C Amikacin

C N C C C C Amiodarone

C C N C C C C C C Anidulafungin C C C C N C C N N Atracurium

Aztreonam

C C

C C N C C C C C C C N N C C C Aztreonam

Bivalirudin

C N C C C C C C C C C N N C

C C C N N C C C C C C

Bumetanide

C C N C C C C C C C C C C C

C C N C C C C C C C

C C C C Bumetanide

Calcium gluconate

C C C C C C C C C C C N C C

C C N C C

C C C C

C C C C Calcium gluconate

Caspofungin

N N C C C C

C C C C N N C

C C C C

C C C C Caspofungin

Cefazolin

C N C C C C C C C C C N C C

N C N C C C C C C N

N C C C Cefazolin

Cefepime

C N

N N

C C N N N C C

Cefotaxime

C N C C C C C C C C C

C C

N C N C C

C C C C

N C

Cefoxitin

C N C C C C C C C C C N C C

N C N C C

C C C C

N C C C Cefoxitin

Ceftaroline

C N C C N N N C N C N C N N N N C

Ceftazidime

C N

C C N C N C C

N C N N C C C C C C

N C C C Ceftazidime

Ceftizoxime

C N C C C C C C C C C C C C

N C N C C C C C C C

N C C C Ceftizoxime

Ceftriaxone

C N C C N C C C C N C C C C

N C N C

C C C C

N C C C Ceftriaxone

Ciprofloxacin

C N C N C N N C C C C

N N

Cisatracurium

N C N N C N N

N C C C C N C C N C Cisatracurium

Clindamycin

C N N C N C C C C C C N C C

C C N C C C C C C N

Daptomycin

Dexamethasone

C N

N N N N N C

C N C

C C C C N C C C C

N C C C

N C

C C C Bivalirudin

C N C N C

C Cefotaxime

Cefepime

C C C C N N C C N C N C Ceftaroline

C C C C N N C C C Ciprofloxacin I

C C C C Clindamycin

C C C C C

N C

C C C N C C C C C C C

C C C C C C

C C

C C N C N C C C C

N C C C Dexamethasone

Dexmedetomidine

C N C C C C C C C C C

N C

C C C C C C C C C C C C C C C Dexmedetomidine

D5W

N C C C C G C C C C C C C C

C C C C C C C N C C N C N C C D5W

Diltiazem

Diphenhydramine

C N C C C C

Dobutamine

Tigecycline

Palonosetron

N C C C C C C C C C

Tacrolimus

Ondansetron

Octreotide

N C

Voriconazole

N C

N N N C

Vecuronium

Vasopressin

N N

N C

Vancomycin

Tobramycin

Propofol

C C C C N N C N C N C C N

C N

Sodium chloride 0.9%

Potassium phosphate

Ampicillin

Sodium bicarbonate

Potassium chloride

Amiodarone

Ringerâ&#x20AC;&#x2122;s, lactated

Piperacillin-tazobactam

Penicillin G Potassium

C C C C

Norepinephrine

Nitroprussidea

C C N

Nitroglycerin

Nicardipine

Morphine sulfate

C N C C C C C C C C C N C C

Midazolam

C N

Amikacin

Micafungin

Acyclovir

Metronidazole

Phenytoin

(Metronidazole through Voriconazole)

Phenylephrine

Table. Compatibility of Selected IV Drugs

C C C Daptomycin

C C

C C C C

C C

C C N C C

C C C C

C C C C Diphenhydramine

N C C C N C C C C

N C

C C C C

C C C C Dobutamine

Dopamine

C C C C C C C C C C C N C C

C C N N C

C C C C

C C C C Dopamine

Doripenem

C C C C N N N C N C N C N C N N C

Doxycycline

C N C C C C C C C C

Enalaprilat

C N C C C C C C C C C N C C

C C C C N C C C C C N C C C C Enalaprilat

Epinephrine

C C C C C C C C C N C C

C C N N C

Eptifibatide

C C C C C C C N C C C N N C

C C C N N C N N C C C C N C N Eptifibatide

Esmolol

C C C C C C C C C C C

C C N C C C C C C C C C C N C C C C Esmolol

Famotidine

C N C C C C C C C C C

C C N

C C C C C C C C C

C C N N N C C C C C C C C C Diltiazem C

I I

N C C C C C N C N N C Doripenem

C N C N

I I

C C N C C C C C

C C C C C C C C C

I I

C C C C Doxycycline C C C C Epinephrine

C C C C Famotidine

KEY A = Physically compatible for at least 2 hours

H = Physically compatible for at least 1 hour

C = Physically compatible

I = Incompatible

D = Physically compatible in dextrose 5% in water

N = Information on compatibility is not available or not adequate

E = Physically compatible for at least 5 minutes

R = Physically compatible for 24 hours under refrigeration

G = Physically compatible in glass bottle only

S = Physically compatible in 0.9% sodium chloride

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

C C N C N C C C C

C C N C C C C C C N

N C C C Hydrocortisone

Hydromorphone

C C C C C C C C C C C N C C

C C C C C

C C C C C C C C N Hydromorphone

Imipenem-cilastatin

C N N C

N N N C

R C C C

N C

Insulin, regular

N N N C C N C N C N C

C N C N C N C C N

C N C C Insulin, regular

Labetalol

C C C C C C C C C

N C

C C C C N C C C C N C C C C Labetalol

Levofloxacin

C C C

N C C C

C C

C N

Linezolid

C N C C C C C C C C C

N C

C C C N C C C C C C N C C C C Linezolid

Lorazepam

C C C C N C C C C

N C

C C

Magnesium sulfate

C C C C C C C C C C C N C C

C C N N C C C C C C N C C C C Magnesium sulfate

Mannitol

C N C C C C C C C C C N C C

C C N C N C N C C C

Meropenem

C N N C

N N C C N C

N N N N N N N

Methylprednisolone

C N N C C C C C C N N

C C

C N N

N C C C N C

N C

Metoclopramide

C N C C C C C C C C C N C C

C C C

C C C C C C

C C C C Metoclopramide

N C N C C C C C C C C Metronidazole

Metronidazole

C N C C C

N C C C C C C C C C I

C C C

C N C N C C C C C C C C Lorazepam

C C C C Mannitol

R C C N N C C C C Meropenem

C C C C C C C N C C

C C N N C C C C C C N C C C C Morphine sulfate

Nicardipine

C C

Nitroglycerin

C C C C C

Nitroprussidea

C C C C C C

Norepinephrine

C C C C C C C

Octreotide

C C C C C C

Ondansetron

C C C C C C C

Palonosetron

C N C C C C C C C N

C C C

C C C C C C

C C C C Nitroglycerin

C C C C N C C

C C C C C C C C C C

C C C

C C C N C C

C C N C C

C C C C Norepinephrine

C C N N C

C C C N N C C C C C C C C C C Octreotide C C C C C

N C

C C C C N C C C C C C C C C N Palonosetron

N C

N C N N C N C C N C

N C N N Penicillin G

C C N N C C C C C C I

C C C C C C C C C C C C C

Phenytoin

Piperacillin-tazobactam C N

C C C C C C N N C

Potassium chloride

C C C C C C C C C C C C C C

Potassium phosphate

C C N N N N C N C C C

C C C C Ondansetron

N C N C N C N N N C

C N C

C Piperacillin-tazobactam

N C C C C C C C N

N C N

G C C N C N C C C

C C

Sodium bicarbonate

C N

C C

C C N N C C

C C C C Potassium chloride

N N N N N Propofol

N N N C C N C N C N Ringer’s, lactated

C N N C

C C N C N

C C C N N C

Tacrolimus

C C C C C C C C C C C N C C

C C C N N C N

Tigecycline

C N C C

C C C C C C C N C

C C C C C C N C

Tobramycin

C N C C C C C C C C C N C C

C N

TMP-SMX

C N

Vancomycin

C N C C C C C C C C C N N C

N C N N C N C C C C

Vasopressin

C C C C C C C C C C C C C C

C C C N N C N C C C N C

Vecuronium

Voriconazole

C N C C C C

C N

C C C C C C C C C I

C C C N

Phenytoin

N C C C N N N C C C Potassium phosphate

Sodium chloride 0.9% N C C C C G C C C C C C C C

Pantoprazoleb

C C N C C C C C

N N

C C C C Phenylephrine

N C N C

Ringer’s, lactated

C C C C

N N N C N

N N N N C C C N C C N N N

Propofol

Nitroprussidea

Phenylephrine

C C C C

C C

C N C C C C Nicardipine

N N C C C C C C N C N N I

N Micafungin

C C

C C C C Midazolam

C C N C G C G C C C

C C C C

C C C C C N C C

N N N N

C N N

Pantoprazoleb

C N N N

C C

Penicillin G

C Methylprednisolone

C C

Morphine sulfate

C C C

C C C C C C C C

N C C C C C C C C C C Levofloxacin

N C C N C N C C N N N N C

C Imipenem-cilastatin

Midazolam

C C C Heparin

N C

C Furosemide

N N N C

Micafungin

Voriconazole

C N N C C C C C C C C N C C

Vecuronium

Vancomycin

C C C N N C C C C C C N C C

Hydrocortisone

C C C C C C

Vasopressin

TMP-SMX

Heparin

Tobramycin

C C C C Gentamicin

Tigecycline

Tacrolimus

N C N

Sodium chloride 0.9%

Sodium bicarbonate

C N C C C C C C C C C N C C

Ringer’s, lactated

Gentamicin

Propofol

N C N C

Potassium phosphate

Piperacillin-tazobactam

C C N C C C C N C C

Potassium chloride

Phenytoin I

Phenylephrine

C N C N

Palonosetron

C C

Ondansetron

C C C C Fluconazole

Furosemide

Octreotide

C C C C Fentanyl

Norepinephrine

Nitroprussidea

C C N C C C C C C C

Nitroglycerin

C C N C C N C C C C C C C

Nicardipine

C C

Morphine sulfate

C N C C C C C C C C C

Midazolam

C N C C C C C C C C C

Fluconazole

Micafungin

Fentanyl

Metronidazole

Penicillin G Potassium

(Metronidazole through Voriconazole)

Pantoprazoleb

Table. Compatibility of Selected IV Drugs

C C C C

N C C N Sodium bicarbonate

C C N C C C C Tacrolimus C C C C C N Tigecycline

C C C C C

N N N

N N C N C N C C Sodium chloride 0.9%

N N C

I I

C C C C Tobramycin I

N C C TMP-SMX C C C Vancomycin C C Vasopressin

N C

C C N C C C C C C C C C

N C

C C C N N N C C N C C C C C

C Vecuronium Voriconazole

Protect from light. b Testing was performed with ethylenediaminetetra-acetic acid (EDTA)-free formulation.

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

Text continued from page 1

incompatibilities are the most easily detected and are evidenced by visible changes, such as particulate formation, haze, precipitation, color change, and gas evolution. Chemical incompatibilities are those that result in decomposition of a drug. Loss of potency of greater than 10% over the defined testing period is considered chemical incompatibility. Most chemical incompatibilities can be detected only with a suitable analytic method. Therapeutic incompatibilities in which a drug combination results in undesirable antagonistic or synergistic pharmacologic activity are beyond the scope of most compatibility references. The purpose of this chart is to provide data in an organized, concise format from which compatibility information can be accessed quickly and conveniently. Although there are differing types of incompatibilities, the type of incompatibility or compatibility is not specified in this chart. A designation of “compatible” indicates that the combination evaluated appears to be compatible based on the tests performed, whether these tests measured physical, chemical, or both types of compatibility. All conditions that may affect compatibility cannot be included in such a format and it is not possible to predict all incompatibilities that may arise, but it is hoped that the information provided may help clinicians minimize their occurrence. Continuing

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

research adding to the existing body of knowledge on IV compatibilities is vital.

Suggested Reading Bertsche T, Mayer Y, Stahl R, Hoppe-Tichy T, Encke J, Haefeli WE. Prevention of intravenous drug incompatibilities in an intensive care unit. Am J Health Syst Pharm. 2008;65(19):1834-1840. Cohen MR, Smetzer JL. ISMP medication error report analysis-drug stability and compatibility; proper use of single-dose vials; what drugs are present on nursing units?; Arixtra—not a hemostat; Pradaxa–Plavix mix-up. Hosp Pharm. 2012;47(8):578-582. Kanji S, Lam J, Johanson C, et al. Systematic review of physical and chemical compatibility of commonly used medications administered by continuous infusion in intensive care units. Crit Care Med. 2010;38(9):1890-1898. DRUGDEX® System (Internet database). Greenwood Village, CO: Thomson Reuters (Healthcare) Inc. Nemec K, Kopelent-Frank H, Greif R. Standardization of infusion solutions to reduce the risk of incompatibility. Am J Health Syst Pharm. 2008;65(17):1648-1654. Newton DW. Crux of drug compatibility and incompatibility. Am J Health Syst Pharm. 2010;67(2):108-112. Singh BN, Dedhiya MG, DiNunzio J, et al. Compatibility of ceftaroline fosamil for injection with selected drugs during simulated Y-site administration. Am J Health Syst Pharm. 2011;68(22):2163-2169. Trissel LA, ed. Handbook on Injectable Drugs. 16th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2011.

Dr. Cayo reports no relevant conflicts of interest.

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REPORT Outsourced Hospital Sterile Compounding: A New and Safer Era To Come medications soon began to overver the past 3 decades, outwhelm the internal capabilities sourcing sterile compoundFaculty of many hospitals, even those ing pharmacies have become an Ernest R. Anderson Jr, RPh, MS with large in-house pharmacies.1 essential partner for most US Pharmacy Consultant hospitals. At one time, most Safety and quality standards for compounded sterile preparaCSPs were poorly defined, howBrockton, Massachusetts tions (CSPs) were mixed at the ever, and nosocomial outbreaks William Churchill, RPh, MS bedside, either by staff nurses or and medication errors became physicians.1 This was an effective common, leading to increased Chief of Service attention and need for safer solution in a different era of medDepartment of Pharmacy compounding practices.1 icine; however, in the 1980s and Chair, Drug Safety Committee 1990s, changes in the US popAttempts to improve safety in Brigham and Womenâ&#x20AC;&#x2122;s Hospital ulation and advances in medical sterile compounding date back Boston, Massachusetts care led to an increasing need to the 1970s, with the estabfor CSPs.1 The aging populalishment of the National CoorThomas Van Hassel, RPh, MPA dinating Committee on Large tion meant a larger demographic President, Arizona State Board of Pharmacy Volume Parenterals (NCCLVP) of adults aged 65 and older, Director of Pharmacy by what was then known as with more comorbidities and Yuma Regional Medical Center the US Pharmacopeial Convenmedication needs. Advances in Yuma, Arizona tion (USP). The NCCLVP was maternalâ&#x20AC;&#x201C;fetal medicine yielded improved survival rates for fragone of the first organizations ile, premature infants, many of to develop standards of pracwhom required total parenteral nutrition (TPN).1 tice for the preparation, labeling, and quality assurance of compounded products prepared by hospital pharmacies.2 This rapid increase in CSP volume put untenable pressure on bedside compounding, leading hospitals to develop The organization dissolved in the 1980s, and over the next their own internal pharmacy-based centralized IV admixture 2 decades, a series of attempts were made to establish (CIVA) programs. But the growing need for compounded consistent safety and quality standards for CSPs.

Supported by

REPORT

• 1992: USP issued Chapter <1074>, Dispensing Practices for Sterile Drug Products Intended for Home Use, a draft recommendation aimed at providing practice standards for CSPs. The recommendation was ultimately finalized as Chapter <1206>, Sterile Drug Products for Home Use, although it carried no legal or regulatory authority.3 • 1993: The American Society of Health-System Pharmacists (ASHP) published a Technical Assistance Bulletin entitled Quality Assurance for Pharmacy-Prepared Sterile Products, which laid out quality assurance measures to be used in the compounding of sterile preparations.3 But follow-up surveys in 1995 and 2002 found that hospital pharmacies largely lacked the necessary controls for their compounding environments. 2 • 1997: The US Food and Drug Administration Modernization Act (FDAMA) was enacted. Section 503A, Pharmacy Compounding, defines legitimate compounding in order to protect patients from harm. The FDA was given the ability to identify certain agents that represented a high risk to public safety. 2 • 2004: USP published Chapter <797>, the first enforceable guidelines for CSPs. State boards of pharmacy, the FDA, and accreditation agencies began using these measures to govern inspections. 2,4 • 2008: USP published revisions to Chapter <797> following cost and resource concerns about the 2004 publication.2 Revisions were made to the sections on environmental and quality control regarding full clean rooms, as well as changes to the sections on sterility, stability, and expiration dates.2,4 Complying with the regulations outlined in USP Chapter <797> became increasingly challenging for many hospitals; institutions needed to dedicate considerable space, staff, and monetary resources to comply with these standards.1 Subsequently, hospitals were forced to adjust their workflow as CSPs had to be prepared by the pharmacy under specific protocol. Pharmacy staff was tasked with mixing more CSPs rather than providing hands-on patient care.1 As a result, many hospitals turned to compounding providers (the term outsourcing was coined) to handle the complexities of preparing CSPs. Moreover, CSPs were required to undergo expensive sterility and stability testing to achieve extended beyond-use dates (BUDs), an important designation to assure quality, improve patient safety, and reduce medication waste. This became especially important with the rise of automated dispensing machines, which allowed rapid and controlled access to CSPs at the point of care rather than waiting for the hospital pharmacy to mix CSPs on demand, with predictably slower turnaround times.5 These factors ultimately led to the rise of “anticipatory compounding”—making limited quantities of compounded medications in preparation for a certain number of expected, although nonspecific, patient orders. The growing number of compounding pharmacies also offered a much-needed solution to the ongoing drug shortage problem.5 Outside vendors can provide access to discontinued medications or drugs in short supply by compounding the specific drug a hospital pharmacy may not be able to get from any other source, in order to fill a patient’s prescription. Today, the vast majority of US hospitals have some form of

CIVA program, and an April 2013 report from the Department of Health and Human Services Office of Inspector General (HHS OIG) found that 92% of acute-care hospitals use CSPs.6 Moreover, approximately 75% of these hospitals currently outsource at least some of their compounding.6 According to the International Academy of Compounding Pharmacists, of the approximately $300 billion in prescription medications sold annually in the United States, up to 3% are filled by entities considered to be a compounding pharmacy,7 although many of them do not supply to hospitals.

Current Legislation and The Price of Inadequacy Compounding pharmacies sit in an unusual middle zone when it comes to regulation. They are, technically, subject to oversight by the FDA—in a 1992 Compliance Policy Guide, the FDA stated that compounding pharmacies are not explicitly exempt from its authority.8 But the FDAMA exempted compounding pharmacies from FDA regulation with a few stipulations: They must only compound drugs for individual patients with valid prescriptions; the drugs must be compounded using approved ingredients and standard manufacturing processes; and the drugs may not be copies of other drugs already commercially available.9 Under the patchwork of current law, compounding pharmacies are primarily governed by the state board of pharmacy in their home state, some of which use safe-practice guidelines established in USP Chapter <797> as well as Chapter <795>, Pharmaceutical Compounding—Non-sterile Preparations.10 The National Association of Boards of Pharmacy (NABP) has incorporated USP Chapter <797> into its Model State Pharmacy Act and Model Rules,3 and some states have adopted Chapter <797> in its entirety. However, as of 2013, only 18 states require full compliance with USP Chapter <797>.11 This “one-license-fits-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 safety regulations and inspection standards.11 Consequently, hospitals must ensure that 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 that quality and process controls are in place. Unfortunately, irresponsible compounding practices by a small minority of vendors combined with inadequate and inconsistent oversight by state regulators have come to threaten public safety. Nowhere was this threat more apparent than the multistate fungal infection outbreak attributed to contaminated compounded methylprednisolone acetate (MPA), which was distributed by the New England Compounding Center (NECC). The first official case was reported on Sept. 18, 2012, and by Oct. 1, the FDA, Massachusetts Department of Health, and Massachusetts Board of Pharmacy had launched a collaborative investigation of NECC. Problematic conditions observed at the NECC facility included12: • The use of nonsterile active pharmaceutical ingredients (APIs) and raw materials to formulate injectable suspensions, although formula worksheets stated that raw materials were sterile. • No documentation or evidence to support the effectiveness of

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the steam autoclave cycle used to sterilize suspensions formulated using nonsterile APIs and raw materials. • Microbial isolates (bacteria and mold) found in multiple locations within the company’s clean rooms. • Air conditioning in the clean rooms shut off nightly between 8 PM and 5:30 AM. • Tarnished discoloration and condensation on the interior surfaces of several autoclaves. • Green and yellow residue on ceiling surfaces, hoods, and other areas of prep and clean rooms. • A boiler leaking water into soiled puddles within 30 feet of the entrance to a prep room. • Visibly soiled mats outside clean rooms. As of July 2013, the NECC outbreak has resulted in 749 confirmed cases and 61 deaths.13 This was the worst tragedy linked to nonsterile practices in pharmaceutical compounding, but it was far from the first. As FDA Commissioner Margaret Hamburg explained in Congressional testimony in April 2013,14 multiple outbreaks of infections and other complications resulting in serious injury and death have been linked to compounded products over the past 20 years,15 including: • California, 2001: 13 patients were hospitalized and 22 received medical care after injections of a contaminated steroid solution. • Virginia, 2005: 5 cases of systemic inflammatory response syndrome resulted from the use of a contaminated cardioplegia solution; 3 of those patients died. • Multiple states, 2007: A Texas compounding pharmacy sold hyper-concentrated doses of an IV solution that were up to 640% higher than the strength listed on the label; 3 people died from multiple organ failure. • Florida, 2011: About 21 patients developed bacterial eye infections from contaminated intravitreal injections. Several suffered long-term vision loss. Multiple warnings from the FDA about the hazards of compounded intravitreal injections have continued. Given the devastating consequences of irresponsible compounding practices, it has become more important than ever for hospitals to understand how responsible compounders should operate and how to identify who those responsible compounding partners are.

The Responsible Outsourced Compounder’s Approach to Safe CSPs Inconsistencies in regulatory and safety standards across state lines make it essential for hospitals to ensure that outside sterile compounding vendors are taking the necessary precautions. However, during his keynote address at the Pharmacy Sterile Compounding Summit in February 2013, Gary Kerr, PharmD, Massachusetts Society of Health-System Pharmacists, explained that he and other directors of hospital pharmacy worry about whether they have the necessary expertise and resources to assess external compounding pharmacies.17 At the very least, a responsible compounding pharmacy will adhere to USP Chapters <795> and <797>, whether or not their state board of pharmacy mandates full compliance. Critical elements of USP Chapter <797> include 4:

Compounding Terminology Traditional compounding: Defined by the FDA as “the combining, mixing, or altering of ingredients to create a customized medication for an individual patient in response to a licensed practitioner’s prescription.”14 This may be done to change the drug’s route of administration (eg, from a pill to a liquid for patients who cannot swallow pills), to remove an ingredient that the patient is allergic to, to obtain an optimal dose, or simply to improve flavor or texture. Compounding of this type is most commonly performed in the case of IV/parenteral nutrition. “Nontraditional” compounding: Historically this term has been used to refer to mass production (even if on a smaller scale) of a compounded product, not for the needs of a specific patient. This treads the line between compounding and manufacturing. Entities that compound on an anticipatory basis, providing CSPs for hospitals based on expected need to match the high-volume demands of today’s institutions, also fall under this category. Congress has proposed a new definition for anticipatory compounders: “compounding manufacturers.” Compounding manufacturers: A new definition proposed by Congress to classify entities that compound a sterile drug without a prescription and introduce it into interstate commerce, or repackage a drug using sterile, preservative-free, single-dose vials or by pooling sterile drugs.16 Nonsterile preparations: Include creams, ointments, or gels applied to the skin, and pills or capsules taken orally. They are lower-risk products and are subject to less regulatory scrutiny. Sterile preparations: These usually are injected or infused drugs that carry a higher risk for infection and other adverse events. This category includes sterile-tosterile products, in which a pharmacist constitutes one sterile product from another; and nonsterile-to-sterile products, which require sterilization of the compounded mixture once it has been prepared from one or more nonsterile ingredients. The risk is highest with products that started with a nonsterile component, as observed in the NECC outbreak.

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• Up-to-date Standard Operating Procedures (SOPs): These include a plan for prevention of microbiologic contamination of sterile preparations, documentation of the validity of these sterile procedures, and written justification. The SOPs also should outline comprehensive procedures for employees, environmental cleaning, and product testing, as well as the frequency of such testing. The manual should be reviewed and updated on a regular basis and be available for inspection by boards of pharmacy, federal regulatory representatives, or hospital pharmacies conducting a site audit of a vendor. • At least one structurally isolated area used only for the preparation of sterile pharmaceutical products: This area must maintain appropriate light, ventilation, temperature, moisture, sanitation, and security levels. It also must be able to accommodate a laminar flow hood. • Well-established maintenance schedule: This must include a system for cleaning and disinfecting all rooms and equipment involved in sterile preparations, and specific processes for cleaning and qualifying laminar flow hoods. • Thorough and complete compounding and dispensation records. • Augmented safety procedures for preparing cytotoxic drugs: This must include a dedicated vertical flow, Class II biological safety cabinet, protective apparel for personnel, written policies and procedures for response to spills of cytotoxic material, and compliance with all applicable laws and regulations of the disposal of such material. • Quality assurance program: This program monitors patient outcomes, adverse events, staff training and development, initial qualifications (particularly training requirements for personnel involved in aseptic manipulations), ongoing staff competency assessments, product integrity, and maintenance of equipment and facilities. Additionally, the program can perform product, employee, and environmental testing. Clean rooms and laminar flow hoods should be examined and certified by an independent inspector at least once every 6 months. The program should have complete documentation available. • A comprehensive, well-established training and competency assessment program: This program ensures that staff understands SOPs and receives routine training and qualification assessments for CSPs and for compliance with SOPs and federal and state regulations. For compounding pharmacies that engage in bulk compounding of nonsterile-to-sterile preparations—the source of many of the outbreaks and other adverse events—additional precautions must be taken. In particular, the pharmacy should be able to demonstrate that it conducts extensive end-product testing for nonsterile-to-sterile materials, including tests for particulate matter, pyrogens, and microbes.4 The compounding pharmacy also must take extra steps to validate that the clinical lab performing this quality testing meets federal and state regulations for performance. Importantly, a critical program must be in place to audit suppliers of bulk APIs.4 Although much discussion of compounding safety has focused on compliance with USP Chapter <797>, less attention

has been paid to Chapter <795>. This section focuses on nonsterile final preparations, and it has important implications about the quality of the product itself. A good compounding pharmacy will pay close attention to Chapter <795>. Among its key elements18 : • Rigorous attention to stability criteria and BUDs, using drugspecific and general stability documentation and literature. Compounders should assign BUDs conservatively, paying attention to drug-specific and general stability documentation and literature. • Use of USP- or national formulary-grade substances whenever possible. • Adherence to principles for compounding products of acceptable strength, quality, and purity: Requires a review of physical and chemical properties, assessment for possibly unfavorable or allergenic added substances, identification of the quality and quantity of each active ingredient, and confirmation of calculations and measurements. • Understanding appropriate methods for compounding various specific formulations of a nonsterile drug: Includes capsules, powders, lozenges and tablets; emulsions, solutions, and suspensions; suppositories; and creams, topical gels, ointments, and pastes. There is also another section of USP that applies to pharmaceutical compounding: Chapter <71>. This section sets standards for sterility testing, including appropriate culture media, time of incubation, minimum quantity of product to be used, and appropriate sterility testing methods for each specific type of product that might be made by a compounding pharmacy, such as ointments and creams, prefilled syringes, aqueous solutions, and antibiotic solids. Compliance with USP Chapters <795>, <797>, and <71> guidelines is essential, but it is not sufficient for good pharmaceutical compounding practice. Truly responsible compounders go beyond these foundational documents to incorporate additional recommendations from entities such as the Institute for Safe Medication Practices (ISMP), the Joint Commission, the Centers for Medicare & Medicaid Services, the ASHP, and other sources of safe medication policies and procedures.

Institute for Safe Medication Practices In December 2012, the ISMP issued finalized proceedings from the October 2011 Sterile Preparation Compounding Safety Summit, titled Guidelines for Safe Preparation of Sterile Compounds. The resource defers to USP Chapter <797> for standards to ensure the sterility of compounded products; instead, the ISMP document focuses on the prevention of IV admixture errors.19 Therefore, it does not address topics such as clean room sterility and laminar flow hoods, but rather focuses on areas that include order entry and verification, drug storage and conservation, and technology solutions such as IV workflow software and automated IV compounding devices.19 The document’s recommendations are categorized as Level 1: best practices that are strongly encouraged but that may not always be applicable; Level 2: minimum standards of practice; and Level 3: legal and regulatory mandates. Hospitals should

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ensure that compounding providers adhere with all Level 2 and 3 recommendations. Ideally, the compounding pharmacy should adhere with all 3 levels. Pharmacies looking to do business with an outsourced IV compounding pharmacy should also evaluate the potential vendor against Level 1 best practice standards before considering potential contracts.19

The Joint Commission Although the Joint Commission has yet to publish specific compounding-focused standards, a number of its medication management standards also pertain to compounding pharmacy practices. Responsible compounding pharmacies should comply with Joint Commission recommendations in all relevant areas of medication management. Beyond adherence to organizational standards and legal and regulatory requirements, hospitals should seek partnerships with compounding vendors that employ innovative packaging, labeling, and technological solutions to help reduce medication errors. Organizations such as the ISMP, the FDA, and the Joint Commission all have endorsed various labeling enhancements. 20 Examples of safer packaging and labeling include: • “Tall Man” lettering to help distinguish sound-alike/lookalike drugs (eg, predniSONE vs prednisolone; buPROPion vs busPIRone). The FDA has an approved list of Tall Man letters, but the ISMP has suggested a more comprehensive list for readily confused drug names (https://www.ismp.org/

tools/tallmanletters.pdf), which a proactive compounder also should employ. • Color-coding to sort preparations by class. For example, prefilled syringes for the OR setting could employ blue labels for opiates, fluorescent red for neuromuscular blockers, yellow for induction agents, orange for sedatives, violet for vasopressors, and green for anticholinergics. • Unique shapes and symbols to avoid confusion over multiple dosage formulations in the same drug family or class. • On the technology side, bar-coded labels should be used to help ensure that the right drug at the proper dose is administered to patients. Vendors should offer bar codes that incorporate drug names, lot numbers, and expiration dates, all within a single scan if possible. Figures 1 and 2 depict the types of clear, concise packaging that outsourcing compounding pharmacies can provide. Finally, the compounding pharmacy’s culture needs to be one of openness, transparency, and commitment to the advancement of quality and safety in pharmaceutical compounding. A responsible compounding pharmacy follows proper licensing procedures with the boards of pharmacy in every state in which it practices; some go as far as registering with the FDA. Site visits not only should be accepted, but also welcomed and encouraged. If errors do occur, or if inspections reveal violations, the compounding pharmacy should employ a full-disclosure policy about these problems and steps it has taken to remedy them, informing customers in a timely fashion.

Figure 1. Distinct labeling for anesthesia syringes in the operating room to help with drug identification. Image courtesy of PharMEDium.

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Risks and Burdens of In-House Compounding Some large hospitals and health systems can absorb the costs and other burdens required for a fully operational in-house compounding pharmacy. The Cleveland Clinic Health System, for example, prepares the majority of its estimated 870,000 annual doses of compounded medications (56% in response to patientspecific orders, 44% prepared in anticipation of need based on previous experience) at its main campus pharmacy, although compounding activities occur at each of its 10 hospitals.17 But even this large health system outsources some high-risk CSPs, such as pain pump refills, as well as parenteral nutrition and some cardioplegia solutions. Inevitably, all institutions face considerable obstacles and risks related to performing all of their compounding internally.

Training and Education Hospitals, and many hospital pharmacists, are not necessarily leading experts in IV sterile compounding processes and procedures. Although the basics of compounding are taught in pharmacy school curricula, the level of this instruction varies widely. A 2007 survey of US pharmacy schools found that although all schools offered some form of instruction in CSPs, only 21% offered a standalone course on the subject. 21 Although 88% of schools taught students about USP Chapter <797> standards for sterile compounding, only 13% of pharmacy school deans felt this CSP training was adequate. 21 Moreover, training and educating staff about USP Chapter <797> compliance remains challenging to in-hospital compounding. The 2012 USP Chapter <797> Compliance Survey found that 19% of respondents (77 of 419) cited a scarcity of training and competency resources to help educate staff as the greatest challenge in compliance. 22 Similarly, 20% of respondents (81 of 419) cited the time required to implement Chapter <797> changes as an obstacle to compliance. 22

Medication Errors In some cases, it has been found that medication errors may be more likely to occur when hospitals make their own 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, with particular hazards linked to the use of unlabeled syringes. 23 Purchasing prefilled syringes from a high-quality compounding pharmacy may help reduce these errors. Recently, physicians at Barnes-Jewish Hospital in St. Louis, Missouri, standardized anesthesia medication trays for their operating rooms (ORs) using such prefilled syringes from an outsourced entity. They found that medication management significantly improved, with inclusion of medication concentration on the label increasing from 31% at baseline to 78% post intervention (P<0.001).24

Labeling and Distribution Figure 2. Clear, concise labeling for IV medications in the ICU. Image courtesy of PharMEDium.

Ensuring that medication labels accurately display the drug and concentration on each preparation may be difficult for hospital pharmacies, particularly those without a robust admixture program. Moreover, providing clear, easy-to-read labels is vital to reduce the risk for medication errors,25 particularly in the OR and ICU.

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Figure 3. Ready-to-use epidural admixture with innovative labeling to enhance safety. Image courtesy of PharMEDium.

Compounding vendors can provide innovative labeling, such as bar coding, Tall Man lettering, and the use of shapes on the labels for ease of selection among medications in the same therapeutic class (Figure 3). Syringes may include color-coded labels based on drug class, as well as drug names displayed on circumferential bands with graduated marks to aid clinicians during medication administration.

Dating, Testing, and Waste Unless the hospital pharmacy has a comprehensive quality and testing program, most in-house sterile compounded medications have a shorter shelf life, which leaves the hospital more vulnerable to waste resulting from preparations that go unused and must be discarded. Current USP requirements mandate that CSPs can only be dated for the length of time outlined in the USP chapters based on the risk level of the preparation, or what information is in the published literature,2 which means that the hospital pharmacy must conduct multiple runs to make their IV preparations on both the day and night shifts. Outsourcers, by contrast, have BUD parameters that better match the ebb and flow of a hospitalâ&#x20AC;&#x2122;s drug supply needs.

Responsible outside vendors have the capability to conduct extensive testing that uses a stability-indicating method (a validated, quantitative analytical procedure that measures the amount of API free from potential interferences) to provide data to support extended BUDs for the same compounds. This testing ensures quality and significantly improves the shelf life of CSPs, thus reducing waste. If a patient is discharged or an order is changed, the extended dating allows the product to be reused. For hospitals with pharmacies that do not operate 24 hours a day, outsourcing ready-to-use CSPs with extended shelf lives is even more important. The medication waste resulting from limited expiration dates that apply to a hospitalâ&#x20AC;&#x2122;s in-house pharmacy can be significant. Research in an OR setting suggests that BUDs provided by outsourced compounders, in conjunction with tamper-evident packaging, can reduce drug waste by up to 61%.26

Physical and Opportunity Costs Equipping an in-house hospital compounding pharmacy that is fully compliant with all relevant USP chapters also can be expensive considering the requirements for clean rooms,

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Table 1. Barriers to USP Chapter <797> Compliance Challenge Spatial Limitations, %

Cost, %

Training/Staff Competency, %

Time, %

Douglas et al (N=412)

Wright et ala (N=236)

49.1

47.4

26.8

39.3

Survey

Respondents were given 3 choices and chose how challenging each measure was; data is listed for percentage of respondents that chose “major challenge.”

Based on references 6 and 22.

negative pressure rooms, storage for hazardous drugs, laminar flow hoods, isolators, and other high-cost capital expenditures. A single chemotherapy hood, for example, could cost more than $40,000—a substantial expenditure for any hospital. According to the HHS OIG survey, only 56% of hospitals surveyed had a USP Chapter <797>–compliant clean room.6 At virtually every hospital, there is competition for the scarce resources allotted to capital projects. Even if there might be a budget for such an investment, the facilities needed for compounding sterile preparations have a significant footprint, and space is often at a premium, particularly in community hospitals. In-hospital compounding also imposes a considerable opportunity cost for hospitals. Preparation and dispensing time impede pharmacists and other staff from providing hands-on clinical services to patients. This opportunity cost is not ideal considering the fact that many hospitals have implemented patient-focused care initiatives. In fact, the ASHP Pharmacy Practice Model Initiative has urged hospitals and other health care institutions to incorporate pharmacists in all aspects of medication management and related patient counseling. 27

Compliance Recent analyses of hospitals’ capabilities to move compounding back in-house have underscored the effect of all of these limitations (Table 1).6,22 The inaugural USP Compliance Survey was conducted in 2011 and was repeated in 2012, with hospital pharmacies representing the vast majority of survey respondents. “Despite the incremental improvements in a few of the key chapter requirements, there continue to be many opportunities to achieve improved compliance with the chapter,” the study directors wrote in their published analysis. 22 Respondents achieved USP Chapter <797> compliance scores of 80% or higher in a number of areas, including inventory storage and handling of CSPs, depyrogenation by dry heat, aseptic technique, and temperature and humidity monitoring; however, compliance scores of 70% or lower were reported in many areas. 22 These included surface sampling, airflow and differential pressure monitoring, sterility testing, and bacterial endotoxin testing. For example,

in 2012 only 53% of hospitals had a current, written environmental sampling plan that documents where viable air sampling and surface sampling occurs within the controlled environments—a very small improvement over 2011, when 49% had such plans. 22 In sum, hospitals face a variety of considerable obstacles and burdens in performing in-house compounding. As a result, the HHS OIG report found that approximately 75% of US hospitals outsource at least some of their sterile compounding needs.6 Outsourcing has become an even more important resource in the current environment of persistent drug shortages. In fact, hospitals that outsource at least some of their CSP supply have voiced serious concerns about the effect that reduced access to these CSPs would have on patient care. Almost half of the hospitals (48%) indicated that an abrupt shortage of outsourced CSPs would have a “non–life-threatening but great impact” on delivery of care in their institutions; an additional 11% believed that such a shortage would lead to a “life-threatening, major disruption at the hospital.”6 Table 2 presents an overview of reasons that hospitals decide to outsource their compounding needs, as well as attributes they look for in an outside vendor.6 Figure 4 shows the most commonly outsourced CSPs according to a national survey by the ASHP.28

Resources for Evaluating Potential Vendors The ASHP offers an extensive online resource center focused on sterile compounding. One of the most important tools included in this resource center for a hospital or health system that outsources any of its sterile compounding—or is considering doing so—is the ASHP Guidelines on Outsourcing Sterile Compounding Services (http:// www.ashp.org/DocLibrary/Bestpractices/MgmtGdlOutsourcingSterileComp.aspx). There are a number of key questions that any hospital or health system that outsources CSPs should ask.29

Regulatory • Does the vendor meet minimum requirements, such as an upto-date pharmacy license in the state where its compounding center resides? • Is the compounding provider licensed to ship to my state? • If non–patient-specific preparations comprise more than 5% of

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Table 2. Motivation To Outsource CSPs and Vendor Selection Criteria Reasons To Outsource

Hospitals Rating It “Very Important,” %

Stability of CSPs

68.6

Drug shortages

68.1

Need a ready-to-administer form

Need extended BUDs

61.8

Stability/sterility testing requirements

61.4

Inability to compound adequate amount

53.7

Vendor Selection Criteria

Hospitals Rating It “Very Important,” %

Product quality

88.6

Experience and expertise

87.3

Reputation

83.8

Accreditation

Inspection history with state board of pharmacy

77.5

Product availability

75.5

Ability to provide extended BUDs

71.1

BUD, beyond-use date; CSP, compounded sterile preparation Based on reference 6.

volume, is the outsourcer registered as a drug manufacturer with the FDA and Drug Enforcement Administration? • Does the outsourcer encourage and cooperate with site visits and reviews of its licenses and certifications by all regulatory agencies, governing bodies, and customers?

Patient Safety and Quality • How does the outsourcer document issues of staff competency, such as knowledge of aseptic technique, proper garbing, and hand hygiene? • How frequently is retraining and requalification required for staff members?

• Are the results of staff training and competency assessments as well as product quality testing available for customer review? A good compounder is willing to share the original results, not an edited report. • What is the outsourcer’s philosophy for mixing nonsterile-tosterile products? • Where does the outsourcer obtain its ingredients, and how is the outsourcer testing the sterility of incoming products? • Does the outsourcer’s product log contain information about the manufacturing site, where and when it was tested, and other information that allows for traceability and reliability? • Is the outsourcer willing and able to show certification records

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100 90 80

73.3

Rate Outsourced, %

65.2

60 50 38.3

40 30

24.1

23.6

Syringe-based anesthesia

TPN solutions

20 10 0 PCA and epidural admixtures

Oxytocin

IV admixtures and small-volume IV solutions

Figure 4. Services commonly outsourced by hospital pharmacies. PCA, patient-controlled analgesia; TPN, total parenteral nutrition Based on reference 28.

for its equipment, including clean rooms, laminar flow hoods, and other automation devices? • Have any safety problems been documented, with detailed records of the ensuing root-cause investigation? Has this information been shared with customers? Responsible compounders should be proactive and provide transparency. • Can the compounder provide current, valid certificates of analysis on products? These should show where the product was manufactured, where it was tested, and where shipped to the company—allowing customers to follow the product’s pedigree train all the way to their own acquisition of the product. ASHP also offers the Outsourcing Sterile Products Preparation: Contractor Assessment Tool, a comprehensive questionnaire that can be used to develop a request for proposals for these services.30 It contains 3 sections: • Minimum requirements: Vendors that do not meet the minimum requirements are disqualified from consideration as an

outsourcing provider of sterile products services. Those that qualify move on for additional assessments. • Vendor assessment: This is a 4-part, 65-question survey that can be used to review and rate multiple vendors that meet the minimum requirements for a sterile compounding pharmacy. The different parts of the survey focus on registration and licensure, quality and patient safety measures, medication administration safety features, and service excellence. • Assessment summary: This scoring section weights answers to questions on the 4 different parts of the survey: quality and safety measures are given 50% of the total value; regulatory and medication administration safety questions each get 20%; and service excellence accounts for 10% of the score. The tool recommends that only vendors who score at least 80% be considered for outsourcing sterile preparations. When used in conjunction with an on-site assessment and USP Chapter <797> gap analysis tool, such as that provided by

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Critical Point for the USP <797> Compliance Study,31 the ASHP questionnaire provides a wealth of information to aid hospital pharmacy leaders in the decision-making process for qualifying and selecting a compounding vendor.

The Future of Pharmaceutical Compounding After multiple smaller violations from irresponsible compounders, the NECC case has proven to be the tipping point that spurred the FDA and Congress into action. In her April 2013 testimony before the House Energy and Commerce Subcommittee on Oversight and Investigations, FDA Commissioner Hamburg recommended that Congress continue to recognize the appropriate role of states in regulating traditional compounding, while at the same time “authorizing clear and appropriate federal standards and oversight needed for non-traditional compounders that produce riskier products.”14 The Senate Committee on Health, Education, Labor and Pensions (HELP), with considerable input from the FDA and other stakeholders, has created legislation that would draw clear boundaries between traditional pharmacy compounding and a newly defined entity, compounding manufacturers. The Pharmaceutical Compounding Quality and Accountability Act (S. 959) was introduced on May 15, 2013, with bipartisan co-sponsorship, and was unanimously voted out of the HELP Committee on May 22. The legislation defines compounding manufacturers as entities that compound sterile drugs without or in advance of a prescription and sell those products across state lines.16 Any entity other than a hospital or health system that pools sterile products, or that repackages sterile, preservative-free vials is also defined as a compounding manufacturer by the legislation.16 It was amended on June 19, 2013, to include provisions that enable drugs to be tracked and traced throughout the distribution system.16 If this bill is enacted, the FDA will oversee compounding manufacturers’ operations. All compounding manufacturers will be required to only make products under the oversight of a pharmacist and in compliance with applicable Good Manufacturing Practices (GMPs), and they must investigate and report serious adverse events.16 In order to establish clear delineation between manufacturers and pharmacies, compounding manufacturers will not be allowed to register as pharmacies in any state.16 The legislation also preserves states’ primary role in regulating pharmacies that perform traditional compounding; a hospital pharmacy within an integrated health care network or integrated delivery system would not be required to register as a compounding manufacturer.16 The legislation also would give the FDA authority to designate drugs that may not be compounded by any entity because of impediments to their safe compounding. FDA-approved drugs that are available on the market may not be compounded; there is an exception to this rule in the case of medications that are on the FDA drug shortage list.16 Prior notice must be given to the FDA. There are some questions that remain to be resolved within the parameters of the proposed legislation. The definition of “traditional compounding” pharmacies could be somewhat variable depending on the state. In many cases, anticipatory compounding is permitted under state law on a very small scale in advance of receiving a prescription to enhance efficiency. For example, if a compounding

pharmacy knows that Dr. Smith typically sends 20 patients a week for a particular CSP, it may prepare a certain amount in anticipation of the needs of Dr. Smith’s patients. Similarly, the high-volume hospital environment often necessitates having an anticipatory inventory of certain CSPs based on historical use. Currently, the proposed legislation does not distinguish between that form of anticipatory compounding and larger-scale manufacturing. Any entity that compounds a sterile preparation either without or in advance of a prescription will be considered a compounding manufacturer if it sells products across state lines. The legislation has been praised by the ASHP,32 and welcomed by many high-volume compounders as an approach that will provide clear-cut legitimacy to those who are already adhering to appropriate guidelines, differentiating them from more slipshod operations that do not invest the necessary resources in quarantining, quality assurance, training, and product testing. Registration and inspection by the FDA, rather than by state boards of pharmacy, and adherence to applicable GMPs represent the highest assurance of quality for CSPs. The NABP has indicated that it is supportive of rules that allow continued monitoring by state boards of pharmacy and the FDA in a comprehensive inspection process of pharmacies and compounders as well as wholesale distributors.33 The NABP is collecting a log of all pharmacists—involved in compounding or not—and this will be continuously updated. This reporting is expected to be a requirement in the future.

Conclusion The old era of pharmaceutical compounding is drawing to a close, a development that responsible compounders welcome. High patient volume, limited space and resources, and noncompliance with USP Chapter <797> all place hospitals, health systems, and patients in an untenable situation. Since fall 2012, a series of FDA inspections found safety and sterility violations at 43 of the 55 compounding pharmacies it inspected. Issues included quality and sterility concerns as well as inappropriate air filtration.14 Hospitals that have outsourced their pharmaceutical compounding over the past decades would experience difficulties in transitioning to in-house services, as many may lack not only sufficiently trained personnel, but also the physical space, equipment, and financial resources necessary to meet the requirements of the FDA, state boards of pharmacy, and other accrediting bodies. Yet the litany of headlines about safety violations by irresponsible compounders may inaccurately paint all sterile compounding vendors with the same broad stroke. A combination of clear lines of federal and state oversight, a data-driven approach toward selecting CSP vendors by hospitals and health systems, 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. Hospital pharmacy leaders may outsource the responsibility for physically preparing CSPs, but they cannot outsource the responsibility for assuring that their outsourcing pharmacy provides safe, accurately prepared CSPs so patients are not subjected to poor outcomes or iatrogenic harm.

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References 1. McCartney L. Sterile Compounding and Aseptic Technique: Concepts, Training, and Assessment for Pharmacy Technicians. St. Paul, MN: Paradigm Publishing; 2012. 2. American Society of Health-System Pharmacists. www.ashp.org/ s_ashp/docs/files/discguide797-2008.pdf. Accessed July 7, 2013. 3. American Society of Health-System Pharmacists. www.ashp.org/ s_ashp/docs/files/HACC_797guide.pdf. Accessed July 7, 2013. 4. Pharmaceutical compounding—sterile preparations (general information chapter 797). In: The United States Pharmacopeia, 27th rev., and The National Formulary, 22nd ed. Rockville, MD: United States Pharmacopeial Convention; 2008. 5. Golembiewski JA. Safe medication compounding. J Perianesth Nurs. 2013;28(2):110-112. 6. 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. 7. International Academy of Compounding Pharmacists. http://www. iacprx.org/displaycommon.cfm?an=subarticlenbr=1. Accessed July 7, 2013. 8. Outterson K. Regulating compounding pharmacies after NECC. N Engl J Med. 2012;367(21):1969-1972. 9. National Association of Boards of Pharmacy. Model State Pharmacy Act and Model Rules. http://www.nabp.net/publications/model-act. Accessed July 7, 2013. 10. Gudeman J, Jozwiakowski M, Chollet J, Randell M. Potential risks of pharmacy compounding. Drugs R D. 2013;13(1):1-8. 11. Kastango ES. Compounding USP <797>: inspection, regulation, and oversight of sterile compounding pharmacies. JPEN J Parenter Enteral Nutr. 2012;36(2 suppl):38S-39S. 12. Food and Drug Administration. http://www.fda.gov/downloads/ AboutFDA/CentersOffices/OfficeofGlobalRegulatoryOperationsandPolicy/ORA/ORAElectronicReadingRoom/UCM325980.pdf. Accessed July 7, 2013. 13. Centers for Disease Control and Prevention. http://www.cdc.gov/ hai/outbreaks/meningitis-map-large.html. Accessed July 7, 2013. 14. Food and Drug Administration. http://www.fda.gov/NewsEvents/ Testimony/ucm348120.htm. Accessed July 7, 2013. 15. Pew Charitable Trusts. http://www.pewhealth.org/uploadedFiles/ PHG/Content_Level_Pages/In_the_News/DSP%20compounding_ Web-final.pdf. Accessed July 10, 2013.

18. Pharmaceutical compounding—sterile preparations (general information chapter 795). In: The United States Pharmacopeia, 27th rev., and The National Formulary, 22nd ed. Rockville, MD: United States Pharmacopeial Convention; 2013. 19. Institute for Safe Medication Practices. Guidelines for SAFE Preparation of Sterile Compounds. www.ismp.org/tools/guidelines/ IVSummit/. Accessed July 8, 2013. 20. Institute for Safe Medication Practices. https://www.ismp.org/ tools/tallmanletters.pdf. Accessed July 8, 2013. 21. Hellums M, Alverson SP, Monk-Tutor MR. Instruction on compounded sterile preparations at U.S. schools of pharmacy. Am J Health Syst Pharm. 2007;64(1):2267-2274. 22. Pharmacy Purchasing and Products. http://www.pppmag.com/ article/1218/October_2012_Cleanrooms_Compounding/The_2012_ USP_797_Compliance_Survey_Measuring_Progress/. Accessed July 8, 2013. 23. Grissinger M. Reducing errors with injectable medications—unlabeled syringes are surprisingly common. P T. 2010;35(8):428-451. 24. Stratman R, Wall M. Enhancing anesthesia medication safety in the intraoperative setting. Presented at: 42nd Critical Care Congress; January 19-23, 2013; San Juan, Puerto Rico. 25. Institute for Safe Medication Practices. http://www.ismp.org/Tools/ guidelines/labelFormats/Piggyback.asp. Accessed July 8, 2013. 26. Pharmacy Purchasing and Products. http://www.pppmag.com/ article/764/October_2010_Cleanrooms_Compounding/Outsourced_Prefilled_Syringe_Conversion_in_the_Operating_Room/. Accessed July 9, 2013. 27. The consensus of the Pharmacy Practice Model Summit. Am J Health Syst Pharm. 2011;68(12):1148-1152. 28. Pedersen CA, Schneider PJ, Scheckelhoff DJ. ASHP national survey of pharmacy practice in hospital settings: Dispensing and administration. Am J Health Syst Pharm. 2012;69(9):768-785. 29. Rinehart JR, Chan D, Cunningham M, et al; American Society of Health-System Pharmacists. ASHP guidelines on outsourcing sterile compounding services. Am J Health Syst Pharm. 2010; 67(9):757-765. 30. American Society of Health-System Pharmacists. http://www. ashpfoundation.org/MainMenuCategories/PracticeTools/SterileProductsTool/SterileProductsAssessmentTool.aspx. Accessed July 8, 2013. 31. Critical Point. www.criticalpoint.info. Accessed July 12, 2013.

16. United States Senate. http://www.gpo.gov/fdsys/pkg/BILLS113s959rs/pdf/BILLS-113s959rs.pdf. Accessed July 11, 2013.

32. American Society of Health-System Pharmacists. http://www. ashp.org/DocLibrary/Advocacy/ASHP-Comments-on-HouseCompounding-Draft.pdf. Accessed July 9, 2013.

17. American Hospital Association. www.aha.org/presscenter/ pressrel/2013/130515-ashp-com-report.pdf. Accessed July 3, 2013.

33. National Association of Boards of Pharmacy. http://www.nabp. net/system/redactor_assets/documents/522/Ltr_of_Support_ Senate_HELP_23May13.pdf. Accessed July 8, 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.

SR1328

Disclosures: Mr. Anderson has received honoraria from the American Society of Health-System Pharmacists. Mr. Churchill reported that he served as a consultant for Sea Medical Systems and has received honoraria from the American Society of Health-System Pharmacists. Mr. Van Hassel reported that he served on the speakers’ bureaus for Cubist Pharmaceuticals and Optimer Pharmaceuticals.

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SEPTEMBER 2013

REPORT Teflaro® (ceftaroline fosamil) for the Treatment of Community-Acquired Bacterial Pneumonia Caused by Designated Susceptible Bacteria Community-acquired pneumonia Streptococcus pneumoniae is the Faculty (CAP) is a common illness that causes most common cause of CAP; comsignificant morbidity and mortality, bined with Staphylococcus aureus, Donald Low, MD particularly among elderly individuals these 2 organisms account for more Chief, Department of Microbiology and in those with serious comorbidithan 50% of cases. Several GramMount Sinai Hospital ties.1 CAP can be caused by bacterial negative pathogens, including HaeToronto, Ontario, Canada mophilus influenzae and Klebsiella pathogens or certain respiratory pneumoniae, are common etiologies viruses, and the etiology is often of CAP.5 unknown initially. For cases with a confirmed bacterial etiology, the FDA uses a more precise Over the past several decades, trends in antimicrobial designation: community-acquired bacterial pneumonia susceptibility patterns have complicated the treatment of (CABP). Despite the availability of potent treatment options CAP.6 For example, mutations to penicillin-binding proand effective vaccines, an estimated 5.4 million cases of teins (PBPs) have resulted in an increased resistance to CAP occur in the U.S. each year, leading to 1.2 million hosβ-lactam antibiotics among strains of S. pneumoniae.7 2,3 4 pitalizations and 53,692 deaths. The cost to treat CAP in The pneumococcal conjugate vaccine (PCV), first introthe U.S. is estimated to exceed $17 billion annually.2 duced in the latter half of 2000, has also led to changes

INDICATION

IMPORTANT SAFETY INFORMATION

• TEFLARO (ceftaroline fosamil) is indicated for the treatment of community-acquired bacterial pneumonia (CABP) caused by susceptible isolates of the following Gram-positive and Gram-negative microorganisms: Streptococcus pneumoniae (including cases with concurrent bacteremia), Staphylococcus aureus (methicillin-susceptible isolates only), Haemophilius influenzae, Klebsiella pneumoniae, and Klebsiella oxytoca, and Escherichia coli.

Contraindications • TEFLARO is contraindicated in patients with known serious hypersensitivity to ceftaroline or other members of the cephalosporin class. Anaphylaxis and anaphylactoid reactions have been reported with ceftaroline.

Please see additional Important Safety Information throughout and brief summary of Prescribing Information on page 8.