The March 2013 Digital Edition of Pharmacy Practice News by McMahon Group

The Pharmacist’s News Source

pharmacypracticenews.com

Volume 40 • Number 3 • March 2013

Printer-friendly versions available online

in this issue CLINICAL

‘A miraculous treatment’ for cardiac drug toxicity.

Compounding Update

NECC Crisis Shifts Focus to Hospital Sterile Preparation he same quality flaws that have come to light in Massachusetts’ crackdown on sterile compounding pharmacies also may exist in many hospital pharmacies that formulate sterile preparations, according to a recent survey by the Institute for Safe Medication Practices (ISMP). Three out of four (74%) of 412 survey respondents—most of them pharmacists—reported that contamination could be a risk for their facilities, and 13% said that contamination actually had occurred during the past year. Those findings came as no surprise to Darryl S. Rich, PharmD, MBA, FASHP, a medication safety specialist at ISMP. Based on hospital visits he has made, Dr. Rich told Pharmacy Practice News, hospital pharmacies are “not quite there yet” in complying with U.S. Pharmacopeia (USP) Chapter <797> standards.

Las Vegas—Despite federal lawss to the contrary, 18 states and thee District of Columbia have legal-ized medical marijuana for a rangge of indications, including cancer, glaug coma, epilepsy, nausea, chronic pain, p muscle spasms and appetite stim mulation. Countless users swear that medim cal marijuana improves their heealth and quality of life. But as access to marijuana eases due to its increasing decriminalizattion, evaluation of its health benefits and risks still presents unique challen nges for pharmacists and other membeers of the patient care team—challenges that simply don’t exist for any otherr prescription drug, according to Lawrence Cohen, PharmD, associate dean for clinical programs at the University of North Texaas System College of Pharmacy, in Fo ort Worth. “I believe there are disorders where medical marijuana has efficacy. But there are a large number of can cannabinoids in marijuana, and there’s no way to predict if it will have the desired effect or if a patient is going to have a misadventure,” Dr. Cohen told Pharmacy Practice News.

see COMPOUNDING, page 29

see MARIJUANA, page 3

9 16

Clinical Pearls in emergency medicine. Q&A: Bob Ignoffo, PharmD, on his HOPA award and the future of hem/onc pharmacy.

OPERATIONS & MGMT

Competitive vs. cooperative negotiation.

POLICY

32 36

A program for bolstering care transitions. It’s time to stop whining about white bagging.

LAST WORD

Readers comment on article debating proposed opioid limits.

EDUCATIONAL REVIEW

ChemotherapyInduced Nausea and Vomiting See page 19.

As Access to Marijuana Eases, Medicinal Use Is Still a Puzzle

•

ChemotherapyFree Regimen Effective for APL

In Operating Room, a Switch To Prefilled Syringes Pays Off

Increased survival, limited toxicity noted in Phase III trial

San Juan, Puerto R Rico—Incorporating standardized, ready-to-u use anesthesia medications in the operatingg rooms helped one hospital in St. Louiss significantly increase proper labeling of medicines and red duce medication waste. Researchers from Barnes-Jewish Hospital say their medication intervention, presented at the Society of Critical Care Medicine’s annual congress, more than doubled labeling compliance and nearly eliminated medication waste.

Atlanta—A chemotherapy-free regimen is poised to become the new standard of care in patients with non–high-risk, acute promyelocytic leukemia (APL), according to results from a Phase III trial. The trial, which showed that the combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO)

•

see APL, page 15

To better meet a medication safety paradigm established during a consensus conference convened in 2010 by the Anesthesia Patient Safety F Foundation (APSF), hospital researchers conducted a medication safety study in three pharmacy satellites and in 78 areas of care where anesthetic agents were used. The primary focus of the study was to look at labeling compliance, medication preparation details and waste data

Special Report Transdermal PCA in Acute Postoperative Pain Management:

•

see PREFILLED SYRINGES, page 13

New Product

A Critical Evaluation of the Investigational IONSYS System

AHP launches three new unit-dose products.

See insert after page 20.

See page 14.

Premix. Ready to Mix. Manual Admix. Your Mix. Drug Delivery. For the way you pharmacy. Clinicians have the right to drug delivery options. After all, no single IV product works for every institution, situation or in every patient care area. So when it comes to premix, ready-to-mix or manual admix, we have the mix that meets your needs. To learn more, talk to your Baxter representative. 888-229-0001. Or visit www.baxter.com

Baxter Healthcare Corporation. Doing our part, so you can do yours. pharmacy workďŹ&#x201A;ow I drug delivery I nutrition I iv access I infusion systems I support & service

Baxter is a registered trademark of Baxter International Inc.

111869 01/13

Clinical 3

Pharmacy Practice News • March 2013

Supportive Care

MARIJUANA continued from page 1

“Will it control nausea without causing excessive sedation or disorientation? Are there contaminants in the plant material that may be very harmful, particularly for immunocompromised individuals? You can’t predict that type of thing nearly as well as you can for most prescription drugs.” A number of his patients have told him that marijuana has been the only treatment that has offered relief from their maladies, added Dr. Cohen, who was one of several speakers to tackle these issues during a session at the 2012 Midyear Clinical Meeting of the American Society of Health-System Pharmacists (ASHP). The session was titled “Medical Marijuana: Rational Medicine or Potential Medication Misadventure?”

A Hazy Picture Attempts to corroborate such anecdotal reports with clinical research have yielded mixed results on safety and efficacy, according to the speakers. That is partly due, they noted, to the difficulty of determining just what compounds and forms of marijuana should be studied. In its most commonly used form—the flower buds of the female marijuana plant—there is no dose standardization, no meaningful way to compare samples from different plants or hybrids, and no way to ascertain if the product is free of potentially dangerous contaminants, such as mold, bacteria and pesticides, all of which have been identified in marijuana smoke. No

Research on the efficacy of marijuana use is mixed, but several uses have garnered FDA approval, including nausea and vomiting in chemotherapy patients and cachexia in patients with AIDS.

other prescription drug is burned and smoked—an act that, in and of itself, is comparable to (and maybe worse than) smoking cigarettes. Some users bake marijuana into food and eat it, or vaporize it with special devices, all of which further confounds assessment of the drug’s value and dangers, the speakers noted. For pharmacists who want to drill a bit deeper and understand the pharmacodynamics of marijuana, the picture gets even murkier. The cannabinoid tetrahydrocannabinol (THC), marijuana’s most psychoactive compound, is also believed by proponents to be the drug’s most therapeutically active constituent, particularly for pain, nausea, glaucoma and spasticity associated with multiple sclerosis. Yet there is another cannabinoid—cannabidiol (CBD)—to keep in mind. Although CBD has far weaker psychoactive properties than THC, it is considered an anti-inflammatory and

anti-anxiolytic. Complicating the picture even further are altered forms of medical marijuana, which include nabiximols (Sativex), a derivative delivered as an oral-mucosal spray and approved in several European countries and Canada; and the oral synthetic cannabinoids, nabilone (Cesamet, Meda Pharmaceuticals) and dronabinol (Marinol, Abbott Laboratories).

A Mixed Bag of Research Researchers have completed dozens of peer-reviewed clinical studies of marijuana in its various forms. Results are mixed, according to Laura Borgelt, PharmD, BCPS, FCCP, an associate professor in the Departments of Clinical Pharmacy and Family Medicine at the University of Colorado, in Aurora, who also spoke at the ASHP session. “If you look for evidence that medical marijuana is effective, you can probably

find that information, and if you look for it to be ineffective you can probably find that too,” Dr. Borgelt said in an interview. Like Dr. Cohen, Dr. Borgelt added that many of her patients have reported health-related benefits from using marijuana. Based on her review of clinical research, the most frequently reported medicinal uses for marijuana are treating pain, muscle spasms related to multiple sclerosis and nausea. “Those are all indications for which data supporting the beneficial effects reach statistical significance, although there’s always the caveat that the studies that don’t show efficacy are less likely to be published,” she said. “Many patients get significant benefits, but some have none at all.” Dr. Borgelt made her case primarily with meta-analyses or systematic study reviews. While acknowledging such compilations aren’t ideal, she deemed them most useful for portraying a broad picture of the medical marijuana landscape (see resource box, page 4). Many individual studies are small and sometimes of dubious methodology, she added. “It’s very difficult to establish welldesigned, controlled clinical trials in this environment with varied marijuana dosages and formulations used.” The most appropriate patients, in her opinion, are those whose conditions are refractory to more orthodox medications, and who experience either inadequate response to, or intolerance of, second- or third-line drugs. “Having said that, most primary care physicians are not the ones

•

see MARIJUANA, page 4

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 3 • March 2013 • pharmacypracticenews.com

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

INTERNAL MEDICINE

EDITORIAL STAFF

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

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

David Bronstein, Editorial Director davidb@mcmahonmed.com

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

NUCLEAR PHARMACY

BIOTECHNOLOGY Jeffrey Norenberg, PharmD, Albuquerque, NM

Indu Lew, PharmD, Livingston, NJ

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

CARDIOLOGY

ONCOLOGY

C. Michael White, PharmD, Storrs, s CT

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

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

CNS/PSYCHIATRY

Robert Ignoffo, PharmD, San Francisco, CA

James Prudden, Group Editorial Director

Charles F. Caley, PharmD, Storrs, CT

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

Robin B. Weisberg, Manager, r Editorial Services

Cindy O’Bryant, PharmD, Aurora, CO

Elizabeth Zhong, Associate Copy Chief

Lawrence Cohen, PharmD, FASHP, FCCP, Fort Worth, Texas Larry Ereshefsky, PharmD, San Antonio, TX COMPLEMENTARY AND ALTERNATIVE MEDICINE

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

Cathy Rosenbaum, PharmD, Cincinnati, OH

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

CRITICAL CARE

PEDIATRICS

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Gretchen Brummel, PharmD, BCPS, Hudson, OH

SALES David Kaplan, Group Publication Director dkaplan@mcmahonmed.com

James O’Neill, Senior Systems Manager Dan Radebaugh, Director of Production and Technical Operations Marty Barbieri, Production Manager Brandy Wilson, Circulation Coordinator

McMAHON PUBLISHING Raymond E. McMahon, Publisher and CEO, Managing Partner Van Velle, President, Partner Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

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

David P. Nicolau, PharmD, Hartford, CT

TECHNOLOGY

Robert P. Rapp, PharmD, Lexington, KY

Thomas Van Hassel, RPh, Yuma, AZ

Alina Dasgupta, Junior Sales Associate, e Classified Advertising adasgupta@mcmahonmed.com

Copyright © 2013 McMahon Publishing, New York, NY 10036. All rights reserved. Pharmacy Practice News (ISSN 0886-988x) is published monthly by McMahon Publishing. Periodicals postage paid at New York, NY, and at additional mailing offices. POSTMASTER: Send address changes to Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036.

WANT TO SUBSCRIBE? CHANGE YOUR ADDRESS? HERE’S HOW All U.S. hospital pharmacists should receive Pharmacy Practice News free of charge. If you are a hospital pharmacist and do not receive the publication, you must add your professional address or make your address change directly

with Pharmacy Practice News, Circulation Dept., 545 W. 45th St., 8th Floor, New York, NY 10036. You can also fax your request to (212) 977-3645, or send it via email, circulation@mcmahonmed.com. If you are not a hospital pharmacist but would like to receive Pharmacy Practice News, please send a check for $70.00 (U.S.) or $90.00 (outside U.S.) for a year’s subscrip-

tion payable to Pharmacy Practice News to McMahon Publishing, 545 West 45th St., 8th Floor, New York, NY 10036. Please allow 8 to 12 weeks for delivery of the first issue. Individual issues are $7.00 (U.S.) or $10.00 (outside U.S.). McMahon Publishing is a 41-year-old, first-generation, family-owned publishing company dedicated to providing medical professionals with essential, up-to-date news. As

the second largest publisher of medical newspapers, McMahon produces Anesthesiology News, Clinical Oncology News, Gastroenterology & Endoscopy News, General Surgery News, Infectious Disease Special Edition, Pain Medicine News, Pharmacy Practice News. Rheumatology Practice News and Specialty Pharmacy Continuum.

INFECTIOUS DISEASES

REIMBURSEMENT

Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH Peggy McKinnon, PharmD, Lexington, M MA

Bonnie E. Kirschenbaum, MS, FASHP, Breckenridge, CO

A family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers and several annual or semiannual Special Editions.

Matt Spoto, Senior Account Manager mspoto@mcmahonmed.com David Nathanson, Account Manager dnathanson@mcmahonmed.com

4 Clinical

Pharmacy Practice News • March 2013

Supportive Care

Medical Marijuana Studies and Resources

MARIJUANA continued from page 3

recommending marijuana to patients,” Dr. Borgelt continued. “Patients typically get the prescription from physicians who specialize in medical marijuana. That’s not ideal, because patients ents are essentially self-medicating when other treatments don’t work, or even before they try more conventional treatmen nts.” Side effects are preetty much inevitable when smoking maarijuana, and most notably—and of no grreat surprise—are euphoria, confusion n, disorientation, and d impaired memory an nd perceptions of time, to name a few. Dr. Cohen agreed d that, as with any medicattion, the potential risks associated iated with marijuana must be weighed against potential benefits. Marijuana has been linked to a range of adverse cardiovascular, respiratory and nervous system effects. Some things for pharmacists to keep an eye on: • Drug interactions. Marijuana interacts with a variety of drugs, including opioids, barbiturates, central nervous system depressants, hypnotics, sedatives and other sedating drugs, protease inhibitors, selective serotonin reuptake inhibitors and alcohol. • Drug–disease interactions. Marijuana may cause tachycardia and transient hypertension, and has been

For comprehensive listings of medical marijuana studies, visit the International Association for Cannabinoid Medicines (http://www.cannabis-med.org/), and ProCon.org (http://medicalmarijuana.procon.org/ view.resource.php?resourceID=000884). For lists of the states that have legalized medical marijuana and conditions for which it can be prescribed, visit http://medicalmarijuana.procon. org/view.resource.php?resourceID=000881. —S.F. Medical marijuana studies (IACM)

associated with syncope and palpita palpitations. It also has been suspected of triggering myocardial infarction and transient ischemic attacks in patients at low risk for developing cardiac abnormalities, but such findings aren’t from controlled studies and the patients were taking other drugs, Dr. Cohen noted. “Most of this is based on case reports,” he said. “It’s difficult to weigh what the cardiac risks are.” • Central nervous system effects. Dry mouth, nausea, drowsiness, dizziness, sleep difficulties, memory impairment, euphoria, disorientation and confusion, and doserelated impairment of cognitive and

Don’t Be ‘the Ethics Police’

n Colorado alone, more than 105,000 people possess a valid medical marijuana registry ID card. Undoubtedly, many more in the state use the drug purportedly for medicinal purposes. Nationwide, the number of people who use medical marijuana runs easily into the millions. Sorting out who uses the drug medicinally and who uses it recreationally is a fool’s errand. But what is a near certainty is that clinical pharmacists can expect to encounter an increasing number of patients who acknowledge their marijuana use to health care providers. The enactment of more lenient laws and lax enforcement in some regions (and nationally) have given many users some comfort that law enforcement authorities will leave them alone.

‘Make sure [patients] understand that there could be effects, beyond getting high, that may be undesirable, and that there’s no way to predict what problems [marijuana] might cause when taken with other medications.’ —Lawrence Cohen, PharmD Marijuana is a Schedule I substance. As defined by the Controlled Substances Act, Schedule I drugs have a high potential for abuse and have no currently accepted medical use in treatment in the United States. Additionally, there is a lack of accepted safety data for their use under medical supervision. “People tend to frame this politically, but the reality is, especially in states where laws have been enacted, that a lot of patients are using marijuana, whether medicinally or recreationally, and they’re using it in combination with many other medications. So it’s important to understand how marijuana can be a player in a patient’s medical regimen,” Dr. Borgelt said.

Medical marijuana studies (ProCon.org)

behaviorral functions are common. Some fear that the drug can cause psycho osis, but the causal relationship b between marijuana use and behavioral disorders in healthy individu uals is weak, Dr. Cohen noted. “Right “R now, it’s just a matter of common sense to not use this drug in people at risk for behavioral disorders, like psychosis or depression,” he said. “I’m only certain of one thing: In an individual with depression or a family history of developing psychiatric disorders, medical marijuana should be used with great care.” • Respiratory. Marijuana smoke contains 50% to 70% more carcinogens than cigarette smoke and clearly irritates the respiratory tract. The smoke is considered a potential risk for lung cancer, although evidence is not definitive (Can Epidemiol Biomarkers Prev 2006;25:1829). Regular

States that have legalized medical marijuana

use is associated with chronic bronchitis ((J Gen Intern Med d 2005;20:33). • Addiction. Marijuana addiction is a risk, but a relatively small one—about 9% of users, according to the National Institute on Drug Abuse (http:// www.drugabuse.gov/publications/ drugfacts/marijuana). The bottom line is that “the data in the medical literature are truly conflicting on matters concerning marijuana’s health risks,” Dr. Cohen said. Still, some knowledge is better than none, added Dr. Borgelt. “The more information we can get, however imperfect, then the more knowledgeable we become and the better prepared we can be to make decisions about whether marijuana will benefit or harm our patients.” —Steve Frandzel Drs. Borgelt and Cohen report no relevant conﬂicts of interest.

Dr. Borgelt told Pharmacy Practice News that pharmacists, regardless of their personal stance on medical marijuana, are obligated to gain some understanding of the drug’s pharmacology and its unique set of potential benefits, risks, drug– drug interactions and drug–disease interactions. Other than perhaps pointing out to patients that possession and sale of marijuana is illegal in the eyes of the federal government (and of many states), Dr. Borgelt advised pharmacists to detach themselves from the legal and moral arguments and approach patients with the same consideration they show to all. If anything, she added, these individuals deserve a pat on the back for stepping forward to provide their health care providers with important medical information, despite it making them uncomfortable. “Please don’t judge the patient or be the ‘ethics police,’” she said. “It’s about keeping lines of communication open between patient and provider and giving patients the full picture of what they’re doing with regard to their health.” That means assessing and monitoring patients for side effects and adverse drug reactions and advising them accordingly, she noted. “We have a responsibility to warn them about marijuana’s potential risk—the fact that there is a risk,” added Dr. Cohen. “I would also praise them for disclosing such sensitive information, but make sure they understand that there could be effects, beyond getting high, that may be undesirable, and that there’s no way to predict what problems it might cause when taken with other medications.” With his own patients, Dr. Cohen tries to get information about when and how much marijuana they use, their perceptions of efficacy, and of course other medications they’re taking. He also encourages them to notify their other health care providers, as appropriate. “A lot depends on the relationship you have with a patient,” Dr. Cohen said. “They’re usually uncomfortable talking about it unless they have no fear you’re not going to disclose it to a law enforcement agency, and I think that fear will continue for a while. There are some real benefits for some patients, and I suspect we will continue hearing from more people that they’ve found something that really improves their quality of life and allows them to feel better day to day.” —S.F.

Grifols ! ,EADING -ANUFACTURER OF 0LASMA 0ROTEIN 4HERAPIES Vertical integration with geographic diversity helps ensure continuous production of therapies s 4HE LARGEST NETWORK OF SOURCE PLASMA DONOR CENTERS IN THE INDUSTRY 1 PROVIDES 'RIFOLS WITH A DEPENDABLE SUPPLY OF THE PLASMA NEEDED TO PRODUCE OUR THERAPIES s 4WO 'RIFOLS OWNED STATE OF THE ART PLASMA TESTING FACILITIES s 4HE LARGEST PLASMA PROTEIN FRACTIONATION CAPACITY IN THE WORLD 1 s 4HREE GLOBAL PLASMA PROTEIN MANUFACTURING FACILITIES

'RIFOLS &RACTIONATION &ACILITY ,OS !NGELES #!

3TATE OF THE !RT 0RODUCTION 0ROCESSES

A Broad Range of Plasma Protein Therapies Albumin (UMAN MARKETED AS AlbuteinÂŽ 5% AlbuteinÂŽ 25% PlasbuminÂŽ-5 AND PlasbuminÂŽ-25 Alpha1- Proteinase Inhibitor (UMAN MARKETED AS ProlastinÂŽ-C Antihemophilic Factor/von Willebrand Factor Complex (UMAN MARKETED AS AlphanateÂŽ Antithrombin III (UMAN MARKETED AS Thrombate IIIÂŽ Coagulation Factor IX (UMAN MARKETED AS AlphaNineÂŽ SD Factor IX Complex MARKETED AS ProďŹ lnineÂŽ SD Immune Globulin Intravenous (UMAN OR IVIG Immune Globulin Injection (UMAN Hyperimmune Globulin Therapy Products MARKETED AS Hypermunesâ&#x201E;˘: Rabies Immune Globulin (UMAN MARKETED AS HyperRABÂŽ S/D Tetanus Immune Globulin (UMAN MARKETED AS HyperTETÂŽ S/D Rho(D) Immune Globulin (UMAN MARKETED AS HyperRHOÂŽ S/D Hepatitis B Immune Globulin (UMAN MARKETED AS HyperHEP BÂŽ S/D

'RIFOLS 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 hospitalâ&#x20AC;&#x2122;s needs at www.grifols.com -ARKETING 2ESEARCH "UREAU DATA *UNE

ÂĽ 'RIFOLS "IOLOGICALS )NC !LL RIGHTS RESERVED 0RINTED IN 53! *UNE #/

6 Clinical

Pharmacy Practice News • March 2013

ED Pharmacy

Insulin, Lipids Overlooked for Treating Cardiac Drug Toxicity New Orleans—Emergency pharmacists and clinicians need to take highdose insulin and lipid emulsion therapy seriously for the treatment of severe calcium channel blocker (CCB) and β-blocker (BB) toxicity, two experts told attendees of the American Society of Health-System Pharmacists (ASHP) 2012 Midyear Clinical Meeting.

Slim ‘but Convincing’ Evidence Phillippe Mentler, PharmD, pointed to a slim “but convincing” body of evidence showing that high-dose insulin, or hyperinsulinemia-euglycemia (HIE), is profoundly effective for severe CCB and BB toxicity, whereas IV fluids, atropine, calcium, vasopressors and glucagon are not. “More than 80 cases have been published to date, and all have shown that HIE is consistently superior to other treatments,” said Dr. Mentler, an emergency medicine pharmacist at Durham Regional Hospital, in North Carolina. Dr. Mentler explained that HIE provides glucose and energy to the stressed myocardium, bypassing the need for a functioning pancreas (Clin Toxicol 2011;49:277-283). Given that CCB and BB toxicity account for the second highest number of deaths among cardiovascular medication–related mortalities (Clin Toxicol 2011;49:910-941), the 85% survival rate among these patients treated with HIE should be taken seriously, he suggested. Moreover, he noted, the survival rate may be even higher when an initial bolus of high-dose insulin is administered earlier (see e.g., Clin Toxicol 2011;49:653-658). Dr. Mentler said that HIE is underused primarily because of a psychological barrier that prevents clinicians who are not familiar with the treatment from administering the unusually high doses of insulin required. A typical treatment protocol calls for an initial IV bolus injection of 1 unit/kg, followed by an infusion of 0.5 to 1 unit/kg per hour, titrated every 15 minutes up to a maximum of 10 units/ kg per hour (Clin Toxicol 2011;49:277-283; Clin Toxicol 2011;49:653-658). “Clinicians might look at you as if you are insane for recommending this dose,” Dr. Mentler said. But Daniel Hays, PharmD, who moderated the ASHP session at which Dr. Mentler spoke, said, “Clinicians need to look past the high doses of insulin and realize the tremendous benefits from this therapy. In patients with known toxicity due to ingestion of calcium channel blockers and β-blockers, insulin therapy should be the first line of treatment,” added Dr. Hays, the clinical coordinator of emergency pharmacy services in the Departments of Pharmacy and Emergency Medicine at the University of Arizona Health Network, in Tucson.

A standardized order set like one developed by pharmacists in Minnesota (see related article, page 8) may help emergency department clinicians and nurses feel more comfortable with the protocol, he told Pharmacy Practice News.

‘A Miraculous Intervention’ Another highly effective but underused treatment for severe CCB and BB toxicity is lipid emulsion therapy, Zlatan

Coralic, PharmD, an emergency department clinical pharmacist at the University of California, San Francisco, told attendees during the ASHP session. “Although the data we have are limited to case reports, they do suggest that lipid emulsion therapy is a miraculous intervention,” Dr. Coralic said. “The treatment has brought patients from active chest compressions to full recovery with minimal to no long-term sequelae.”

According to Dr. Coralic, lipid emulsion therapy has been used for some time to treat toxicity related to other lipid-binding medications such as local anesthetic agents (Clin Toxicol 2011;49:801-809). Although the treatment’s precise mechanism of action is under debate, its efficacy is likely due to the lipid sink effect it exerts, swallowing drug molecules in the intravascular space. Like insulin therapy, it also provides energy

Clinical 7

Pharmacy Practice News • March 2013

ED Pharmacy to the stressed heart via fatty acids, and it increases intracellular fatty acid content, provides intracellular cytoprotection and increases calcium ion uptake ( (Anesthesiology 2012;117:180-187). Dr. Coralic said the treatment does carry “at least a theoretical risk” for pancreatitis, hyperlipidemia and interference with laboratory test results, but published case reports have found no serious complications. He said that although case reports should be cautiously interpreted given the potential for overrepresentation of positive

‘Clinicians need to look past the high doses of insulin and realize the tremendous benefits from this therapy.’ —Daniel Hays, PharmD results in the literature, the benefits of treatment outweigh any risks. “The potential adverse effects of lipid therapy are minimal when compared with the morbidity and mortality from severe CCB toxicity,” Dr. Coralic told Pharmacy Practice News. “Emergency department pharma-

cists and clinicians need to be aware of both HIE and lipid therapy as these are inexpensive, easily available and extremely efficacious treatments,” concluded Dr. Hays. For more detail on the rationale, evidence and treatment protocols for both HIE and lipid emulsion therapy, see “New

Treatments Tested for Cardiac Drug Poisonings” in the April 2012 issue of Pharmacy Practice News. (To access the article with your mobile phone, scan the QR code above.) For more information on lipid therapy, visit lipidrescue.org. —David Wild Drs. Mentler, Coralic and Hays reported no relevant ﬁnancial conﬂicts of interest.

8 Clinical

Pharmacy Practice News • March 2013

ED Pharmacy

Insulin Therapy Order Set Helps Guide an ‘Unusual Treatment’ New Orleans—Emergency department pharmacists in Minnesota have developed a standardized order set for hyperinsulinemia-euglycemia (HIE) treatment that may reduce apprehension about using the uncommon but effective therapy for severe calcium channel blocker (CCB) and β-blocker (BB) toxicity. Presenting the order set at the American Society of Health-System Pharmacists Midyear Clinical Meeting (poster

5-082), investigator Kimberly Glasoe, PharmD, noted that the impetus for development of the order set was inconsistencies and confusion when HIE had been initiated. “The first time HIE was tossed around as an option for CCB and BB toxicity, my pharmacist colleagues were uncomfortable filling the orders,” recalled Dr. Glasoe, an emergency medicine clinical pharmacist at Mercy Hospital, part of Allina

Health, in Coon Rapids, Minn., who developed the order set with Stacey VanSickle, PharmD, also an emergency medicine clinical pharmacist at Mercy. “We had experienced a lot of hesitation with both the nursing staff and the physicians caring for patients administered HIE,” said Dr. Glasoe. She and Dr. VanSickle examined pharmacy orders for four patients who had received HIE treatment for CCB or BB

overdose and found d tha h t the patients received r different acttivated charcoal dosess, dextrose and in nsulin concentrations and calcium salt formulations , as well as different potassium re p l a c e m e n t products and vasopresssors. There also a were inconsistenciees in the monitoring of arterial blood gases and d iionized i d calcium and the interval between blood glucose measurements, as well as variations in lactate testing. After reviewing the literature and consulting with local toxicology experts, they developed a standardized protocol that specifies, among other parameters, administering an initial IV bolus of 1 unit/kg followed by a concentrated infusion of 10 units/ mL at a rate of 1 to 10 units/kg per hour. It also recommends concurrent dextrose infusion, electrolyte administration and measurement of glucose every 10 minutes when insulin is being titrated and every 30 minutes once insulin is stabilized. The protocol also recommends measuring ionized calcium every 30 minutes with calcium gluconate administration, monitoring a basic metabolic panel and measuring lactate and arterial blood gas. Dr. Glasoe added that “because we had to build the drip into our electronic medical record each time we ordered an infusion, we built it in permanently.” She suggested other pharmacies should do the same to avoid potential treatment delays. Daniel Hays, PharmD, the clinical coordinator of emergency pharmacy services in the Departments of Pharmacy and Emergency Medicine at the University of Arizona Health Network, in Tucson, who was not involved in the research, said an order set like this should indeed make HIE treatment more manageable and shorten the time between the decision to go ahead with HIE and actual initiation of treatment. “Pharmacists should feel more comfortable, less apprehensive and know exactly what they need to order,” Dr. Hays said. “From a clinician’s point of view, the order set would be a reassuring guide to an unusual treatment.” —David Wild Drs. Glasoe and Hays reported no relevant ﬁnancial conﬂicts of interest.

Clinical 9

Pharmacy Practice News • March 2013

ED Pharmacy

ED Pharms Offer Handy Tips at Pearls Session

mergency department pharmacists shared their tips of the trade during the ED Pearls session at the recent American Society of Health-System Pharmacists Midyear Clinical Meeting. They offered advice on treating alcohol withdrawal, anticholinergic toxicity, pain during dermal procedures and more. Topical Options for Analgesia In ED Depend on Procedure There are various indications for topical analgesia in the emergency department (ED), and pharmacists should be aware of the available products and the clinical situations for which each product is best suited, said critical care pharmacist Courtney B. McKinney, PharmD, BCPS, in her ED pearl presentation. The multiple uses of topical analgesic products in the ED—including venipuncture, laceration or abrasion debridement, first-degree burns, etc—as well as the different patient populations being treated, have different analgesic requirements. “The product you choose depends on the clinical scenario,” and the procedure being performed, said Dr. McKinney, from Intermountain Medical Center, in Salt Lake City. There are many available formulations, such as aerosols, creams, gels, ointments and solutions for injection, as well as compounded products. The key considerations in product selection include whether the skin is broken or intact, the surface area of the involved skin, what procedure is being done, and how long the procedure takes. Three commonly used products are lidocaine 2.5%, prilocaine 2.5% oil-in-water eutectic mixture (EMLA); lidocaine 4% liposomal cream (LMX, Ferndale); and lidocaine 4%, epinephrine 0.05%, tetracaine 0.5% (LET) solution or gel. The dose of EMLA is 1 to 2 g/cm2 with a maximum of 5 mg/kg of lidocaine. It can be applied only to intact skin and requires an occlusive dressing. The onset of action is 45 to 60 minutes and the effect lasts two hours after removal of the dressing. Dr. McKinney noted that the benefits of EMLA are that “it is long-lasting, can be used on mucous membranes and has been used in neonates.” However, because of its relatively long onset, she said that it is best used in “planned dermal procedures.” Lidocaine 4% liposomal cream is another commonly used topical anesthetic. The dose is also 1 to 2 g/cm2 with a maximum of 5 mg/kg of lidocaine. It also should be used on intact skin only and the skin should not be washed before application “because the oils actually help it to get absorbed down into the dermal layers,” noted Dr. McKinney. Lidocaine 4% liposomal cream does not require an occlusive dressing,

but she said it is recommended. Its onset is 30 minutes and the duration is 60 minutes. Dr. McKinney noted that

it is good for minor burns or planned/ nonemergent dermal procedures, but there are no safety data on this product in children younger than age 2. LET solution or gel is a sterile compounded product that also has a role in certain ED pain scenarios, noted Dr. McKinney. The dose she recommended is 1 to 3 mL, again with a maximum of 5 mg/kg of lidocaine, applied directly to open lacerations and wounds. It has a

relatively fast onset (20 minutes) and its duration is 45 to 60 minutes. An advantage of this product is that it can be used on open skin, she said, adding, “this is our winner for lac repairs and debridements.” Also, the epinephrine component can help “stem bleeding if you’re doing a lac repair, so that’s a bonus.” One disadvantage of this product, however, is that the epinephrine “may cause vascular compromise,” said Dr. McKinney. “So you just want to be careful and watch out for that.”

•

see PEARLS, page 10

Accurate, Safe, Sterile Drug Compounding Automation

Right at Your Fingertips

Introducing the first user-controlled automated compounding system for the safe preparation, reconstitution, and delivery of hazardous drugs. The Diaana system lets you reduce the risk of exposure to hazardous drugs w while helping to maintain the sterility of the mix and minimize physicaal stress to pharmacists and technicians. Using many of ICU Meedical’s clinically proven ChemoClave™ needlefree closed system components, Diana fits under the hood of your existing biological safety cabinett to protect clinicians from exposure to hazardous drugs and accidental needlesticks, while protecting the final patient preparation

Diana

from exposure to environmental contaminants.

™

Hazardous Drug Compounding System

800.824.7890 | go.icumed.com/dianaPPN

10 Clinical

Pharmacy Practice News • March 2013

PEARLS continued from page 9

For wounds that cover a very large surface area, she said, “sometimes it’s not practical to use those prepackaged products … you may exceed your maximum dose of lidocaine.” Another option for wounds that cover a large surface area is a “make your own” product known as “Lido-Lube.” A recipe she learned while a resident consists of 3 to 4 mg/kg of lidocaine (as 1% or 2% solution for injection) combined with surgical lubricant until it reaches the consistency of a thin gel. This product then can be applied generously to the wound.

Physostigmine Resurrected For Anticholinergic Toxicity Despite historical controversy, physostigmine can be used to treat anticholinergic toxicity, according to ED pharmacist Nicole M. Acquisto, PharmD, BCPS. The controversy over the use of physostigmine “is rooted in a handful of case reports from the late 1970s to early 1980s,” said Dr. Acquisto. When used for anticholinergic toxicity, most often with tricyclic antidepressant [TCA] overdoses, it “was found to cause seizures and asystole,” she said. However, she added, the seizures were “most often due to a fast rate of administration or … other medications the patient ingested that cause seizure activity” and the asystole was “most often seen in patients with underlying cardiac arrhythmias or conduction disorders” ((Ann Emerg Med 1980;9:588-590; Curr Opin Pediatr 2007;19:201-205). Dr. Acquisto, an emergency medicine clinical pharmacy specialist and an assistant professor in the Department of Emergency Medicine at the University of Rochester Medical Center, in Rochester, N.Y., pointed to additional data supporting the effectiveness of ED pharmacy. A study of 52 patients, for example, showed that physostigmine worked better and faster than benzodiazepines for reversing agitation and delirium associated with anticholinergic toxicity due to pure anticholinergic agents, antihistamines, atypical antipsychotics and cyclic antidepressants ((Ann Emerg Med d 2000;374-381). She also pointed to a review of eight years of experience using physostigmine in this setting that showed a low rate of seizures (<1%) (Clin Toxicoll 2010;48:648. Abstract 214.) and no cardiac arrhythmias and one 39-patient study during which one patient had a brief seizure ((Ann Emerg Med d 2003;42:14-19). Dr. Acquisto noted that the ED staff at the University of Rochester Medical Center uses “physostigmine for patients with moderate to severe anticholinergic toxicity” to prevent patients from worsening to the point of needing intervention such as intubation, catheterization, or chemi-

cal or physical restraints. For adults, they use a dose of 0.5 to 2 mg, undiluted and given by IV push over 10 minutes, and in children, they use 0.01 to 0.03 mg/kg, also undiluted and given by IV push over 10 minutes. The onset is five to 10 minutes and the duration is 30 minutes to two hours, said Dr. Acquisto, noting that additional doses may be needed. She said that they will even use it in patients who have anticholinergic toxicity related to TCA overdoses but not in patients who have contraindications, such as cardiac conduction abnormalities, bradycardia and gastrointestinal/ urinary obstructions.

Propofol Makes Sense For Alcohol Withdrawal The neurobiochemistry of propofol makes it a useful option for treating patients with alcohol withdrawal, according to Darrel W. Hughes, PharmD, BCPS, a clinical specialist in emergency medicine at the University of Texas Health Science Center (UTHSC) at San Antonio. Alcohol withdrawal “affects up to onethird of hospitalized patients, and it is associated with an increased mortality” of up to 300% in that population, said Dr. Hughes, referring to several studies ((N Engl J Med d 1995; 333:1058-1065; Crit Care Med d 2010; 38[suppl]:s494-s501). The criteria for diagnosing alcohol withdrawal include two or more of the following symptoms that develop hours to days after cessation or reduction of alcohol: autonomic hyperactivity, increased hand tremor, insomnia, nausea or vomiting, visual, tactile or auditory hallucinations or illusions, psychomotor agitation, anxiety and grand mal seizures. Chronic ingestion of alcohol decreases γγ-aminobutyric acid type A (GABA-A) receptor function and increases N-methyl-d-aspartate (NMDA) receptor function. When someone is drinking, alcohol acts as a GABA agonist, creating a balance between the two neurotransmitters, but during alcohol withdrawal, the

GABA NMDA

GABA

NMDA

decreased GABA activity results in tremors, diaphoresis, tachycardia, anxiety and seizures, and the NMDA overload results in delirium, hallucinations and seizures. Benzodiazepines, which are commonly used to treat alcohol withdrawal, bind GABA-A, controlling agitation and reducing the duration of withdrawal symptoms, complications and mortality. But Dr. Hughes said that chronic use of benzodiazepines could lead to GABA-A receptor downregulation and refractoriness. “We do see patients who need really high doses because they often have downregulation of receptors.” To address this problem, at UTHSC at San Antonio, once a patient is “determined to be refractory” to benzodiazepines, they try propofol, according to Dr. Hughes. At a dose of 5 to 80 mcg/kg per minute, propofol activates GABA-A receptors and inhibits the NMDA and glutamate receptor, better imitating the neurobiochemistry of alcohol. “It has been shown to be effective for benzodiazepine-resistant [alcohol] withdrawal,” he said. Additionally, propofol has a short half-life and predictable metabolism, which make “it an attractive medication.” Dr. Hughes pointed out a few side effects to be aware of when using propofol in this setting: hypotension, hypertriglyceridemia and propofol-related infusion syndrome.

Intranasal Formulations Allow Quick Delivery in the ED New mucosal atomizers make it easier to administer medications intranasally, allowing for faster onset of effect for a variety of medications used in the emergency setting, according to a team from Chicago. In her ED pearl presentation, Renee Petzel Gimbar, PharmD, a clinical pharmacist and clinical assistant professor at the University of Illinois Hospital and Health Sciences System, said that the hospital uses intranasal (IN) formulations of drugs including midazolam, fentanyl and naloxone for its emergency medical services (EMS) and in its ED. Dr. Petzel Gimbar noted that mucosal atomizer devices deliver medication in a fine mist absorbed via the nasal mucosa. The maximum volume administered in each nostril is 1 mL, she noted, so it is important to use the highest medication concentration available to stay within that volume. “In adult patients, you are going to be limited by volume. You can only give that 2 mL total, so you may have to limit your use in overweight adult patients.” For patients with pain conditions, such as fractures, burns and sickle cell crisis, IN delivery of fentanyl “can get them their medication very quickly” to provide pain relief. This was demonstrated in a study of patients aged 1 to 15 years who were given either IV

Credit: Scancrit.com

ED Pharmacy

morphine or IN fentanyl as determined by their physician. According to the researchers, fentanyl dosed at 1.5 mcg/ kg decreased the time to administration by almost half compared with standard doses of morphine (32 minutes with fentanyl and 59 minutes with morphine) ((Acad Emerg Med d 2010;17:214-217). This is “key,” said Dr. Petzel Gimbar. “You can give a dose in triage if, for example, you have a long bone fracture, to get them some pain relief almost immediately” before they even go for an x-ray. The benefit of this approach was shown in a prospective, nonblinded interventional study of 81 patients aged 3 to 18 years with clinically suspected fractures ((Acad Emerg Med d 2010;17:1155-1161). During the study, the patients were weighed in triage and given IN fentanyl (2 mcg/kg, maximum dose 100 mcg). The investigators measured pain scores at 10, 20 and 30 minutes. Dr. Petzel Gimbar noted that 72% of the patients had relief within 10 minutes, with 70% to 78% having a sustained decrease in pain relief over the study period. “Only 9% required a rescue analgesic after 20 minutes,” she said, adding that “no side effects were reported.” Offering general dosing guidelines for fentanyl in this setting, Dr. Petzel Gimbar recommended 1 to 2 mcg/kg up to a maximum dose of 100 mcg, repeated once if no effect. Fentanyl at that same dose, as well as midazolam, can be used to achieve moderate sedation in the ED, noted Dr. Petzel Gimbar. In pediatric patients with seizures/status epilepticus, studies comparing IN midazolam with rectal diazepam in the prehospital and ED settings showed that IN midazolam was “as effective, if not more effective” ((J Child Neuroll 2002;17:123-126; Pediatr Neurol 2006;34:355-359; Pediatr Emerg Care 2007;23:148-153). For moderate sedation, she recommended an IN midazolam dose of 0.3 mg/kg up to a maximum of 10 mg, repeated once if no effect is seen. For opioid toxicity, Dr. Petzel Gimbar pointed to a retrospective study of EMS patients comparing IN and IV naloxone (dose for both, 0.4 to 2 mg initially, up to a maximum of 10 mg), during which paramedics in the field found the IN formulation “to be as effective as IV naloxone” ((Am J Emerg Med d 2010;28:296-303). She further noted that IN naloxone can be used in the ED in patients without IV access, but she cautioned that it is important to obtain IV access in such patients as soon as possible. —Sarah Tilyou

a Novartis company

Sandoz now offers Enoxaparin Sodium Injection, USP

WARNING: SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • Use of indwelling epidural catheters • Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • A history of traumatic or repeated epidural or spinal punctures • A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. Please see brief summary of full prescribing information including boxed warning on following page. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. www.us.sandoz.com © 2012 Sandoz Inc., a Novartis company. All rights reserved. SDZ0297 10/2012

Available in 7 strengths in pre-filled syringes. • 30 mg/0.3 mL pre-filled syringe 40 mg/0.4 mL pre-filled syringe 60 mg/0.6 mL pre-filled syringe 80 mg/0.8 mL pre-filled syringe 100 mg/1.0 mL pre-filled syringe 120 mg/0.8 mL pre-filled syringe 150 mg/1.0 mL pre-filled syringe • Sandoz is a member of the Novartis family of companies — a name you can trust for quality and reliability

Choose the full potential of generics.

Enoxaparin Sodium Injection,USP WARNING: SPINAL/EPIDURAL HEMATOMA Epidural or spinal hematomas may occur in patients who are anticoagulated with low molecular weight heparins (LMWH) or heparinoids and are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • Use of indwelling epidural catheters • Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • A history of traumatic or repeated epidural or spinal punctures • A history of spinal deformity or spinal surgery Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary. Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis.

- - - - - - INDICATIONS AND USAGE - - - - - Enoxaparin sodium injection, USP is a low molecular weight heparin [LMWH] indicated for: • Prophylaxis of deep vein thrombosis (DVT) in abdominal surgery, hip replacement surgery, knee replacement surgery, or medical patients with severely restricted mobility during acute illness • Inpatient treatment of acute DVT with or without pulmonary embolism • Outpatient treatment of acute DVT without pulmonary embolism • Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction [MI] • Treatment of acute ST-segment elevation myocardial infarction [STEMI] managed medically or with subsequent percutaneous coronary intervention [PCI] - - - - - - DOSAGE AND ADMINISTRATION - - - - - Indication

Dose

DVT prophylaxis in abdominal surgery

40 mg SC once daily

DVT prophylaxis in knee replacement surgery

30 mg SC every 12 hours

DVT prophylaxis in hip replacement surgery

30 mg SC every 12 hours or 40 mg SC once daily

DVT prophylaxis in medical patients

40 mg SC once daily

Inpatient treatment of acute DVT with or without pulmonary embolism

1 mg/kg SC every 12 hours or 1.5 mg/kg SC once daily*

Outpatient treatment of acute DVT without pulmonary embolism

1 mg/kg SC every 12 hours *

Unstable angina and non-Q-wave MI

1 mg/kg SC every 12 hours (with aspirin)

Acute STEMI in patients <75 years of age [For dosing in subsequent PCI, see Dosage and Administration]

30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg SC every 12 hours (with aspirin)

Acute STEMI in patients ≥75 years of age

0.75 mg/kg SC every 12 hours (no bolus) (with aspirin)

• See recommended durations for enoxaparin sodium injection therapy • *See recommendations regarding transitioning to warfarin therapy • Adjust the dose for patients with severe renal impairment

- - - - - - DOSAGE FORMS AND STRENGTHS - - - - - 100 mg/mL concentration: Prefilled syringes: 30 mg/0.3 mL, 40 mg/0.4 mL Graduated prefilled syringes: 60 mg/0.6 mL, 80 mg/0.8 mL, 100 mg/mL 150 mg/mL concentration: Graduated prefilled syringes: 120 mg/0.8 mL, 150 mg/mL - - - - - - CONTRAINDICATIONS - - - - - Active major bleeding Thrombocytopenia with a positive in vitro test for anti-platelet antibody in the presence of enoxaparin sodium Hypersensitivity to enoxaparin sodium Hypersensitivity to heparin or pork products - - - - - - WARNINGS AND PRECAUTIONS - - - - - Increased risk of hemorrhage: Use with caution in patients at risk Percutaneous coronary revascularization: Obtain hemostasis at the puncture site before sheath removal Concomitant medical conditions: Use with caution in patients with bleeding diathesis, uncontrolled arterial hypertension or history of recent gastrointestinal ulceration, diabetic retinopathy, renal dysfunction, or hemorrhage History of heparin-induced thrombocytopenia: Use with caution Thrombocytopenia: Monitor thrombocytopenia closely Interchangeability with other heparins: Do not exchange with heparin or other LMWHs Pregnant women with mechanical prosthetic heart valves and their fetuses may be at increased risk and may need more frequent monitoring and dosage adjustment

- - - - - - ADVERSE REACTIONS - - - - - Most common adverse reactions (>1%) were bleeding, anemia, thrombocytopenia, elevation of serum aminotransferase, diarrhea and nausea To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. - - - - - - DRUG INTERACTIONS - - - - - Discontinue agents which may enhance hemorrhage risk prior to initiation of enoxaparin sodium injection or conduct close clinical and laboratory monitoring - - - - - - USE IN SPECIFIC POPULATIONS - - - - - Severe renal impairment: Adjust dose for patients with creatinine clearance <30 mL/min Geriatric patients: Monitor for increased risk of bleeding Patients with mechanical heart valves: Not adequately studied Hepatic Impairment: Use with caution Low-weight patients: Observe for signs of bleeding

Manufactured by Baxter Pharmaceutical Solutions LLC for Sandoz Inc., Princeton, NJ 08540 Rev. May 2011

Clinical 13

Pharmacy Practice News • March 2013

Critical Care

PREFILLED SYRINGES READY-TO-USE MEDICATIONS

continued from page 1

during the first surgical cases of the day, with an eye toward resolving any significant safety gaps found, explained Rachel Stratman, PharmD, the lead study author and a clinical pharmacist for perioperative services at BarnesJewish Hospital. After collecting initial data for 100 cases, Dr. Stratman and her colleagues found several problems that could have led to patient harm. For example, anesthesia providers often would prescribe, prepare and administer medications with no double-check, and providers usually would include only partial information on the blank portions of syringe labels, such as the drug name, but not necessarily other important details, such as drug concentration or expiration date. Moreover, anesthesiologists often would prepare medicines such as atropine for emergent situations; however, if the drugs were not administered during the case, they were discarded or inappropriately kept beyond their expiration for use on subsequent cases. Based on those findings, Dr. Strat-

man’s team made several improvements to the handling processes for anesthesia medications. One step, she noted, was to standardize anesthesia medication trays across 64 ORs and 14 remote areas. The trays incorporated ready-to-use syringes of medications commonly used for anesthesia induction, reversal and emergencies. The quality improvement team also standardized vasoactive drip concentrations and diluents across the institution, and increased production of compounded sterile products dispensed to anesthesiologists upon request. The pharmacy purchased premixed ready-to-use syringes of eight commonly used medications, including lidocaine, succinylcholine and neostigmine, from a compounding pharmacy. The department also boosted the production of vasoactive drips such as epinephrine and dobutamine, and provided bolus doses of drugs such as insulin, epinephrine and norepinephrine. The ready-to-use, prefilled syringes had tamper-evident seals, so if they were not used for one patient, they could be used safely for another patient.

‘In our hospital, [outsourcing anesthesia drug preparation] has been instrumental in improving the management of medications in the anesthesia environment.’ —Rachel Stratman, PharmD

Are Outside Compounders Safe?

urchasing premixed, ready-to-use syringes can be a boon to timestrapped pharmacy and anesthesia deparments. But the strategy comes with a heightened risk, based on the continuing fallout from a fungal meningitis outbreak last fall that has been tied to contaminated epidural steroid injections prepared by the New England Compounding Center (NECC), in Massachusetts (see related article, page 1). As of Feb. 4, 696 patients in 20 states reported cases of fungal infection including meningitis; 45 of those patients died. Massachusetts regulators last fall found problems at five other compounding pharmacies, including Ameridose, owned by the same parent as NECC. (In December, NECC filed for bankruptcy.) At press time, several additional compounders had been cited by officials for serious safety lapses. Before these developments, “I would have assumed that the label reflected the drug and that it was sterile,” said Robert Johnstone, MD, a professor of anesthesiology at West Virginia University, in Morgantown. “Now that really has me concerned.” Dr. Johnstone said pharmacists and anesthesiologists at his hospital have since been trying to do more of their own compounding—a process that itself is not free of risk—and the pharmacy purchasing team has gone back to relying on major suppliers for their drug shipments. Shutdowns at NECC and other compounders also have led to a series of “rotating, unpredictable shortages” of some anesthetics, he said. In fact, “two days out of every week now, I’m dealing with some shortage and substituting a drug that isn’t as effective in order to get the anesthetic [case] done.” Dr. Meyer said that the goal at her hospital now “is to try to do as much compounding as possible in-house” and cut back on outsourcing. The NECC event has “cast a shadow of doubt in many pharmacists’ minds about how we should select a compounder,” she said. One can have checklists, interview companies and conduct site visits to observe processes, Dr. Meyer added, but it’s difficult to ensure that the process observed one day is maintained every day. —Karen Blum

Six months after the intervention, the team observed the medication management practices of 100 additional cases. They found that the rate at which the medication concentration was included on the label increased significantly, from 31% before the intervention to nearly 78% after ((P<0.001). The percentage of provider-prepared IV admixtures was reduced from 91% to nearly 3% ((P<0.001). Using ready-to-use medications also significantly reduced medication waste, Dr. Stratman said. The largest reductions noted were for emergency medications such as atropine and phenylephrine (96% reduction) and succinylcholine (nearly 95% reduction). Dr. Stratman said she estimates the intervention has been “cost neutral” to the hospital, with the costs of outsourcing medications partially offset by the savings in otherwise wasted medicines (Table). “But when you look at

the [impact of the initiative on] quality and safety for the patients … it’s what’s right to do even if it costs a little more.” She added that the safety initiative “has been very successful from the anesthesiology perspective and the pharmacy perspective.” Outsourcing ready-to-use medications is a trend, Dr. Stratman said, although “the financial impact associated with outsourcing costs can cause institutions to hold off on making the transition…. In our hospital, it has been instrumental in improving the management of medications in the anesthesia environment.”

Avoid Do-It-Yourself Drug Prep Tricia Meyer, PharmD, FASHP, the director of pharmacy at Scott & White Healthcare, in Temple, Texas, and an assistant professor of anesthesiology at Texas A&M University College of Medicine, in College Station, participated in

•

see PREFILLED SYRINGES, page 14

Table. Cost of Medication Wastea Pre-Outsourcing

Post-Outsourcing Waste

Costb

Mg Reduction

$87.36

300 mg

$10.56

90.6%

2,250 mg

$176.91

200 mg

$22.32

91.1%

Succinylcholine

9,600 mg

$132.96

500 mg

$26.15

94.8%

Vecuronium

80 mg

$37.12

30 mg

$22.38

62.5%

Glycopyrrolate

10 mg

$13.80

1 mg

$4.61

90%

Phenylephrine

77.6 mg

$79.15

3 mg

$11.40

96.1%

Atropine

55 mg

$127.68

2 mg

$6.22

96.4%

Medication

Waste

Cost

Lidocaine

3,200 mg

Rocuronium

Waste is defined as withdrawal of medication from the manufacturer’s packaging or removal of tamperevident seal but not documented as administered during the surgical case. b

$1 added to the hospital cost of the vial to account for cost of preparation, labor and supplies.

14 Clinical

Pharmacy Practice News • March 2013

Critical Care

PREFILLED SYRINGES

‘Prefilled syringes save time for anesthesiologists, allowing that time to be utilized for necessary monitoring of the patient and the anesthesia equipment.’

continued from page 13

the APSF Medication Safety Conference. She said the APSF recommends that provider-prepared medications should be discontinued whenever possible in favor of providing prefilled syringes for anesthesia care providers. “Prefilled syringes save time for anesthesiologists, allowing that time to be utilized for necessary monitoring of the patient and the anesthesia equipment,” she said. “That’s why it’s important, but there’s a premium price [to be paid] for purchased, prefilled syringes. When you buy from a compounding pharmacy, you have to pay not only for the drug but for the preparation time, as expected.” In the wake of the Massachusetts compounding crisis, however, vetting vendors can be a risky proposition (see sidebar, “Are Outside Compounders Safe?,” page 13). Still, Dr. Meyer said she supports flexibility—that is, using prefilled syringes drawn up by the hospital pharmacy, or purchased when possible and when budgets or staffing resources allow. As for the strategy employed at Barnes-Jewish, “their project results were impressive,” Dr. Meyer said. “The ability to document cost neutrality is important for other hospital pharmacies to consider and possibly use to help justify use of prefilled syringes.” For those concerned with costs, she said, evaluate what drugs are most consistently used and/or frequently wasted and begin with a minimal number of medications in prefilled syringes. The issue of waste in the OR set-

ting is important, she stressed. Many times, anesthesia care providers may predraw syringes waiting for emergent cases, and the predrawn syringes need to be destroyed within an hour if they’re unused. The Barnes-Jewish researchers “were able to determine the cost of waste, which is not easy, and use the amount saved with their new process to justify the cost of the prefilled syringes,” she said. “That’s strong work.”

—Tricia Meyer, PharmD Managing the prefilled or premixed medications “does take more vigilance on the part of pharmacists because of shorter beyond-use dating,” Dr. Meyer said. Premixed syringes may have expiration dating of 30 to 90 days, whereas

merican Health Packaging (AHP) announced that it has launched three additional products to its growing unitdose line: Desmopressin Acetate 0.1 mg and 0.2 mg tablets (AB-rated to DDAVP®); Naltrexone HCl 50 mg tablets (AB-rated to Revia®); and Sildenafil Citrate 20 mg tablets (AB-rated to Revatio®). The latter two products are AHP exclusives, according to a company press release, as is the 0.1-mg dosage of Desmopressin. AHP’s line of products now contains more than 380 SKUs, many of them industry exclusives, the company noted. “These unit-dose launches are part of an ongoing commitment to support health systems’ BCMA initiatives while also promoting efficiency in pharmacy operations,” the press release stated. “All American Health Packaging unit-dose items are bar coded to the dose level and feature an extended shelf life. In addition, our cartons feature color-coded labels with ‘tall man’ lettering to more easily distinguish them in the pharmacy prior to dispensing.” For more information, visit http://www.americanhealthpackaging.com.

—Karen Blum

Download the

App available on iTunes Read the latest issue on your iPad

New Product American Health Packaging Launches New Unit-Dose Products

a vial from the manufacturer can last much longer. As a result, she noted, pharmacy staffers need to check inventory for expirations more frequently.

3 Ways to Download: Go to the App Store on your iPad and search for ‘Pharmacy Practice News’ Go to www.clinicaloncology. com/apps and click on Available on the App Store icon to download the app from the iTunes store. Scan this code with your iPad and download the app from the iTunes store.

Hem/Onc Pharmacy 15

Pharmacy Practice News • March 2013

In Focus

APL continued from page 1

improved survival over ATRA and chemotherapy, was reported at the annual meeting of the American Society of Hematology (ASH; abstract 6). “These results are very important. This is the first highly effective treatment of APL ... without chemotherapy,” said Pierre Fenaux, MD, PhD, a professor of hematology at the Hopital Avicenne in Bobigny, France, who was not involved with the study. “It is applicable to the

majority of APL [patients]. It has limited toxicity and, therefore, allows treatment in frail patients and in emerging countries. It paves the way for targeted therapies in other acute leukemias.” Frontline management of APL includes ATRA, a derivative of vitamin A, plus chemotherapy and ATRA plus ATO, but the latter strategy has only demonstrated high efficacy with reduced toxicity in small, single-center studies. To put the ATRA plus ATO regimen to a thorough test, researchers from the Italian GIMEMA (Italian Group for Hae-

matological Diseases in Adults) cooperative group and the German cooperative groups of SAL (Study Alliance Leukemia) and AMLSG (German AML Cooperative Group) randomized 79 patients to ATRA plus ATO and 80 patients to ATRA plus chemotherapy. The study included lowand intermediate-risk patients aged 18 to 70 years, with World Health Organization performance status of 2 or lower. Patients randomized to arm A received ATO 0.15 mg/kg plus ATRA 45 mg/m2 daily until a complete response, then ATO five days per week, four weeks on,

Table. Intergroup APL0406 Study: Survival at Two Yearsa

e-Newsletters and e-Alerts Get the latest news from the best-read health-system m pharmacy pub blication in the country delive ered directly ectl to o your computerr or mo mobile device for free e!

ATRA Plus Chemotherapy

Event-free survival

97.1%

85.6%

Overall survival

98.7%

91.1%

ATRA, all-trans retinoic acid a

pharmacypracticenews.com

ATRA Plus Arsenic Trioxide

P=0.02 for all comparisons.

‘[The new regimen] provides patients with an option that minimizes the longterm toxicities associated with anthracylines. This is important in a cancer where cure rates are reaching 80%.’ —Cindy L. O’Bryant, PharmD, BCOP

Each ch installment con ontains articles fro om the cur urrent month’s issue ahead of print, as well as llinks nk to podcasts and other Web-exc clusive s content

Scan this QR code to register for free

Read the latest issue on your iPad Download it for free in the App Store Now available on

iTunes

four weeks off, for a total of four courses; and ATRA two weeks on and two weeks off for a total of seven courses. Patients in arm B received the standard ATRA plus idarubicin induction followed by three cycles of anthracycline-base plus ATRA consolidation and low-dose chemotherapy and ATRA for maintenance. The median follow-up was 34.3 months. Event-free survival at two years, the primary end point, was improved in patients receiving ATRA plus ATO compared with ATRA plus chemotherapy (97.1% vs. 85.6%; P=0.02; Table). Overall survival was improved in patients receiving the chemotherapy-free regimen (98.7% vs. 91.1%; P=0.02). Diseasefree survival was improved in the ATRA plus ATO arm compared with the ATRA plus chemotherapy arm (97.1% vs. 90.3%; P=0.14). All patients in the ATO arm and 95% of patients in the chemotherapy arm achieved a complete remission. Grade 3/4 thrombocytopenia occurring for more than 15 days was more frequent in the chemotherapy arm in both induction therapy (69% vs. 45%; P≤0.0001) and consolidation cycles 1 (13% vs. 4%; P≤0.0001), 2 (46% vs. 4%) and 3 (10% vs. 2%; P≤0.0004). Grade 3/4 neutropenia occurring for more than 15 days was also more common in patients

•

see APL, page 16

Hem/Onc Pharmacy

Pharmacy Practice News • March 2013

In Focus

A Career of Excelllence Robert J. Ignoffo, PharmD, professor of pharmacy at Touro University California and clinical professor emeritus, University of California, San Francisco (UCSF), has been honored with the Award of Excellence for 2012 from the Hematology/Oncology Pharmacy Association (HOPA). This award, which recognizes a member who has made significant, sustained contributions to hematology/oncology pharmacy practice, will be presented at the HOPA annual meeting on March 20, 2013. Pharmacy Practice News editor David Bronstein recently spoke with Dr. Ignoffo about the award and the honoree’s views on the state of the specialty. PPN: It’s easy to shrug off awards as something that other people care about—until you get one yourself. How did you feel when you found out you had won the HOPA award? Dr. Ignoffo: It feels wonderful to be appreciated and recognized by your colleagues. You work so hard to reach a high level in your career, one that you are truly proud of. And although it’s important to have an inner sense of accomplishment, when someone else recognizes you for those efforts and achievements, it’s absolutely a great feeling. PPN: Is there one achievement in your career that you are particularly proud of? Dr. Ignoffo: The development of my clinical practice in the 1970s—at a time when the concept of clinical pharmacists playing a significant role in oncology care was really in its infancy—is a highlight for me. From the start, my strategy was to emphasize collaboration between pharmacists, oncology nurses, physicians and students. To be able to bring all of those players together and have it, rather early on, be such a successful merger—that is always something I will be proud of. PPN: Speaking of your work with students, you’ve won a past award for your work as a pharmacy preceptor. How satisfying is it to mentor students in oncology pharmacy?

Dr. Ignoffo: It’s hard to ad dequately express the satisfaction I hav ave gotten over the years teaching and d guiding these students. Bringing them m along to learn this complicated ffield, even though I’m only with theem for about six weeks per rotaation, to see them come into the program totally green, and by the end, having learned a great deal about oncology and how to manage patients, it’s just incredibly rewarding to see that progression. And it gives me the opportunity to convey to them that graduating pharmacy school isn’t the end goaal; you need to be a continual seeeker and learner. That’s true of anyy profession, but in oncology phaarmacy, it’s particularly important, given its complexity and never-ending stream of new information. I’m also proud of the fact that these early teaching and mentoring efforts at UCSF eventually led to the development of the university’s full-fledged oncology pharmacy residency program. It was one of the first to be launched in the United States, and continues to this day to be very popular, with two oncology pharmacy residents doing postgraduate year 2 experiential rotations. So, it has grown over the years and I am

APL

low-/intermediate-risk patients with APL,” said Francesco Lo-Coco, MD, from the University of Tor Vergata in Rome, who presented the study at ASH. “This regimen is associated with less hematologic toxicity and more, yet manageable, hepatic toxicity and QTc prolongation. We think this regimen may become the new standard of care for [patients who are at] low/ intermediate risk for acute promyelocytic leukemia.”

continued from page 15

receiving chemotherapy in induction therapy (62% vs. 35%) and consolidation cycles 1 (25% vs. 4%; P=0.0001), 2 (54% vs. 4%; P≤0.0001) and 3 (17% vs. 3%; P=0.0117). Toxicities more common in the ATRA plus ATO arm included QTc prolongation (13% vs. 0%; P=0.0005), grade 3/4 toxicity (57% vs. 5%; P<0.0001) and leukocytosis, greater than 10 × 10 9/L (47% vs. 24%; P=0.007). “ATO plus ATRA is at least not inferior to ATRA plus chemotherapy for the two-year event-free survival in

Hem/Onc Pharmacist’s Take Cindy L. O’Bryant, PharmD, BCOP, an associate professor at the University of

proud to say that I got it started. PPN: The practice of oncology pharmacy has seen a lot of change since you first began in the specialty. Can you point to a few that are particularly striking? Dr. Ignoffo: The advent of the 5-HT3 antagonist drugs in the early-1990s caused a huge shift towards outpatient oncology care, because drugs such as

Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, in Denver, said the study “demonstrates that targeting therapy, as has been done in solid tumors for the last decade, is a viable option for hematologic malignancies.” The treatment, she added, “provides patients with an option that minimizes the long-term toxicities associated with anthracylines. This is important in a cancer where cure rates are reaching 80%.” Dr. O’Bryant stressed, however, that the chemotherapy-free therapy “will require us to think differently about treatment-associated toxicities and rou-

ondansetron gave us a powerful new treatment for controlling emesis and thus discharging patients earlier, where their continued care could be managed outside of the hospital. That shift toward the outpatient setting gained even more traction in the late 1990s and early 2000s, when targeted cancer therapies such as the tyrosine kinase inhibitors—many of them oral agents— became available. To this day, this continues to raise a huge issue: Once these patientts leave the hospital or the cancer outpaatient clinic, how do you ensure theey’re complying with their medicaations or that their adverse reacttions are being managed adeequately? This is a huge co ontinuity of care challenge th hat still has not been fully aaddressed. PPN: Where do you think the focus needs to be in order to strengthen continuity of care? Dr. Ignoffo: We need to do a better job of educating ccommunity pharmacists on how to help manage these h paatients’ side effects or compliaance issues, or when they have a problem obtaining the drug. In the case of adverse reactions, with h many of the new targeted therapies, wee are dealing with toxicity profiles that aare very different than older chemotherapy agents. For example, hypertension and dermatologic reactions require a different approach than we have had to deal with before. So we need to bring more community pharmacy representation into the fold, and HOPA is aware of the issue, but it’s quite a challenge: There aren’t many pharmacists who are board-certified in oncology pharmacy who work in the

•

see EXCELLENCE, page 26

tine drug screening prior to therapy, because ATO has a distinct side-effect profile,” she said. Additionally, “concurrent medications will need to be screened to minimize QTc prolongation events and more frequent monitoring of electrolytes, blood glucose, coagulation and hematologic toxicities will need to be performed.” —Kate O’Rourke Drs. Fenaux and O’Bryant have no relevant disclosures. Dr. Lo-Coco disclosed being on the speakers’ bureau for Cephalon and advisory committees for Boehringer Ingelheim.

TRANEXAMIC ACID INJECTION t "1 3BUFE UP $ZLMPLBQSPO¥Ħ t -BUFY 'SFF t 1SFTFSWBUJWF 'SFF NDC 0517

Strength

Size

Shelf Pack

0960-10

1000 mg/10 mL

10 mL

(100 mg/mL)

Single Dose Vial

1 Cyklokapron® is a registered trademark of Pfizer Health AB

Customer Service

Growth

Quality

Partnership

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

One Luitpold Drive | PO Box 9001 | Shirley, NY 11967 | Phone 800-645-1706 | Fax 631-924-1731

Visit us online at: www.americanregent.com

TRANEXAMIC ACID INJECTION

Rx Only

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

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

Clinical 19

Pharmacy Practice News • March 2013

Educational Review

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

CINDY L. O’BRYANT, PHARMD, FCCP, BCOP Associate Professor Department of Clinical Pharmacy Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado Anschutz Medical Campus Aurora, Colorado

hemotherapy-induced

nausea and vomiting (CINV) can significantly affect

patient care and quality of life, resulting in potential complications of metabolic disturbances, decreased functional ability, diminished general physical and mental well-being, weight loss, anorexia, esophageal tears, and reduced treatment compliance.1

The pathogenesis of CINV is multifactorial, involving release of multiple emetic transmitters—such as dopamine, serotonin, and substance P—that stimulate emesis by binding receptors in the gastrointestinal tract and central nervous system.2,3 Today’s approved antiemetics work by binding to the receptors of these proemetic neurotransmitters, thus preventing the emetic stimulus. Risk factors for CINV are numerous. The primary risk factor remains the emetic potential of the chemotherapy regimen based on the agent, dose, schedule and route of administration. Other risk factors include patient characteristics such as female gender, high levels of anxiety, age younger than 50 years, and a history of CINV with previous chemotherapy. CINV results in higher health care resource utilization, including hospital admissions and outpatient visits.4 Although substantial progress has been made in the treatment and prevention of CINV over the past 2 decades, this patient-focused treatment complication remains an important issue.

Antiemetic Information Today’s oncology practitioners have many antiemetic agents at their disposal. One of the most frequently used classes of antiemetic drugs is the serotonin (5-HT3) receptor antagonists. Three first-generation agents and 1 second-generation agent are available (Table 1). The drugs in this class are well tolerated, with constipation and headache being the most common adverse effects. Although the 5-HT3 receptor antagonists have relatively few drug–drug interactions, they have been associated with QT-interval prolongation. More specifically, IV dolasetron is not recommended for the prevention of CINV due to a potential increased risk for cardiac arrhythmias.1 Therefore, it is important to use caution in patients who are being managed with 5-HT3 receptor antagonists and are receiving other agents that prolong the QTc interval. Routine electrocardiogram monitoring for these patients is recommended during treatment.1 The neurokinin (NK1) antagonists are the newest class of medications for CINV. Aprepitant (Emend, Merck), the first drug in this class, is used with a

corticosteroid and a 5-HT3 receptor antagonist to prevent CINV associated with high-risk regimens. Aprepitant, a major substrate of cytochrome P450 (CYP) 3A4, has clinically significant drug–drug interactions with strong CYP 3A4 inhibitors, moderate-strong CYP 3A4 inducers, and other substrates of CYP 3A4. Fosaprepitant (Emend, Merck), the IV prodrug of aprepitant, also is used in combination with a corticosteroid and a 5-HT3 receptor antagonist for patients receiving high-risk CINV regimens; fosaprepitant should be given on day 1 only. Although this adds another option for route of administration, drug–drug interactions still must be considered and addressed. Corticosteroids are among the oldest agents used in prevention of CINV, and they remain a backbone of therapy. They are highly effective at preventing delayed CINV and they increase the effects of other antiemetic agents. Due to ease of dosing and experience with its use, dexamethasone is the preferred corticosteroid for antiemetic regimens. Common adverse effects of short-term use of dexamethasone include Text continues on page 21

20 Clinical

Pharmacy Practice News • March 2013

Educational Review Table 1. Ch Characteristics i i off C Commonly l Used dA Antiemetic i i A Agents

Drug

Place in Therapy

Common Adverse Drug Events

Drug–Drug Interactionsa

How Supplied

Dose

Other Notes

IV, PO capsules

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

Fatigue, hiccups, weakness

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

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

IV, PO

PO: 100 mg, day 1; as indicated, days 2-3 IV: Not recommended for CINV prophylaxis due to QT prolongation and risk for fatal arrhythmias

Constipation, diarrhea, fatigue, headache

Not clinically significant

Granisetron

IV, PO solution, PO tablets, transdermal patch

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

Not clinically significant

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

Ondansetron

IV, ODT tablets, PO soluble film, PO solution, PO tablets

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

Strong 3A4 inducers

Palonosetron (Aloxi, Eisai)

IV: 0.25 mg once

Not clinically significant

IV, PO, PO solution

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

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

Moderatestrong 3A4 inhibitors and inducers, 3A4 substrates

IV, PO solution, PO tablet

PO: 1-2 mg q4-6h PRN

Confusion, drowsiness, dystonia, QTc prolongation

Moderatestrong 2D6 and 3A4 inhibitors and inducers

Metoclopramide

PO tablet, PO solution, IV, ODT tablets

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

Dystonia, drowsiness, fatigue, restlessness, diarrhea

Not clinically significant

Prochlorperazine

IV, PO tablet, rectal suppository

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

Not clinically significant

Promethazine

IV, PO syrup, PO tablet, rectal suppository

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

Anticholinergic effects, extrapyramidal symptoms, reports of QTc prolongation, sedation, somnolence, tardive dyskinesia, urinary retention

Moderatestrong CYP 2B6 and 2D6 inhibitors and inducers

IV should be given via freeflowing IV catheter to prevent extravasation and tissue necrosis

PO capsule

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

Abnormal thinking, appetite stimulation, euphoria, paranoia, somnolence

Not clinically significant

Caution in elderly patients

Neurokinin antagonists Aprepitant/ Fosaprepitant (Emend, Merck)

High-risk regimens

Serotonin antagonists Dolasetron (Anzemet, Sanofi-aventis)

High- and moderaterisk regimens

Corticosteroids Dexamethasone

High-, moderateand low-risk regimens

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

Dopamine receptor antagonists Haloperidol

Adjunctive

Decrease dose by 50% for CrCl <40

Cannabinoids Dronabinol

Adjunctive

Clinical 21

Pharmacy Practice News • March 2013

Educational Review Table 1. Ch Characteristics i i off C Commonly l U Used dA Antiemetic i i A Agents

Drug

Place in Therapy

Common Adverse Drug Events

Drug–Drug Interactionsa

How Supplied

Dose

Other Notes

ODT, PO solution, PO tablet

Anticipatory: 0.5-2 mg PO tid Abnormal coordination, beginning the night before through appetite changes, day of treatment constipation, depression, impaired cognition, irritability, lightheadedPO/IV: 0.5-2 mg q4-6h PRN ness, memory impairment, Anticipatory: give night before sedation, somnolence, and morning of treatment weight gain/loss, xerostomia

Moderatestrong 3A4 inhibitors and inducers

ODT tablet, PO tablet

PO: 10 mg/d

Constipation, dizziness, extrapyramidal symptoms, insomnia, somnolence, weakness, weight gain, xerostomia

Moderatestrong 1A2 inhibitors and inducers

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

IV, PO elixir, PO capsule/ tablet

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

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

Major 2D6 substrates

Useful for dystonic reactions due to dopamine antagonists; should not be used as monotherapy

Benzodiazepines Alprazolam

Anticipatory, adjunctive

Lorazepam

IV, PO solution, PO tablet

Not clinically significant

Atypical antipsychotics Olanzapine

Adjunctive

Antihistamines Diphenhydramine Adjunctive

bid, twice daily; CINV, chemotherapy-induced nausea and vomiting; CrCL, creatinine clearance; CYP, cytochrome P450; HTN, hypertension; ODT, orally disintegrating tablets; PO, orally; PR, per rectum; PRN, as needed; tid, three times a day a

clinically significant CYP-enzyme drug–drug interactions.

Based on prescribing p g information and references 1 and 5.

Text continued from page 19

hyperglycemia, hypertension, and agitation (with higher doses); long-term use may result in immunosuppression. Historically, dopamine antagonists were among the first agents to show benefit in preventing CINV. However, effective prevention requires high doses of these agents and their efficacy is limited by an increased incidence of extrapyramidal reactions associated with these drugs at these doses. The development of 5-HT3 receptor antagonists has shifted the role of dopamine antagonists from primary prevention and treatment to the management of breakthrough or refractory nausea and vomiting (N/V).

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

delayed CINV refers to N/V with an onset of 24 hours up to 5 days after chemotherapy. Antiemetic prophylaxis for acute and delayed CINV should include treatment on day 1, with additional treatment on days 2 and 3 as indicated by the emetic risk associated with the agent(s) administered. Patients receiving high-risk chemotherapy regimens should receive an NK1 antagonist, a 5-HT3 receptor antagonist, and a corticosteroid on day 1 to prevent acute CINV. The 5-HT3 receptor antagonist and corticosteroid should be continued on days 2 to 3 (or 4) to prevent delayed CINV. Patients being treated with moderate-risk chemotherapy should receive a 5-HT3 receptor antagonist and corticosteroid on day 1 as prophylaxis for acute CINV. The ASCO guidelines note that the preferred 5-HT3 receptor antagonist is palonosetron (Aloxi, Eisai), as discussed below. An NK1 antagonist may be considered for select moderate-risk regimens such as AC (anthracycline plus cyclophosphamide). The 5-HT3 receptor antagonist and corticosteroid should be continued on days 2 to 3 of the moderately emetic regimen. If palonosetron is used, it should only be administered on day 1 due to its long half-life. If an NK1 antagonist is used, any of the 5-HT3 receptor antagonists are appropriate. A corticosteroid on day 1 only is recommended for regimens with a low risk for CINV, and minimal-risk regimens do not require routine prophylaxis.

Acute and Delayed Nausea and Vomiting Acute CINV refers to N/V occurring up to 24 hours after receiving chemotherapy, whereas

Breakthrough Nausea and Vomiting Breakthrough or refractory CINV can occur at

any point in a treatment cycle, despite adequate therapy for acute and delayed CINV. Clinical recommendations advise reevaluation of emetic risk and adjustment of therapy by adding an agent with a different mechanism of action, such as a dopamine antagonist. This escalation should be administered empirically with future cycles of the chemotherapy regimen. Other principles of management include using scheduled rather than as-needed antiemetics and assessing the patient for other potential causes of nausea and vomiting.

Radiation-Induced Nausea and Vomiting The risk for developing radiation-induced nausea and vomiting (RINV) depends on the characteristics of the treatment administered, including location of the radiation field, doses administered, and patterns of fractionation.5-7 The guidelines for RINV prevention are summarized in Table 3. A 5-HT3 receptor antagonist should be administered before the first fraction of highly emetic radiation therapy, and continued for 24 hours after completion of radiation. Patients also should receive dexamethasone during fractions 1 to 5. Patients undergoing moderately emetic radiation therapy should receive a 5-HT3 receptor antagonist with the same dosing as for highly emetic radiation (dexamethasone optional). Routine prophylaxis is not recommended for mildly or minimally emetic radiation therapy, although patients Text continues on page 22

22 Clinical

Pharmacy Practice News • March 2013

Educational Review Text continued from page 21

should have breakthrough medications (such as a 5-HT3 receptor antagonist or dopamine antagonist) available. Patients who experience breakthrough RINV should receive prophylaxis with subsequent radiation doses. If patients are receiving chemotherapy with radiation, the prophylactic regimen should be tailored to the treatment with the highest emetic risk. For example, if a patient is receiving moderately emetic chemotherapy with emetic radiation that has a low risk, the prophylactic regimen should be tailored for moderate-risk chemotherapy.

Table 2. Guideline Summary of Treatment Options For CINV: ASCO, ESMO, MASCC, NCCN Emetic Risk Category Higha

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

Moderatea

Day 1: 5-HT3 receptor antagonist (palonosetron preferred) + corticosteroidb ± NK1 antagonistc Days 2 and 3: 5-HT3 receptor antagonist (if did not use palonosetron) or corticosteroidb or NK1 antagonistc + corticosteroidb ± 5-HT3 receptor antagonist (if did not use palonosetron)

Lowa

Day 1: Corticosteroidb orr 5-HT3 receptor antagonist or metoclopramided or prochlorperazined Days 2 and 3: No routine prophylaxis

Minimal

No routine prophylaxis

Anticipatory

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

Multiple-day regimens

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

Anticipatory Nausea and Vomiting Anticipatory N/V can occur hours to days before chemotherapy and is estimated to occur in up to 29% of patients receiving chemotherapy.8 As anticipatory N/V is considered a learned response due to classical conditioning (ie, Pavlovian response), it is important to prevent CINV by using appropriate antiemetic regimens as noted in Tables 2 and 3. In this setting, behavioral interventions are effective and are a primary treatment modality. Techniques that may be used include hypnosis, systematic desensitization, relaxation techniques, and distraction. Due to their anxiolytic effects, benzodiazepines such as lorazepam and alprazolam also play a role in the management of anticipatory N/V.

Breakthrough

Clinical Challenges MULTIPLE-DAY REGIMENS Many patients receive multiday treatment regimens for their cancer. It is important that these patients receive appropriate CINV prevention and treatment on all days they are receiving chemotherapy. The antiemetic regimen chosen is based on the agent with the highest emetic risk. For moderately to highly emetic regimens, a 5-HT3 receptor antagonist and dexamethasone is recommended. Dexamethasone should be avoided with regimens that contain immunomodulating agents such as interleukin and interferon. Aprepitant or fosaprepitant can be added if significant delayed CINV has been associated with the regimen. Another treatment option would be the granisetron transdermal patch (Sancuso, Strakan), which is approved for use in chemotherapy regimens of up to 5 days in length. The use of palonestron and the need for repeated dosing in this setting is being investigated. ORAL CHEMOTHERAPY Management of CINV in patients receiving oral chemotherapy is critical to patient adherence, so swift action should be taken to control CINV. The number of new oral anticancer therapies approved and in development is increasing. Select oral agents, including temozolomide, busulfan (Myleran, GlaxoSmithKline), etoposide, procarbazine, and cyclophosphamide (≥100 mg/m2 per day), require prophylactic therapy for CINV that typically consists of a 5-HT3 receptor antagonist.1,2 Prophylactic therapy should be administered 30 to 60 minutes before the oral chemotherapy dose to ensure adequate serum concentrations. Because oral therapies may be continued for many days, it is important to consider the toxicities of antiemetic medications in addition to their

Antiemetic Regimen

• • • •

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

5-HT3, serotonin; ASCO, American Society of Clinical Oncology; CINV, chemotherapy-induced nausea and vomiting; ESMO, European Society for Medical Oncology; H2RA, histamine-2 receptor antagonist; MASCC, Multinational Association for Supportive Care in Cancer; NCCN, National Comprehensive Cancer Network; NK1, neurokinin 1; PPI, proton pump inhibitor a

Consider addition of lorazepam ± H2RA or PPI starting on day 1 per NCCN guidelines.

Dexamethasone preferred.

For select patients (eg, anthracycline + cyclophosphamide).

NCCN only.

Hypnotherapy, acupuncture, acupressure, etc.

Based on references 1, 2, and 5.

efficacy. When oral chemotherapy is being used in addition to parenteral chemotherapy, CINV prophylaxis for the parenteral agent should be given in addition to therapy required for prevention of CINV secondary to the oral agent. The majority of approved oral chemotherapy agents fall within the low to minimal emetic risk categories and do not typically require prophylactic therapy, although the patient should have breakthrough N/V medication available. The NCCN guidelines suggest administering metoclopramide or prochlorperazine prior to the first dose, then as needed during treatment.1 Adjuvant agents such as proton pump inhibitors, histamine 2-receptor antagonists, and lorazepam should be considered.

Economic Considerations There has been much discussion in the literature regarding the most cost-effective means of preventing CINV. As mentioned previously, CINV also can significantly increase health care resource utilization. A retrospective review of hospital database information for patients receiving highly and moderately emetogenic chemotherapy noted that delayed CINV was responsible

for the majority of health care visits associated with CINV.4 The mean costs of these visits ranged from $900 (emergency department visit) to $5,300 (hospitalization). This represents the potential for significant cost savings and emphasizes the financial effect of developing and initiating appropriate CINV prophylaxis in a patient receiving emetogenic chemotherapy.

New Directions Olanzapine is an atypical antipsychotic that antagonizes multiple neurotransmitters involved in the pathogenesis of CINV. It has an effect on dopamine, serotonin, α-adrenergic, muscarinic, and histamine receptors.9 In a study of patients receiving highly or moderately emetic regimens, olanzapine resulted in better quality of life and less delayed CINV compared with standard antiemetic therapy, but it did not have an effect on acute CINV. Olanzapine also has been evaluated in the treatment of breakthrough CINV in patients receiving highly emetogenic chemotherapy.10 Patients developing breakthrough N/V despite appropriate prophylaxis were randomized to receive olanzapine 10 mg daily or metoclopramide 1 mg 3 times daily Text continues on page 24

24 Clinical

Pharmacy Practice News • March 2013

Educational Review Table 3. Treatment Recommendations for RINV Text continued from page 22

Level of Radiation Emetogenicity (Area of Treatment) Recommended Therapy

for 3 days. More patients treated with olanzapine did not have emesis compared with those treated with metoclopramide (70% vs 31%, respectively), and olanzapine was associated with better nausea control. Navari and colleagues also conducted a randomized, placebo-controlled trial comparing olanzapine with aprepitant for prevention of CINV.11 All patients received palonosetron on day 1 of highly emetogenic chemotherapy. Patients in

Highly emetogenic (total body irradiation)

5-HT3 receptor antagonist + corticosteroid (days 1-5)

Moderately emetogenic irradiation (upper abdomen)

5-HT3 receptor antagonist ± corticosteroid (days 1-5)

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

Rescue with a 5-HT3 receptor antagonist. If patient experiences N/V administer a 5-HT3 receptor antagonist before future radiation

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

Rescue with a dopamine antagonist or 5-HT3 receptor antagonist. If patient experiences N/V administer a 5-HT3 receptor antagonist before future radiation

5-HT3, serotonin; N/V, nausea and/or vomiting; RINV, radiation-induced nausea and vomiting Based on references 1, 2, 5, and 6.

...To be Steadfastly Focused on Quality, Integrity and Reliable Supply. In just five short years, Amneal Pharmaceuticals has become the seventh largest generic pharmaceutical company in the U.S.* Our focus on quality, superb service levels and building strong relationships hasn’t changed. Now, we’re bringing that philosophy to the institutional market. With injectable and unit dose products populating our portfolio, we are fullyequipped to meet the critical need for dependable, high-quality product supply. Amneal’s collaborative, transparent and responsive way of doing business

delivers unsurpassed customer service, consistent quality, convenience and a steady pipeline of essential products to your organization. At Amneal, we understand that you are committed to providing each and every patient with the best care, in the right form, accurately and in a timely manner. Amneal has proven itself as a vital partner in that equation. * In prescriptions of unbranded generics per IMS, June 2012

the aprepitant group also received aprepitant on days 1 through 3 and dexamethasone on days 1 through 4. Patients in the olanzapine group received olanzapine 10 mg daily on days 1 through 4 and dexamethasone on day 1 only. Investigators found that olanzapine achieved rates of CINV control (defined using episodes of emesis and use of rescue medications) that were similar to those of aprepitant during the acute (97% vs 87%, respectively) and delayed (77% vs 73%, respectively) periods. Similar rates of nausea control were reported, and there were no significant differences in toxicity between the groups. The authors concluded that olanzapine has similar efficacy to aprepitant as antiemetic prophylaxis for highly emetogenic chemotherapy. Although it has not replaced aprepitant in the clinical guidelines, olanzapine is an important treatment option for CINV. Although considerable progress has been made in preventing and treating CINV, there still is significant room for improvement— particularly in preventing delayed CINV. Gabapentin, an analogue of γ-aminobutyric acid, has demonstrated some efficacy in postoperative N/V. A prospective study studied the effects of adding gabapentin to antiemetic prophylaxis on prevention of overall and delayed CINV.12 Patients were randomized to receive placebo or gabapentin 300 mg as follows: once daily on days 5 and 4 before chemotherapy, twice daily on days 3 and 2 before chemotherapy, and 3 times daily on 1 day before through 5 days after chemotherapy. CINV control was similar during the acute period (70% for both groups), and patients receiving gabapentin demonstrated a trend toward improved control of delayed CINV that was not statistically significant (control rates 72.5% vs 52.5%, respectively; P=0.06). For the overall study period, gabapentin showed a statistically significant benefit (65% for gabapentin vs 42.5% for placebo; P=0.04) in the rate of complete response. In this study, complete response was

Clinical 25

Pharmacy Practice News â&#x20AC;˘ March 2013

Educational Review defined as the absence of any nausea or vomiting and no use of rescue medications. The role of gabapentin in CINV prevention remains to be further clarified.

Conclusion Appropriate CINV prophylaxis in patients receiving emetogenic chemotherapy is critical. Effective, cost-conscious prevention of CINV can improve quality of life, patient compliance, and treatment outcomes, as well as foster appropriate consumption of medical resources. Newer antiemetics have significantly improved the control of acute N/V but have had less effect in the delayed setting. Continued research and the development of new antiemetics likely will lead to improved outcomes for patients. The recommendations in the major antiemetic guidelines are comparable and are represented in this review of CINV and RINV. It is important to realize that although these guidelines provide highly supported treatment plans they should be considered general recommendations. An individual risk assessment should be performed, the emetogenicity of a regimen identified, and an individualized treatment plan developed for each patient receiving chemotherapy or radiation therapy to achieve optimal CINV outcomes.

References 1.

National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Antiemesis v.1.2013. http:// www.nccn.org/professionals/physician_ gls/f_guidelines.asp. Accessed February 14, 2013.

2. Roila F, Herrstadt J, Aapro M, et al. Guideline update for MASCC and ESMO in the prevention of chemotherapyand radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(suppl 5): v232-v243. 3. Trigg ME, Higa GM. Chemotherapyinduced nausea and vomiting: antiemetic trials that impacted clinical practice. J Oncol Pharm Pract. 2010;16(4):233-244. 4. Burke TA, Wisniewski T, Ernst FR. Resource utilization and costs associated

Follow PPN on

@PharmPracNews

with chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy administered in the US outpatient hospital setting. Support Care Cancer. 2011;19(1):131-140. 5. Basch E, Prestud AA, Hesketh PJ, et al. Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol. 2011;29(31):4189-4198. 6. Feyer PC, Maranzano E, Molassiotis A, et al. Radiotherapy-induced nausea and vomiting (IRINV): MASCC/ESMO guideline for antiemetics in radiotherapy: update 2009. Support Care Cancer. 2011;19(suppl):s5-s14.

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

10. Navari RM, Nagy CK, Gray SE. The use of olanzapine versus metoclopramide for the treatment of breakthrough chemotherapyinduced nausea and vomiting in patients receiving highly emetogenic chemotherapy. Support Care Cancer 2013 Jan 12. [Epub ahead of print].

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

11. Navari RM, Gray SE, Kerr AC. Olanzapine versus aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a randomized phase III trial. J Support Oncol. 2011;9(5):188-195.

9. Tan L, Lui J, Lui X, et al. Clinical research of olanzapine for prevention of chemotherapyinduced nausea and vomiting. J Exp Clin Cancer Res. 2009;28:131-137.

12. Cruz FM, de Iracema Gomes Cubero D, Taranto P, et al. Gabapentin for the prevention of chemotherapy-induced nausea and vomiting: a pilot study. Support Care Cancer. 2012;20(3):601-606.

Hem/Onc Pharmacy

Pharmacy Practice News • March 2013

In Focus

EXCELLENCE continued from page 16

community setting. So there’s training, education and credentialing issues to work through. And as far as membership goes, HOPA has traditionally been very focused on hospital-based oncology pharmacy practice. So, bringing in the community practitioner that focuses on oncology requires a lot more consideration. The good news is that with the advent of Accountable Care Organizations, opportunities may be

available for collaboration between independent and chain drugstores in trying to educate community pharmacists about how best to follow their patients, and partnering with them in ways that ensures optimal outcomes. Another potential solution is to incorporate more technology into the equation, using telepharmacy, for example, to keep tabs on the degree to which patients are adhering to their oral chemotherapy. Several health systems have had success with this, but we need more of these programs implemented

nationwide to really address this issue. PPN: Another practice challenge that has been affecting pharmacy in general is ongoing drug shortages. What do you think the prospects are for these shortages being fixed any time soon? Dr. Ignoffo: People in the United States are not going to stand for continued non-access to important, potentially lifesaving cancer drugs. When you see outcomes that are worsened by shortages of important chemotherapy agents, as a recent NEJM M study outlined [2012;367:2461-2463; Pharmacy

Practice News, page 1, February issue], it’s an embarrassment for our country. So I am hoping, and actually am fairly confident, that some legislation eventually will solve this and keep the pipeline of these medications open. This is certainly part of HOPA’s legislative agenda. PPN: If you were to take the metaphorical pulse of oncology pharmacy, what would it indicate about the overall health of the specialty? Dr. Ignoffo: There’s no question that an oncology pharmacist offers a great deal to the care of the cancer patient, so in that sense, this is indeed a healthy and valuable specialty. Thus, I don’t think it’s a surprise that there continues to be a great demand for pharmacists with oncology expertise. The problem is whether we can continue to meet that demand. And I raise that question because as it stands right now, there simply are not enough pharmacy residencies available, not just in oncology but in all of pharmacy practice, to meet the growing demand for our valuable clinical services. We need to be proactive in this regard, and so we’re working on a project right now at Truro, in collaboration with several organizations, including BPS [Board of Pharmacy Specialties], ASCO [American Society of Clinical Oncology], NCI [National Cancer Institute], AACP [American Association of Colleges of Pharmacy] and hopefully HOPA, where we are going to examine the state of the oncology pharmacy workforce. This is important work, because it will give us a sense of how we are positioned to respond to a related workforce issue: a looming shortage of medical oncologists. A survey by researchers at the American Association Of Medical Colleges [AAMC] estimates that by 2012, there will be a shortage of approximately 15,000 medical oncologists [[J Oncol Practt 2007;3:79-86]. This should result in the increased use of physician extenders. The AAMC study cites nurse practitioners and oncology nurses as potential caregivers who could fulfill that role, but does not mention pharmacists. This is a problem we need to address, but the larger issue is the lack of residency programs in oncology pharmacy. If we don’t fix that problem, we are going to miss the boat when it comes to filling the looming physician gap. So, we face many exciting challenges ahead—and opportunities as well. One key to success will be for pharmacists to obtain health care provider status. It will take a concerted effort on our part and HOPA’s to be at the table to effect legislation that will give us that status. On a personal level, I know that I certainly won’t slow down any time soon, and look forward to continue helping this specialty grow and prosper. ■

Ops & Mgmt 27

Pharmacy Practice News • March 2013

Leadership in Action

Competitive Vs. Cooperative Negotiation

s managers we are routinely involved in negotiations. Negotiations may be with a boss, a subordinate, a peer or a vendor. Or perhaps you are negotiating for a new job. Regardless of with whom you are negotiating, you need to determine your mindset going into the negotiation. Are you approaching it as a zero-sum game? Is it a win/lose contest? Or is it a “fixed pie,” where you want to get the greatest number of pieces? We’ve been looking at some of the principles of conflict resolution from Ken Sande’s The Peace Maker (Baker Books, 2004). In this article, we look at conflict resolution in the process of negotiation. Scarcity mentalityy often is the approach used in many negotiations. This infers that there indeed is a fixed pie—that is, there are limited resources and the total size of the pie cannot increase. Abundance mentality, in contrast, means that the size of the entire pie can increase. For example, let’s say that you are negotiating for a new piece of automation equipment in your pharmacy. The key to your negotiation is your return on investment (ROI). In other words, it is the creation of new sources of dollars to help pay for the equipment. Can you reduce your inventory to have a one-time savings that will help support the purchase of this new equipment? If we are fighting for a limited amount of capital dollars that are fixed, then we may be in a “dogfight” with other managers. If, however, we can show additional savings that will create new capital, then we are increasing the size of the pie or pool of dollars available.

Cooperative Vs. Competitive Negotiation Many people automatically resort to a competitive style of negotiation. This may be the result of conditioning in their professional upbringing. It’s like a tugof-war; whoever can pull on the rope the hardest wins. The fixed- pie competitive attitude discourages communication, openness, flexibility and creative solutions. It also often destroys relationships, which hinders future negotiations. This attitude actually is quite self-centered. “I want it my way.” I frequently see this play out between pharmacists and physicians during the process of standardizing order sets or treatment pathways. I have even seen many instances of intimidation coming from department heads and other professionals “pulling rank.” So what is the best solution? Using cooperative negotiating is actually more

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, of Brockton, Mass. Mr. Anderson welcomes your input on leadership issues, at anderson489@ comcast.net.

Ernest R. Anderson Jr., MS, RPh

efficient in the long run, allows creativity and new information sharing and preserves relationships. It demonstrates concern for others and shows humility. This does not mean, however, that you are a “pushover”—the intention is that both sides contribute to the solution. Mr. Sande uses the acronym PAUSE to encourage cooperative negotiations (box). Let’s take a look at each aspect and determine how we can practically use each one toward a successful negotiation.

Prepare Ask anyone who has put together a Pharmacy & Therapeutics committee agenda and he or she will tell you how important preparation is to the success of the meeting. This applies to any committee or negotiation. The following are aspects that you may want to consider in your preparation: • Get the facts. To do so, speak with the key experts in a given therapeutic or operational area. • Identify the issues and interests. Dig deep to determine if there is more to someone’s position than initially may meet the eye. Perhaps there is a matter of someone’s job at stake, and that hidden agenda is making the negotiation more complicated. • Develop options. Brainstorming ahead of a meeting to think through possible options that will benefit your opponent will give you the opportunity to show you are thinking about them. • Anticipate reactions. Try to anticipate the possible responses to each of your options. • Develop an alternative to the negotiated agreement. This is a useful tactic if the negotiation is not successful or not going well. • Consider the best place for the meeting. Should it be in the other person’s office, your office or on “neutral” ground? • Plan your opening remarks. Frame the issue in a positive manner that encourages cooperation. • Seek counsel. If you feel uncomfortable about your process, seek the counsel of a trusted mentor. If the opportunity allows, you may want to bring someone along with you to the meeting, especially if you do not feel confident in your knowledge of the topic to be discussed.

•

Clinicians count on you for accuracy.

Count on CLSI’s AST standards to help you deliver reliable results. new for 2013 Find New or Revised Breakpoints and QC Ranges M100-S23 Vol. 33, No. 1 Replaces M100-S22 Vol. 31 No. 1

M100-S23 Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Third Informational Supplement

This document provides updated tables for the Clinical and Laboratory Standards Institute antimicrobial susceptibility testing standards M02-A11, M07-A9, and M11-A8.

A standard for global application developed through the Clinical and Laboratory Standards Institute consensus process.

M100-S23 | Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Third Informational Supplement This document provides updated tables for CLSI antimicrobial susceptibility testing (AST) standards M02-A11, M07-A9, and M11-A8.

Instantly Access M100-S23 Information— All You Need is a Web Connection introducing

NOW AVAILABLE as an Interactive Searchable Database for Drug Selection, Interpretation, and Quality Control Procedures!

Quickly ﬁnd the information you need to make informed patient recommendations.

Learn How to Put CLSI AST Standards Into Practice Join us for upcoming webinars: The Basics: Using CLSI Antimicrobial Susceptibility Testing CLSI 2013 AST Update

10TH anniversary

Learn more at www.aphl.org/clsi.

see NEGOTIATION, page 28

P: 610.688.0100

Toll Free (US): 877.447.1888

E: customerservice@clsi.org

www.clsi.org

28 Operations & Management

Pharmacy Practice News • March 2013

Leadership in Action

NEGOTIATION continued from page 27

Affirm Relationships Most people focus on the problem at the core of a conflict or negotiation, and do not consider the feelings or concerns of the individuals involved. This further alienates the other person and frequently makes them defensive. Affirming the other person, recognizing all the effort that he or she has put into a project or issue, explaining your admiration of their contribution and stating that you want to find a mutually acceptable solution puts the other person at ease and opens them to possible alternatives.

negotiating an agreement.” It also is a good idea to make a list of your own interests. Asking clarifying questions helps you understand others’ interests and shows a caring attitude.

the example of presenting ROI data to justify the initial cost of a new piece of equipment. As you search for creative solutions, show your “opponent” how this benefits him or her.

Search for Creative Solution

Evaluate Options Objectively And Reasonably

The next strategy is to search for creative solutions that will satisfy as many of the interests of both parties as possible. Creativity and imagination should be included to attain a solution that is truly synergistic. This is the step that we use to “expand the pie,” as in

The final step in the PAUSE strategy is to evaluate possible solutions objectively and reasonably to reach the best agreement. In our work, we frequently talk about using an evidence-based approach to reaching objective deci-

sions. This also is the area in which we rely on content experts in a particular therapeutic arena. Once an agreement has been reached, it is important to document what has been decided, the potential time line, and the action steps each party has agreed to complete, and set a time for review of progress toward the goals. Negotiation does not need to be a painful tug-of-war. When approached properly, most people will respond favorably and solutions will satisfy all parties involved. ■

Understand Interests Another step in the PAUSE process is to understand the interests of the other person. As Mr. Sande states, “The more fully you understand and look out for your opponent’s interests, the more persuasive and effective you can be in

PAUSE Strategy For Cooperative Negotiation

P A U S E

repare ffirm Relationships nderstand Interests

earch for Creative Solution valuate Options Objectively And Reasonably

Follow PPN on

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

@PharmPracNews Leading anemia management.™

Policy 29

Pharmacy Practice News • March 2013

Medication Safety

COMPOUNDING continued from page 1

For hospital pharmacies trying to upgrade their facilities to comply with USP standards, it is “mostly the facilitybased issues that are the toughest” to contend with, said Dr. Rich, noting that cramped pharmacy space was often the biggest obstacle. “When hospitals do it successfully,” he added, “it’s either because the pharmacy has moved or they were able to get space next door. In some cases, it is just not a priority to

‘Hospital pharmacies are “not quite there yet” in complying with USP Chapter <797> standards.’ —Darryl S. Rich, PharmD, MBA, FASHP

The science behind the molecule behind the formulation... The efficacy behind the safety behind the trust A distinctive hydrogel core...a long history of clinical excellence... over 260 million units*1 prescribed...and counting

There’s CORE Experience in every drop ™

Millions prescribed. Millions treated.

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

Please see brief Prescribing Information on adjacent page.

improve the pharmacy’s IV room.” As a result, he continued, “a lot of pharmacies have gone to outsource vendors because they figured they couldn’t do it themselves, particularly with regard to higher-risk compounded products.” The problem, he said, was their “level of trust” that there were “regulatory bodies out there” that were evaluating the outsourcers and making sure they remained compliant. “That obviously turned out not to be true,” he said.

•

see COMPOUNDING, page 30

30 Policy

Pharmacy Practice News • March 2013

Medication Safety

COMPOUNDING continued from page 29

More Stringent Inspections In the wake of the fungal meningitis outbreak, the inspections carried out during the resultant crackdown in Massachusetts were extremely rigorous. Of the 40 sterile compounding pharmacies that received unannounced visits by teams of internal investigators and outside consultant experts hired by the Department of Public Health (DPH), 11 were ordered to halt all or part of their

(Table 1. Continued)

BRIEF SUMMARY OF PRESCRIBING INFORMATION

Adverse Reactions (Preferred Term)

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

HDD-CKD Venofer (N=231) %

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

Venofer (N=75) %

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

78.8

76.3

73.4

72.0

65.2

2.2

0.7

0.4

2.7

2.9 10.1 0 12.2 8.6

4.0 8.0 0 5.3 8.0

6.5 4.3 0 4.3 2.2

3.5 5.2 0.9 14.7 9.1

1.4 7.2 7.9 8.6 5.0

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

HDD-CKD Venofer (N=231) %

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

Venofer (N=75) %

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

2.2 6.1 3.0 0 0 2.6 3.0

0.7 1.4 0 5.8 2.2 7.2 0.7

2.2 0 0 0 0 5.0 0.7

2.7 2.7 0 0 0 5.3 1.3

0 0 0 0 0 10.9 0

2.6

2.2

4.3

16.0

4.3

9.5

1.4

3.0 0 0 0.4

1.4 2.9 2.9 0.7

0.7 1.4 0 0.7

1.3 0 0 4.0

0 0 2.2 0

3.5 2.2 29.4 0 5.6

1.4 2.2 0.7 3.6 4.3

2.2 3.6 0.7 0 0

4.0 1.3 2.7 1.3 2.7

4.3 4.3 0 0 6.5

6.5 12.6

6.5 2.9

1.4 0.7

1.3 4.0

4.3 0

3.0 3.5 0

2.2 5.8 1.4

0.7 1.4 2.2

1.3 1.3 1.3

0 2.2 0

3.9

2.2

4.3

2.7

6.5 39.4

6.5 2.2

4.3 0.7

8.0 2.7

6.5 2.2

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

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

IN2340BS, Rev. 6/2011

compounding activities, and 21 were cited for minor infractions that since have been corrected. The serious violations included noncompliance with required USP standards for preparation, storage and dispensing of sterile products, including some hazardous medications. Several pharmacies were cited for faulty facility design and controls. The thoroughness of the inspections contrasted sharply with the regulatory laxity that existed prior to the multistate meningitis outbreak, attributed to contaminated methylprednisolone shipped by the now-shuttered New England Compounding Center (NECC), of Framingham, Mass. “When you’re under the microscope, you don’t just get the walk-through, you get the fine-toothed comb,” said Michael Cotugno, RPh, the director of pharmacy patient services at Brigham and Women’s Hospital, in Boston. Mr. Cotugno was a member of the pharmacy compounding oversight commission appointed by Gov. Deval Patrick to recommend actions to strengthen the state’s regulatory surveillance in the wake of the NECC-linked public health disaster. The oversight commission’s chairman, Christian Hartman, PharmD, MBA, the director of clinical quality and patient safety at Wolters Kluwer, said that before the meningitis outbreak, the annual budget for the volunteer state Board of Registration in Pharmacy and inspection staff was insufficient to provide comprehensive inspections. The new FY 2014 budget submitted by Gov. Patrick is for $1.3 million. “The new funding is intended to support increased inspections of compounding pharmacies and increased training of inspectors,” according to the Massachusetts Budget and Policy Center. Under the current, FY2013 budget the board received $182,600. Additionally, the DPH hired the pharmacy consulting firm Comprehensive Pharmacy Services (CPS) to help carry out the inspections. “We were able to provide the resources needed to establish a comprehensive checklist for the pharmacy inspections,” said Edward Choy, PharmD, a divisional vice president for CPS. “They’re using pharmacists” for inspections now, Dr. Hartman said, “and that’s a good thing. The unfortunate piece,” he added, is that there are “a lot more pharmacies that are doing medium- to high-risk compounding.” He said that it was time that all compounding pharmacies, including those operating within the state’s hospital systems, receive the same level of scrutiny as the smaller outsource pharmacies targeted in the initial inspection wave. “Raising the bar for providing high-quality and safe compounding services is something pharmacists welcome,” said Dr. Hartman.

Policy 31

Pharmacy Practice News • March 2013

Medication Safety Hospital compounding practices may be among the next in line to undergo DPH scrutiny. “We expect that to be the case,” Mr. Cotugno said. “Obviously they started with where the problem came from. But when this broke in Massachusetts, the DPH contacted all the hospitals and said we want to make sure you’re doing all you can to be compliant with USP <797>.”

Constant Monitoring Required That requires constant vigilance, Mr. Cotugno noted. “Just because you look good today, doesn’t mean that you’re going to look good tomorrow. That’s why you have to keep monitoring because you never know when someone is going to cut a corner. All it takes is one day for a break in technique” to occur, he said. So far eight of the 11 Massachusetts pharmacies whose compounding activities were halted have submitted corrective plans. But the DPH said that cease-and-desist orders would remain in place until pharmacies come into compliance with USP <795> and <797>. “That is all for the greater good of patients,” Mr. Cotugno said. “We will get a better quality compounding pharmacy, and maybe we’ll have fewer of them. Some of them are behind the times and won’t want to invest the resources” needed to upgrade to the new standards. “If that’s the case, they need to get out,” he said. In the ISMP survey, most respondents (74%) said that accrediting agen-

cies, such as the Joint Commission, should be responsible for monitoring external compounding pharmacies’ compliance with USP <797>. “I think that’s great,” Dr. Rich said, “but it’s just that it’s not what the accrediting agencies are doing.” He added that most accrediting agencies’ surveys cover only their own standards, and in the case of the Joint Commission, although compliance with state law and regulation is required, USP <797> compliance is neither part of its standards nor surveyed.

One answer, he said, might be for regulatory bodies to mandate accreditation for external compounding pharmacies, just as the Centers for Medicare & Medicaid Services (CMS) requires Joint Commission accreditation for hospitals. The regulatory bodies then could mandate compliance with <797> and the accrediting agencies would have to survey for that. Also, if CMS mandated that the agencies that accredit hospitals comply with USP <797>, then those agencies would have to survey for it.

However, he said, “right now if it is just going to be left up to the accrediting agencies and the states, it doesn’t become mandatory unless it becomes law.” —Bruce Buckley

Web Exclusive: FDA Tightens Reins on a major compounder www.pharmacypracticenews.com

CRITICAL CARE

TIMING IS EVERYTHING

‘When you’re under the microscope, you don’t just get the walkthrough, you get the fine-toothed comb.’ —Michael Cotugno, RPh

We’re proud to add the ﬁrst generic Acetylcysteine Injection to our APP brand of products.

Medical Information 800-551-7176 Customer Service 888-386-1300 www.APPpharma.com

32 Policy

Pharmacy Practice News • March 2013

Practice Pearl

Pilot to Program: Facilitating Transitions of Care Karen Trenkler, PharmD, MS, BCPS Pharmacy Clinical Coordinator

Justin Schneider, PharmD Pharmacy Director Mount Sinai Hospital/Sinai Health System Chicago, Illinois

he term transitions of care was introduced to most of the health care world as a concept relatively recently; however, elements of transitions of care are not new concepts to health care practitioners. The importance of reviewing the medication profile at both admission and discharge (or any change in level of care within a given hospitalization), patient education in the hospital in preparation for the ambulatory care setting, and counseling for discharge were identified more than 2 decades ago as areas that presented opportunities to improve care. The execution of transitional care provides a perspective of movement of the patient through the care process. It integrates each element with the objective of ensuring patient transition in a seamless manner, thereby optimizing therapy. Each care transition step warrants evaluation and possible action by a pharmacist, especially for high-risk patients. The linking of readmission rates to Centers for Medicare & Medicaid Services reimbursement likely has fueled recognition of the importance of transitions of care. Mount Sinai Hospital in Chicago established a program to foster transitions of care as part of an effort to reduce readmission rates for several chronic disease states. The efforts to reduce readmission rates at this urban safety-net hospital were initiated with a pilot program targeting heart failure (HF) in 2011. A pharmacist was incorporated into a multidisciplinary pilot team that included representatives from the medical, nursing, social work, dietary, and physical therapy staffs. The pilot—implemented using Project Re-Engineered Discharge, or Project RED—was conducted without additional pharmacy staff. The pharmacy clinical coordinator, in conjunction with Advanced Pharmacy Practice Experiential (APPE) students, worked with pilot patients. Over time, the processes to be accomplished by pharmacists were defined and executed. These processes included conducting medication histories and medication reconciliation, educating patients, optimizing pharmacotherapy, conducting medication reconciliation at discharge, and contacting patients at home after discharge. Not only does involving pharmacists reinforce each separate component of the process, but it also

is a logical and effective approach to ensuring safe and effective patient care over the care continuum (Figure). The post-discharge phone call was a new function for the pharmacist. The pharmacists enhanced the usefulness of the post-discharge call by focusing on key information, including prescriptions not filled (eg, due to a missing script or coverage/funding issues), potential adverse effects versus HF symptoms/exacerbation, and the need

Transition From Home to Inpatient Setting

for more education. During the pilot period, tasks for pharmacists were broken into modules, with specific components of the process defined. A data-recording tool, specific to the data collection requirements of the pharmacist, was designed and implemented. This tool served to both prompt appropriate action by pharmacists and to record key information for the pharmacists completing the post-discharge phone call and in

Inpatient Setting

the event of a subsequent readmission. Data fields included preadmission compliance, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker tolerance, dose titration for optimization, and others. As the pilot evolved into a program, patient numbers and pharmacist functions increased and the pharmacy process was reconfigured. At that point, a transitions of care longitudinal postgraduate year 1 (PGY1) rotation was

Transition From Inpatient Setting to Home

Figure. The transition from preadmission to hospital inpatient to post-discharge. ACEI, angiotensin-converting enzyme inhibitor; ADEs, adverse drug effects; ARB, angiotensin receptor blocker; CMS, Centers for Medicare & Medicaid Services; HF, heart failure; PGY1, postgraduate year 1 a

Movement from preadmission to inpatient status is executed by pharmacist or student with pharmacist oversight via medication history, then medication reconciliation.

For HF patients, the medication list is evaluated for ACEI/ARB and β-blocker dose optimization, as well as with respect to medications with the potential to exacerbate HF.

Initial discussion with the patient affords the opportunity to assess knowledge of disease and drugs. For knowledgeable patients, education may be handled during the initial meeting. Also, the initial discussion with the patient may point to ADEs versus symptoms of HF exacerbation.

Pharmacists work toward pharmacotherapy optimization, with the medical team. The discharge medication list is completed by a medical resident or attending physician; a clinical pharmacist monitors progress toward discharge completion.

Given that discharge may occur abruptly, discharge reconciliation may not always be completed before discharge. If reconciliation is not completed before discharge, more detail must be obtained post-discharge from the medical record (eg, discharge instructions and medication list, with a focus on new medications added to the profile) before contacting the patient.

Policy 33

Pharmacy Practice News • March 2013

Practice Pearl established, to expose the pharmacy residents to this emerging area of practice and to meet the patients’ needs. Documentation of success, based on a reduction in HF-related readmissions, led to expansion of the program to include diabetes in 2012. This expansion of the program resulted in further modification of pharmacists’ roles and responsibilities to incorporate the clinical pharmacists more extensively, in addition to PGY1 residents.

Measuring the Pharmacist’s Role The Mount Sinai team analyzed its program to foster transitions of care and reduce HF readmissions, presenting the data at the 2012 Midyear Clinical Meeting of the American Society of Health-System Pharmacists. The group examined data to determine the extent of pharmacist interventions and to examine the overall and relative effectiveness of the iterations of the process used. The 3 phases—the pilot phase; the phase primarily handled by the PGY1 pharmacy residents; and the current hybrid phase, which uses both clinical pharmacists and the PGY1 pharmacy residents—extended for variable durations, with varying numbers of patients. The pilot phase lasted 6 months and covered 62 admissions and 51 patients; the phase primarily managed by PGY1 residents lasted 8 months and covered 115 admissions and 100 patients; and

the hybrid phase, which uses a coordinated effort between clinical pharmacists and residents at the time of the analysis had lasted 2 months and covered 32 admissions and 27 patients. In the care of 209 admissions, on a per-patient basis, the overall number of interventions by pharmacists was 3.8, with the highest intervention rate of 4.1 per patient, achieved with the current hybrid state. Ultimately, the focus of the program is patient outcomes. The multidisciplinary team significantly and consistently affected readmissions, demonstrating a decrease in the 30-day HF readmission rates from 17.6% to 7.8%. Although it is difficult to isolate the contributions of specific professionals on the team, it is generally recognized that HF is a disease that is heavily medication-centric. The multidisciplinary team worked together seamlessly, meeting and communicating frequently. The phone call to the patient subsequent to discharge, which extends the role of the inpatient pharmacist into the ambulatory care setting, was deemed to be a worthwhile effort.

Discussion At the outset, the team recognized the need to strengthen the connection to the ambulatory care setting but was confronted with limitations in communicating with nonaffiliated clinics and inde-

Pearls for Setting Up A Care Transitions Program • Pharmacists have an essential role in the transitions of care, given the significant role of pharmacotherapy, in general. • Students, appropriately supervised, can serve as extenders of care. • Definition and modularization of processes can delineate the necessary steps and allow for workload (re)distribution, with minimal effect on the subsequent effectiveness of processes. • Pilots allow demonstration of potential accomplishments. Even without designated resource allocation, a pilot can effectively demonstrate value and generate resources for that effort in the future. • Documentation and measurement of pharmacist contributions is a key aspect of pharmacy practice and can facilitate an expanded role for pharmacists.

pendent practitioners. Clearly, this is an area warranting further study and effort to ensure optimal care for patients not integrated fully into the health system. Efforts early in the program resulted in the addition of one full-time equivalent (FTE) pharmacist. This position was integrated into the decentralized pharmacist team to expand departmental contributions to the transitions of care. Demonstration of continued effect resulted in the very recent granting of a 0.5 FTE ambulatory care position. The imminent expansion to diseases beyond HF (ie, diabetes and chronic

obstructive pulmonary disease) will facilitate the optimization of care for a far greater number as well as different types of patients. A focus on transitions of care bridges the ambulatory care setting to the inpatient setting and then back to the home or another facility. As executed at Mount Sinai Hospital, it includes optimizing admission, planning for chronic disease management, optimizing inpatient stay, patient education, preparing for discharge on or shortly after admission, and ensuring connections to the patient’s home, post-discharge. ■

in Your Inbox ... to receive the monthly e-newsletter from

at www.pharmacypracticenews.com

Get the latest news delivered directly to your computer and PDA. The new interactive format has embedded website 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.

34 Policy

Pharmacy Practice News • March 2013

Care Transitions

More Hospitals Setting Up Discharge Prescription Services

t HealthPark Medical Center in Fort Myers, Fla., patients being discharged pick up their medications at a pharmacy in the atrium. At South Pointe Hospital, in Warrensville Heights, Ohio, most patients being discharged receive their filled prescriptions while still in their rooms. Both are examples of a growing trend: discharge prescription services to improve patient satisfaction and reduce readmissions.

‘Pharmacists, as the medication experts, are really the best people to be assisting with the medication reconciliation process, including medication counseling for patients going home and ensuring access to new needed prescriptions prior to leaving the hospital.’ —Erika Smith, PharmD, BCPS “There is a greater emphasis on making sure patients understand their medications and obtain them upon discharge

and reduce the chances of their being readmitted,” said Douglas J. Scheckelhoff, MS, the vice president of the

Building leadership, clinical excellence, and professional expertise in hematology/oncology pharmacy

American Society of Health-System Pharmacists’ Office of Professional Development. “One way is to provide a discharge prescription service.” Other strategies, he noted, include discharge counseling, educational printed materials, follow-up calls after patients return home, and transmission of the order to the patient’s local pharmacy so the patient can pick it up on the way home. Penalties by the Centers for Medicare & Medicaid Services (CMS) for excess readmissions, effective for discharges beginning Oct. 1, 2012, have propelled the trend toward discharge prescription services. “The CMS penalties are adding fuel to the fire, as is the potential for better reimbursement under the ACO [accountable care organization] model if we reduce total health care costs by better compliance and fewer readmissions. And professionally, it is the right thing to do for the patient,” said Mike Sacks, RPh, a regional manager at Fairview Pharmacy Services, in Minneapolis. The outpatient pharmacy is not a new idea. “For a long time, a lot of hospitals either owned a community pharmacy or rented space to an independent community pharmacy,” said Mark B. Collum, PharmD, CPh, the director of ambulatory pharmacy services at Lee Memorial Health System, in Cape Coral and Fort Myers, Fla., which offers discharge prescription services at its HealthPark Medical Center and Lee Memorial Hospital, both in Fort Myers. Early approaches “relied on patients walking up—efforts were not coordinated,” he said. “During the 1990s, a lot of hospitals closed their owned pharmacies due to declining reimbursement, and now they’re getting back into it to better coordinate care and provide an excellent customer experience.”

A Mix of Old and New

Join HOPA today. www.hoparx.org

Some discharge prescription services have been around for a while. Fairview Pharmacy Services—an arm of Fairview Health Services, whose seven metropolitan area hospitals now offer discharge prescription services—started in 1990, Mr. Sacks said. Penobscot Bay Medical Center’s service in Rockport, Maine, was launched in 1998, reported the pharmacy director, Jeffrey Kubel, RPh. But many of these services are fairly new. The Cleveland Clinic began introducing discharge prescription services

Policy 35

Pharmacy Practice News • March 2013

Care Transitions in September 2011, and now several of its hospitals offer them, according to Mike Wascovich, RPh, MBA, the senior director of ambulatory pharmacy services at the Cleveland Clinic in Ohio. The services at HealthPark Medical Center and Lee Memorial Hospital have been operating only since August, said Dr. Collum. As part of some discharge prescription services, there is a pharmacy store, often in the hospital lobby. At Penobscot Bay Medical Center, said Mr. Kubel, “once the prescriptions are filled, we call the patient’s room and notify them that the prescriptions are ready.” Then, he added, “the patient and an escort come to the pharmacy on the main floor and meet with a pharmacist. It’s our policy that every discharge prescription patient sees a pharmacist for counseling.” In other hospitals, the medications are brought to the patient’s bedside in what sometimes is called “concierge” service. At Froedtert Hospital, in Milwaukee, the bedside service is part of the medication reconciliation process. “Pharmacists, as the medication experts, are really the best people to be assisting with the medication reconciliation process, including medication counseling for patients going home and ensuring access to new needed prescriptions prior to leaving the hospital,” noted Erika Smith, PharmD, BCPS, a clinical pharmacy manager at the hospital. Costs for starting a discharge prescription service vary, from $10,000 at South Pointe Hospital, according to Dawn Wiemer, PharmD, a pharmacist at the hospital, to $250,000 per hospital at Lee Memorial Health System, by Dr. Collum’s account. “Startup costs vary regionally, ranging from $125 a square foot to $850 a square foot,” said Mr. Sacks. “After startup, the cost of doing business will vary with volume and the number of pharmacists and technicians needed to complete the business.”

Nearly a $250,000 Profit From Discharge Program Once established, discharge prescription services can be financially self-sustaining and even profitable. “Our ‘Bedside Meds’ prescription delivery service has … generated a year-to-date net profit of over $240,000 (November 2011 through August 2012),” said Dr. Smith of Froedtert Hospital. Fairview’s service also “generates quite a bit of revenue for our pharmacies,” said Mr. Sacks. There are other measures of success, including volume and productivity of technicians, improved HCAHPS scores (the Hospital Consumer Assessment of Healthcare Providers and Systems survey) and stakeholder/client satisfaction. Laura Britton, PharmD, BCPS, CACP, a pharmacy clinical coordinator in ambu-

latory care services at the University of Utah Health Care, in Salt Lake City, told Pharmacy Practice News that since dis-

charge prescription services were initiated three to four years ago at both the University of Utah Hospital and the

Now available for download:

Immune globulin comparison chart Developed for the iPad Sponsored by

From the publisher of

pharmacypracticenews.com

Scan the QR code above or visit www.pharmacypracticenews.com to download the app.

Huntsman Cancer Hospital, “we have seen a drop in readmissions.” Additionally, inpatient satisfaction scores have improved and “we found that we were making interventions in the discharge orders/prescriptions about 80% of the time at the main hospital and 100% of the time at the cancer hospital, thus showing a tremendous patient safety need.” The idea of the discharge prescription service has not spread everywhere yet. But, said Dr. Wiemer, “It is becoming more common.” —George Ochoa

36 Policy

Pharmacy Practice News • March 2013

Reimbursement Matters

It’s Time To Stop Whining About White Bagging P

atient assistance programs (PAPs) and white bagging share many characteristics. Why, then, are attitudes toward these drug acquisition and distribution programs so different? After all, both practices have several attributes in common. In both cases, for example, a distributor, manufacturer or specialty pharmacy sends the drugs to the pharmacy at no cost. Actually, we could add a third category to this as well: nominally or zero-priced drugs such as alemtuzumab (Campath, Genzyme) for leukemia patients. The principle behind each of these scenarios is that either the drug manufacturer or a payer who has purchased product from the drug manufacturer is making product available to the patient; the hospital pharmacy is serving as the intermediary to orchestrate this patient-specific transaction and to prepare the product for administration (Table 1). In the case of PAPs, the general trend is to applaud how successful the department has been in trimming drug spending, in helping a patient through a course of therapy and in navigating the complexities that may arise. When faced with white bagging, in contrast, facilities often take an “absolutely not in my hospital” stance, often due to (largely unfounded) concerns about drug integrity, proper storage and so on. In such scenarios, the hospital may, in effect, repurchase a white-bag medication and dispense it to the patient—an almost guarantee that the payer will reject the drug claim, thus burdening the patient with additional bills. This dichotomy in attitude is very disturbing. Perhaps some basic information on how white bagging works will shed some light on how to shift attitudes.

First, let’s define some terms in a bit more depth. As noted, white bagging is the practice of having patient-specific medications or supplies delivered directly to the practice setting. That setting may be an outpatient infusion center, a physician’s office or a hospital, but the common link is that the drug is intended for use by a specific patient. As the medications may be prepaid or complimentary, no billing for these products/supplies transpires. However, billing for the clinic visit where the drugs are administered and for the drug administration itself still brings income to the facility. The Centers for Medicare & Medicaid Services has specific requirements for how this transpires. Thus, following the guidelines determined by your Medicare administrative contractor or fiscal intermediary is essential. Basically, the drug is billed at a zero charge to indicate that it was given; this then allows the drug administration fee to be processed.

Making It Work So now you’ve got your first weapon in the fight to take some of the tarnish off white bagging: letting your colleagues know that the hospital can in fact generate revenue by handling the administration of these medications. But to get maximum payments, you have to make sure that you or someone on your reimbursement team understands the nuances of proper coding for these drugs. One key point to remember: Common procedural terminology (CPT) codes are used to describe and bill for services/tasks performed, while Healthcare Common Procedure Coding System (HCPCS) codes are used to describe and bill for drugs and other items. There are no less than 40 CPT

Table 2. Key Steps To White Bagging • Form a multidisciplinary team to include: -Pharmacy -Patient navigators -C-suite representative -Hospital insurance team rep • Determine participating outpatient clinic areas • Identify medications to be white bagged • Determine the specialty pharmacies used by the predominant payers • Vet the specialty pharmacies that will be a part of the program

Table 1. Program Features Patient Assistance

Nominal Price

White Bag

Yes

Drug is supplied at no charge

Yes

Billing for the medication is not allowed

Yes

Billing for the drug administration is possible

Yes

Drug is sent directly to the facility by the manufacturer, distributor or specialty pharmacy

Yes

Pharmacy must follow special storage requirements

Yes

Returns of unused medications are not allowed

Yes

Pharmacy is responsible for disposal of unused drug

Yes

Feature

codes that are used to bill for drug administration. Some are specific to the type of drug administered, with more complex administrations receiving considerably higher reimbursement. Both private payers and Medicare reimburse for drug administration using these codes. Thus it’s important to look at the CPT definition of drug administration. It includes the following exact wording, according to CMS: use of local anesthesia; starting the IV; access to IV, catheter or port; routine tubing, syringe and supplies; preparation of the drug; flushing catheters at completion and hydration fluid. Remember, in the eyes of the payer, they are reimbursing for handling and preparation. If the pharmacy has not worked internally to carve out that part of the payment bundle they are due, the payer doesn’t really want to get involved in that internal accounting. It’s actually what pharmacies are going to have to deal with when handling all aspects of

Yes

• Design the flow to ensure product availability at the time of the administration clinic visit • Examine infrastructure and correct weaknesses: -Outpatient pharmacy does not have sufficient refrigerated storage for segregating white-bag drugs in a patientspecific manner -Pharmacy does not know the payer status of the patient when receiving a medication order -Pharmacy does not have a working relationship with the patient navigators -Pharmacy does not have a working relationship with the insurance team

“Reimbursement Matters” is a tool for maintaining your health system’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

bundled payment. Drugs costing less than $80 per day and being bundled into the clinic visit would be another good example. Unfortunately, pharmacy often is woefully unprepared to do this and quite naive as to how all this works. Alternatively, some pharmacy departments have been able to advocate for separate handling payment by negotiating directly with the principal payers in their local geography. Such efforts are usually done through the negotiating team at the facility. Commercial models for this handling already exist in the patient assistance world.

Changing Perceptions Perhaps the most difficult part of implementing a white-bagging program at your facility is to change widely held negative attitudes toward this distribution model. You can start that process, as noted, by pointing out that your facility can generate revenue by handling these drugs—and help the patients clinically and financially in the process. Your next task may be to allay concerns over product integrity, storage and so on. I would suggest letting your staff know that when white-bag medications are sent directly from the specialty pharmacy to the hospital or other practice site, the drugs are sent in their original packaging, with appropriate shipping packaging and usually insurance due to their high cost. This would be similar to PAP drugs or routine wholesaler shipments; the drugs do not go to the patient. As you hopefully gain some adherents with these types of discussions, your next step will be to develop an organized, careful multidisciplinary approach that includes several steps as outlined in Table 2. Good luck!

This column was designed to be provocative, to remind you that the patient always comes ﬁrst and to start you thinking about how to solve this conundrum with white-bagging at your facility. As always, we’re interested in your thoughts or comments. Post them online at the end of the web version of this article at www.pharmacypracticenews.com. Or you can email me directly at bkirschen@ aol.com. We need—and welcome— your feedback!

The bookstore division of

MCMAHONMEDICALBOOKS.COM An Online Bookstore

ORDER BOOKS ONLINE

THE BOOK PAGE PUBLISHER’S TOP PICKS OF THE MONTH ON MCMAHONMEDICALBOOKS.COM These books and thousands more...

Comprehensive Pharmacy Review for NAPLEX®

Lippincott Williams & Wilkins February 1, 2013 This indispensible guide deciphers the nuances of the test and provides authentic exercises and actionable strategies. Using two full-length tests, 32 brand-new patient cases and more than 200 practice calculations, you can challenge your understanding of current pharmacological practices and enhance your test-taking skills.

Scan here for our complete catalog of medical books.

ORDER ONLINE For pricing, a more complete review and easy ordering with a credit card, go to McMahonMedicalBooks.com. We can supply any medical book in print, so if you don’t find the book you want, email your request with billing information to RMcMahon@McMahonMed.com. If you are an author and would like your medical book featured in this book section, contact Ray McMahon, Publisher, at RMcMahon@McMahonMed.com.

Drug Information Handbook 21st Edition

Lexicomp April 1, 2012 This handbook delivers trusted pharmacotherapy knowledge to health care professionals. This resource follows a user-friendly, dictionary-like format, providing clinicians with fast access to Lexicomp’s clear, concise drug information. Endorsed by the American Pharmacists Association (APhA), Lexicomp’s Drug Information Handbook k is relied on daily by clinicians everywhere to improve medication safety and enhance patient care.

Extended Stability for Parenteral Drugs, Fifth Edition

Caryn M Bing, RPh, MS, FASHP; Anna Nowobilski-Vasilios, PharmD, MBA, FASHP, CNSC, BCNSP March 28, 2013 Extended Stability for Parenteral Drugs s is an essential reference for anyone working in alternate-site infusion practice. The 160 stability monographs in this fifth edition include updates to nearly all of the monographs from the fourth edition.

Handbook on Injectable Drugs: 17th Edition

Lawrence A. Trissel, FASHP October 31, 2012 With a 35-year track record, the Handbook on Injectable Drugs s is the premier reference for compatibility, stability, storage and preparation of parenteral drugs. The 17th edition is completely updated and peerreviewed with new monographs, new references, additional information and the latest guidelines—essential for your confidence as a profess o a who sional o makes a es critical c t ca decisions dec s o s on o a daily da y basis. bas s

Internal Medicine: A Guide to Clinical Therapeutics

Rebecca L. Attridge; Monica L. Miller; Rebecca Moote; Laurajo Ryan December 26, 2012 This peer-reviewed guide highlights important treatment options for the most common diseases managed by clinicians practicing in internal medicine.

Martin’s Physical Pharmacy and Pharmaceutical Sciences: Sixth Edition

Patrick J. Sinko February 21, 2010 Martin’s Physical Pharmacy and Pharmaceutical Sciences s is considered the most comprehensive text available on the application of the physical, chemical and biological principles in the pharmaceutical sciences. It helps students, teachers, researchers and industrial pharmaceutical scientists use elements of biology, physics and chemistry in their work and study.

Mosby’s Pharmacy Review for the NAPLEX®

Mosby April 20, 2010 In this guide to the NAPLEX®, an outline format lets you review imporr tant test topics quickly and efficiently. Review questions cover areas such as the evaluation of patient conditions, communicating with the patient or health care professional, and preparing and dispensing medications safely and effectively. A companion CD lets you practice with two 185-question exams that mirror the NAPLEX®.

Pharmaceutical Calculations

Howard C. Ansel November 7, 2012 Widely recognized as the leading calculations textbook, Ansel’s Pharma-ceutical Calculations s is the most trusted resource for calculations support. Time-tested after 13 editions, it is the most comprehensive and in-depth dept treatment t eat e t of o pharmacy p a acy calculations ca cu at o s available. a a ab e PPN0313

38 Last Word

Pharmacy Practice News • March 2013

More Proposed Limits on Opioids Spur Debate In late January, an FDA advisory committee voted in favor of placing new restrictions on the prescribing of Vicodin and other formulations containing oxycodone. The decision comes on the heels of several fiery public debates in recent months over just how much control needs to be placed on prescription pain medications—including one debate detailed in Pharmacy Practice News (“The Great Opioid Debate: PROP, PROMPT Square Off,” November 2012, page 1). The web comments we received on the article came in a bit later than usual due to a technical glitch. So we’re publishing them now, because many of the issues raised are the same ones clinicians are again debating as a result of the FDA advisory committee’s decision to rein in the use of these controversial medications. And yes, some of these comments come from patients—a group that has every right to express its views on proposed policies that may change their access to rationally prescribed pain therapy.

From the

‘It Is Easy To Get Addicted to Not Hurting’

No Room for Politics in Pain Policy?

s a person who suffered 25 years with constant intense pain from ankylosing spondylitis, I too wonder why noncancer pain isn’t as important to treat as cancer-caused pain. Having lived with pain gives me a different perspective from some. If you tell me there are risks to treating my pain, I say, “OK, thanks for letting me know. Now treat the pain.” Fortunately, I finally got diagnosed and am on one of the TNF inhibitors, a miracle drug for me. But if you told me my current pain medication would cut 10 years off my life, I would smile and say, “OK! Next dose please.” Patients aren’t babies, and you aren’t their mom. Be open and honest with patients. Let them know the pros and cons. Let them know what their responsibilities are (safe storage, etc.). Let them know the risks and then let them take responsibility for their own treatment. Who are any of us to tell them how much they should hurt? When taking fairly large doses of opioids for my condition, I was asked, “Can’t you become addicted to that medicine?” My response: “Yep, you have to be careful; it is easy to get addicted to not hurting.” In the balancing act between effective treatment and safety, remember that it may be hard for those in pain to understand and trust the not-in-pain decision makers.

Web

agree with Dr. [Jeffrey] Fudin in that it was “absurd” of PROP to ignore the multiplicity of therapeutic options required to treat all of the “unique disorders” that cause CNCP [chronic noncancer pain]. Moreover, he said, “A lot of patients [with chronic pain] can’t take [other] analgesics for one reason or other.” Dr. [Andrew] Kolodny seems to be advancing a pure political agenda; in my opinion, he does not have an understanding of pain management. According to PubMed, he has five lifetime publications, all of which are opinion as opposed to legitimate research studies. If PROP’s proposals are implemented by the FDA, these proposed label changes will only make our lives as clinicians much more difficult and will negatively impact the quality of pain care that we provide to our patients. What does Dr. Kolodny think the treatment for chronic pain should be? Where is the data that suggests that opiates should only be prescribed for severe pain—and then only for a maximum of 90 days at no more than the equivalent of 100 mg of morphine daily?

—ericp...

Opioids ‘Dangerous and Ineffective’

oo much pain can cause damage and even death. When pain is controlled, medications for the underlying disease or disorder tend to work better. Opioid analgesia is one of the most pro-life therapies that we have to offer patients with cancer pain, and there is no reason to think that patients with other diseases are any less deserving of relief or that their pain is any less amenable to treatment.

t’s remarkable how some people believe that opioids should be used for migraines, arthritis, prostate pain, fibromyalgia—even most doctors know better, but it’s sad that people have been victimized into believing that opioids should be the prime treatment for such medical conditions. Opioids are dangerous and ineffective, and there are always safer alternatives. To treat migraines or arthritis with opioids is poor practice. Even cancer pain doesn’t have to be treated with opioids. Regrettably, doctors don’t bother to do neurotransmitter tests or do thorough assessments of pain, and so treatments are suboptimal and often foster an unsatisfying dependency.

—golde...

—bdavi...

—s_mul...

Opioids: ‘A Pro-Life Therapy’

Funding/Staffing Issues Pose Barriers to Drug Safety Ed

a budget meeting and hear my chief financial officer say, “It appears that you forgot to include a line item for Nursing/Medical Staff orientation!”

(Hospitals Too Often Neglect Drug Safety Education: ISMP, from February 2013)

r. Grissinger, along with many of his colleagues, fails to understand that in most community hospitals, the high cost of pharmacists translates to bare-minimum staffing. I do not know of any pharmacist who wouldn’t love to spend more time orienting nurses and medical staff to principles of safe medication use. But the sad truth is that every year we are asked to do more with less. It seems that all of the studies that underscore the improvements in patient care and safety, accrued when pharmacists are involved, come from academic and government centers that have massive resources. I respectfully disagree with Dr. Hultgren that the process needs to be from the “bottom-up.” If you take that approach, you are preaching to the choir. Rather, ISMP needs to encourage us to focus on CFOs and CEOs to improve their understanding of the positive impact that pharmacy can have on the bottom line. I would love to attend

—kiacz…

ll hospitals will be forced to change and implement safer medication practices when penalties are applied for frequent readmission due to drug errors. Did hospital pharmacy change on its own when the Joint Commission wanted to improve inpatient anticoagulation? No. Did hospital pharmacy change on its own when medication reconciliation became the issue of the day? No. It is time to start internally with your staff and ask, “What else can we try? How can we improve the outcomes of drug therapy?” Maybe then, the CEO and CFO will see a special effort by pharmacy and subsequently fewer errors, and want to reward that behavior with an investment in more pharmacy staff. Or maybe not—in which case, let’s just sit and do nothing.

—wnjon...

Pre-Discharge Medication Reconciliation Is Important Too (Post-Discharge Outreach a Key To Reduced Readmissions, from December 2012)

s an almost 40-year practitioner of hospital pharmacy, I agree with the need for follow-up after an inpatient visit. My problem has been convincing my boss to allow me to call patients before they come in to verify their home meds. For a period of about six months, I was getting reconciliation sheets from presurgery interviews done by intake nurses. I work the surgery floors and I would call patients to verify unusual doses or drugs on those lists, or to remind them to bring nonformulary medications with them. Then someone decided that the physicians couldn’t just check off medications and instead had to write orders based on those sheets. This hasn’t helped the quality of care, since many surgeons don’t know doses; so I get orders like Wellbutrin 15 mg. How can I convince my boss that this is a very important thing to get straight before the patient comes in?

—DanSu...

SAMSCAÂ® (tolvaptan) tablets for oral use %ULHI 6XPPDU\ RI 3UHVFULELQJ ,QIRUPDWLRQ )RU FRPSOHWH SUHVFULELQJ LQIRUPDWLRQ FRQVXOW RIÂ¿FLDO SDFNDJH LQVHUW \ J J J WARNING: INITIATE AND RE-INITIATE IN A HOSPITAL AND MONITOR SERUM SODIUM SAMSCA should be initiated and re-initiated in patients only in a hospital where serum sodium can be monitored closely. Too rapid correction of hyponatremia (e.g., >12 mEq/L/24 hours) can cause osmotic demyelination resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma and death. In susceptible patients, including those with severe malnutrition, alcoholism or advanced liver disease, slower rates of correction may be advisable. INDICATIONS AND USAGE: 6$06&$ LV LQGLFDWHG IRU WKH WUHDWPHQW RI FOLQLFDOO\ VLJQLÂ¿FDQW K\SHUYROHPLF DQG HXYROHPLF K\SRQDWUHPLD VHUXP VRGLXP P(T / RU OHVV PDUNHG K\SRQDWUHPLD WKDW LV V\PSWRPDWLF DQG KDV UHVLVWHG FRUUHFWLRQ ZLWK Ã&#x20AC;XLG UHVWULFWLRQ LQFOXGLQJ SDWLHQWV ZLWK KHDUW IDLOXUH FLUUKRVLV DQG 6\QGURPH RI ,QDSSURSULDWH $QWLGLXUHWLF +RUPRQH 6,$'+ Important Limitations 3DWLHQWV UHTXLULQJ LQWHUYHQWLRQ WR UDLVH VHUXP VRGLXP XUJHQWO\ WR SUHYHQW RU WR WUHDW VHULRXV QHXURORJLFDO V\PSWRPV VKRXOG QRW EH WUHDWHG ZLWK 6$06&$ ,W KDV QRW EHHQ HVWDEOLVKHG WKDW UDLVLQJ VHUXP VRGLXP ZLWK 6$06&$ SURYLGHV D V\PSWRPDWLF EHQHÂ¿W WR SDWLHQWV CONTRAINDICATIONS: 6$06&$ LV FRQWUDLQGLFDWHG LQ WKH IROORZLQJ FRQGLWLRQV Urgent need to raise serum sodium acutely: SAMSCA has not been studied in a setting of urgent need to raise serum sodium acutely. Inability of the patient to sense or appropriately respond to thirst: 3DWLHQWV ZKR DUH XQDEOH WR DXWR UHJXODWH Ã&#x20AC;XLG EDODQFH DUH DW VXEVWDQWLDOO\ LQFUHDVHG ULVN RI LQFXUULQJ DQ RYHUO\ UDSLG FRUUHFWLRQ RI VHUXP VRGLXP K\SHUQDWUHPLD DQG K\SRYROHPLD Hypovolemic hyponatremia: 5LVNV DVVRFLDWHG ZLWK ZRUVHQLQJ K\SRYROHPLD LQFOXGLQJ FRPSOLFDWLRQV VXFK DV K\SRWHQVLRQ DQG UHQDO IDLOXUH RXWZHLJK SRVVLEOH EHQHÂ¿WV Concomitant use of strong CYP 3A inhibitors: .HWRFRQD]ROH PJ DGPLQLVWHUHG ZLWK WROYDSWDQ LQFUHDVHG WROYDSWDQ H[SRVXUH E\ IROG /DUJHU GRVHV ZRXOG EH H[SHFWHG WR SURGXFH ODUJHU LQFUHDVHV LQ WROYDSWDQ H[SRVXUH 7KHUH LV QRW DGHTXDWH H[SHULHQFH WR GHÂ¿QH WKH GRVH DGMXVWPHQW WKDW ZRXOG EH QHHGHG WR DOORZ VDIH XVH RI WROYDSWDQ ZLWK VWURQJ &<3 $ LQKLELWRUV VXFK DV FODULWKURP\FLQ NHWRFRQD]ROH LWUDFRQD]ROH ULWRQDYLU LQGLQDYLU QHOÂ¿QDYLU VDTXLQDYLU QHID]RGRQH DQG WHOLWKURP\FLQ Anuric patients: ,Q SDWLHQWV XQDEOH WR PDNH XULQH QR FOLQLFDO EHQHÂ¿W FDQ EH H[SHFWHG WARNINGS AND PRECAUTIONS: Too Rapid Correction of Serum Sodium Can Cause Serious Neurologic Sequelae (see BOXED WARNING): Osmotic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Ã&#x20AC;XLG )OXLG UHVWULFWLRQ GXULQJ WKH Â¿UVW KRXUV RI WKHUDS\ ZLWK 6$06&$ PD\ LQFUHDVH WKH OLNHOLKRRG RI RYHUO\ UDSLG FRUUHFWLRQ RI VHUXP VRGLXP DQG VKRXOG JHQHUDOO\ EH DYRLGHG Gastrointestinal Bleeding in Patients with Cirrhosis: ,Q SDWLHQWV ZLWK FLUUKRVLV WUHDWHG ZLWK WROYDSWDQ LQ K\SRQDWUHPLD WULDOV JDVWURLQWHVWLQDO EOHHGLQJ ZDV UHSRUWHG LQ RXW RI WROYDSWDQ WUHDWHG SDWLHQWV DQG RXW RI SODFHER WUHDWHG SDWLHQWV 6$06&$ VKRXOG EH XVHG LQ FLUUKRWLF SDWLHQWV RQO\ ZKHQ WKH QHHG WR WUHDW RXWZHLJKV WKLV ULVN Dehydration and Hypovolemia: 6$06&$ WKHUDS\ LQGXFHV FRSLRXV DTXDUHVLV ZKLFK LV QRUPDOO\ SDUWLDOO\ RIIVHW E\ Ã&#x20AC;XLG LQWDNH 'HK\GUDWLRQ DQG K\SRYROHPLD FDQ RFFXU HVSHFLDOO\ LQ SRWHQWLDOO\ YROXPH GHSOHWHG SDWLHQWV UHFHLYLQJ GLXUHWLFV RU WKRVH ZKR DUH Ã&#x20AC;XLG UHVWULFWHG ,Q PXOWLSOH GRVH SODFHER FRQWUROOHG WULDOV LQ ZKLFK K\SRQDWUHPLF SDWLHQWV ZHUH WUHDWHG ZLWK WROYDSWDQ WKH LQFLGHQFH RI GHK\GUDWLRQ ZDV IRU WROYDSWDQ DQG IRU SODFHER WUHDWHG SDWLHQWV ,Q SDWLHQWV UHFHLYLQJ 6$06&$ ZKR GHYHORS PHGLFDOO\ VLJQLÂ¿FDQW VLJQV RU V\PSWRPV RI K\SRYROHPLD LQWHUUXSW RU GLVFRQWLQXH 6$06&$ WKHUDS\ DQG SURYLGH VXSSRUWLYH FDUH ZLWK FDUHIXO PDQDJHPHQW RI YLWDO VLJQV Ã&#x20AC;XLG EDODQFH DQG HOHFWURO\WHV )OXLG UHVWULFWLRQ GXULQJ WKHUDS\ ZLWK 6$06&$ PD\ LQFUHDVH WKH ULVN RI GHK\GUDWLRQ DQG K\SRYROHPLD 3DWLHQWV UHFHLYLQJ 6$06&$ VKRXOG FRQWLQXH LQJHVWLRQ RI Ã&#x20AC;XLG in response to thirst. Co-administration with Hypertonic Saline: 7KHUH LV QR H[SHULHQFH ZLWK FRQFRPLWDQW XVH RI 6$06&$ DQG K\SHUWRQLF VDOLQH &RQFRPLWDQW XVH ZLWK K\SHUWRQLF VDOLQH LV QRW UHFRPPHQGHG Drug Interactions: Other Drugs Affecting Exposure to Tolvaptan: CYP 3A Inhibitors: 7ROYDSWDQ LV D VXEVWUDWH RI &<3 $ &<3 $ LQKLELWRUV FDQ OHDG WR D PDUNHG LQFUHDVH LQ WROYDSWDQ concentrations [see Dosage and Administration (2.3), Drug Interactions (7.1)] 'R QRW XVH 6$06&$ ZLWK VWURQJ LQKLELWRUV RI &<3 $ [see Contraindications (4.4)] DQG DYRLG FRQFRPLWDQW XVH ZLWK PRGHUDWH &<3 $ LQKLELWRUV CYP 3A Inducers: $YRLG FR DGPLQLVWUDWLRQ RI &<3 $ LQGXFHUV H J ULIDPSLQ ULIDEXWLQ ULIDSHQWLQ EDUELWXUDWHV SKHQ\WRLQ FDUEDPD]HSLQH 6W -RKQÂ¶V :RUW ZLWK 6$06&$ DV WKLV FDQ OHDG WR D UHGXFWLRQ LQ WKH SODVPD FRQFHQWUDWLRQ RI WROYDSWDQ DQG GHFUHDVHG HIIHFWLYHQHVV RI 6$06&$ WUHDWPHQW ,I FR DGPLQLVWHUHG ZLWK &<3 $ LQGXFHUV WKH GRVH RI 6$06&$ PD\ QHHG WR EH increased [see Dosage and Administration (2.3), Drug Interactions (7.1)]. P-gp Inhibitors: 7KH GRVH RI 6$06&$ PD\ KDYH WR EH UHGXFHG ZKHQ 6$06&$ LV FR DGPLQLVWHUHG ZLWK 3 JS LQKLELWRUV H J cyclosporine [see Dosage and Administration (2.3), Drug Interactions (7.1)]. Hyperkalemia or Drugs that Increase Serum Potassium: 7UHDWPHQW ZLWK WROYDSWDQ LV DVVRFLDWHG ZLWK DQ DFXWH UHGXFWLRQ RI WKH H[WUDFHOOXODU Ã&#x20AC;XLG YROXPH ZKLFK FRXOG UHVXOW LQ LQFUHDVHG VHUXP SRWDVVLXP 6HUXP SRWDVVLXP OHYHOV VKRXOG EH PRQLWRUHG DIWHU LQLWLDWLRQ RI WROYDSWDQ WUHDWPHQW LQ SDWLHQWV ZLWK D VHUXP SRWDVVLXP ! P(T / DV ZHOO DV WKRVH ZKR DUH UHFHLYLQJ GUXJV NQRZQ WR LQFUHDVH VHUXP SRWDVVLXP OHYHOV ADVERSE REACTIONS: Clinical Trials Experience: %HFDXVH FOLQLFDO WULDOV DUH FRQGXFWHG XQGHU ZLGHO\ YDU\LQJ FRQGLWLRQV DGYHUVH UHDFWLRQV UDWHV REVHUYHG LQ WKH FOLQLFDO WULDOV RI D GUXJ FDQQRW EH GLUHFWO\ FRPSDUHG WR UDWHV LQ WKH FOLQLFDO WULDOV RI DQRWKHU GUXJ DQG PD\ QRW UHÃ&#x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Â&#x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able 1. Adverse Reactions (>2% more than placebo) in Tolvaptan-Treated Patients in Double-Blind, Placebo-Controlled Hyponatremia Trials System Organ Class MedDRA Preferred Term

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

Placebo (N = 220) n (%)

Gastrointestinal Disorders 'U\ PRXWK

Constipation

General Disorders and Administration Site Conditions a 7KLUVW

Asthenia

Pyrexia

Metabolism and Nutrition Disorders b +\SHUJO\FHPLD

Anorexia c Renal and Urinary Disorders

3ROODNLXULD RU SRO\XULD d 7KH IROORZLQJ WHUPV DUH VXEVXPHG XQGHU WKH UHIHUHQFHG $'5 LQ 7DEOH a b c d SRO\GLSVLD GLDEHWHV PHOOLWXV GHFUHDVHG DSSHWLWH XULQH RXWSXW LQFUHDVHG PLFWXULWLRQ XUJHQF\ QRFWXULD ,Q D VXEJURXS RI SDWLHQWV ZLWK K\SRQDWUHPLD 1 VHUXP VRGLXP P(T / HQUROOHG LQ D GRXEOH EOLQG SODFHER FRQWUROOHG WULDO PHDQ GXUDWLRQ RI WUHDWPHQW ZDV PRQWKV RI SDWLHQWV ZLWK ZRUVHQLQJ KHDUW IDLOXUH WKH IROORZLQJ DGYHUVH reactions RFFXUUHG LQ WROYDSWDQ WUHDWHG SDWLHQWV DW D UDWH DW OHDVW JUHDWHU WKDQ SODFHER PRUWDOLW\ WROYDSWDQ SODFHER QDXVHD WROYDSWDQ SODFHER WKLUVW WROYDSWDQ SODFHER GU\ PRXWK WROYDSWDQ SODFHER DQG SRO\XULD

SAMSCAÂ® (tolvaptan) RU SROODNLXULD WROYDSWDQ SODFHER 7KH IROORZLQJ DGYHUVH UHDFWLRQV RFFXUUHG LQ RI K\SRQDWUHPLF SDWLHQWV WUHDWHG ZLWK 6$06&$ DQG DW D UDWH JUHDWHU WKDQ SODFHER LQ GRXEOH EOLQG SODFHER FRQWUROOHG WULDOV 1 WROYDSWDQ 1 SODFHER RU LQ RI SDWLHQWV LQ DQ XQFRQWUROOHG WULDO RI SDWLHQWV ZLWK K\SRQDWUHPLD 1 DQG DUH QRW PHQWLRQHG HOVHZKHUH LQ WKH ODEHO Blood and Lymphatic System 'LVRUGHUV 'LVVHPLQDWHG LQWUDYDVFXODU FRDJXODWLRQ &DUGLDF 'LVRUGHUV ,QWUDFDUGLDF WKURPEXV YHQWULFXODU Â¿EULOODWLRQ Investigations: Prothrombin time prolonged; Gastrointestinal Disorders: Ischemic colitis; Metabolism and Nutrition Disorders: Diabetic ketoacidosis; Musculoskeletal and Connective Tissue Disorders: Rhabdomyolysis; Nervous System: Cerebrovascular accident; Renal and Urinary Disorders: Urethral hemorrhage; Reproductive System and Breast Disorders (female): Vaginal hemorrhage; Respiratory, Thoracic, and Mediastinal Disorders: Pulmonary embolism, respiratory failure; Vascular disorder: Deep vein thrombosis. DRUG INTERACTIONS: Effects of Drugs on Tolvaptan: Ketoconazole and Other Strong CYP 3A Inhibitors: 6$06&$ LV PHWDEROL]HG SULPDULO\ E\ &<3 $ .HWRFRQD]ROH LV D VWURQJ LQKLELWRU RI &<3 $ DQG DOVR DQ LQKLELWRU RI 3 JS &R DGPLQLVWUDWLRQ RI 6$06&$ DQG NHWRFRQD]ROH PJ GDLO\ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PJ NHWRFRQD]ROH GDLO\ RU ZLWK RWKHU VWURQJ &<3 $ LQKLELWRUV H J FODULWKURP\FLQ LWUDFRQD]ROH WHOLWKURP\FLQ VDTXLQDYLU QHOÂ¿QDYLU ULWRQDYLU DQG QHID]RGRQH DW WKH KLJKHVW ODEHOHG GRVH ZRXOG EH H[SHFWHG WR FDXVH DQ HYHQ JUHDWHU LQFUHDVH LQ WROYDSWDQ H[SRVXUH 7KXV 6$06&$ DQG VWURQJ &<3 $ LQKLELWRUV VKRXOG QRW EH FR DGPLQLVWHUHG [see Dosage and Administration (2.3) and Contraindications (4.4)]. Moderate CYP 3A Inhibitors: 7KH LPSDFW RI PRGHUDWH &<3 $ LQKLELWRUV H J HU\WKURP\FLQ Ã&#x20AC;XFRQD]ROH DSUHSLWDQW GLOWLD]HP DQG YHUDSDPLO RQ WKH H[SRVXUH WR FR DGPLQLVWHUHG WROYDSWDQ KDV QRW EHHQ DVVHVVHG $ VXEVWDQWLDO LQFUHDVH LQ WKH H[SRVXUH WR WROYDSWDQ ZRXOG EH H[SHFWHG ZKHQ 6$06&$ LV FR DGPLQLVWHUHG ZLWK PRGHUDWH &<3 $ LQKLELWRUV &R DGPLQLVWUDWLRQ RI 6$06&$ ZLWK PRGHUDWH &<3 $ LQKLELWRUV VKRXOG WKHUHIRUH JHQHUDOO\ EH DYRLGHG [see Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Grapefruit Juice: &R DGPLQLVWUDWLRQ RI JUDSHIUXLW MXLFH DQG 6$06&$ UHVXOWV LQ D IROG LQFUHDVH LQ H[SRVXUH WR WROYDSWDQ [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. P-gp Inhibitors: 5HGXFWLRQ LQ WKH GRVH RI 6$06&$ PD\ EH UHTXLUHG LQ SDWLHQWV FRQFRPLWDQWO\ WUHDWHG ZLWK 3 JS LQKLELWRUV VXFK DV H J F\FORVSRULQH EDVHG RQ FOLQLFDO UHVSRQVH [see Dose and Administration (2.3) and Warnings and Precautions (5.5)]. Rifampin and Other CYP 3A Inducers: 5LIDPSLQ LV DQ LQGXFHU RI &<3 $ DQG 3 JS &R DGPLQLVWUDWLRQ RII ULIDPSLQ DQG 6$06&$ UHGXFHV H[SRVXUH WR WROYDSWDQ E\ 7KHUHIRUH WKH H[SHFWHG FOLQLFDO HIIHFWV RI 6$06&$ LQ WKH SUHVHQFH RI ULIDPSLQ DQG RWKHU LQGXFHUV H J ULIDEXWLQ ULIDSHQWLQ EDUELWXUDWHV SKHQ\WRLQ FDUEDPD]HSLQH DQG 6W -RKQÂ¶V :RUW PD\ QRW EH REVHUYHG DW WKH XVXDO GRVH OHYHOV RI 6$06&$ 7KH GRVH RI 6$06&$ PD\ KDYH WR EH LQFUHDVHG [Dosage and Administration (2.3) and Warnings and Precautions (5.5)]. Lovastatin, Digoxin, Furosemide, and Hydrochlorothiazide: &R DGPLQLVWUDWLRQ RI ORYDVWDWLQ GLJR[LQ IXURVHPLGH DQG K\GURFKORURWKLD]LGH ZLWK 6$06&$ KDV QR FOLQLFDOO\ UHOHYDQW LPSDFW RQ WKH H[SRVXUH WR WROYDSWDQ Effects of Tolvaptan on Other Drugs: Digoxin: 'LJR[LQ LV D 3 JS VXEVWUDWH DQG 6$06&$ LV D 3 JS LQKLELWRU &R DGPLQLVWUDWLRQ RI 6$06&$ DQG GLJR[LQ UHVXOWV LQ D IROG LQFUHDVH LQ WKH H[SRVXUH WR GLJR[LQ Warfarin, Amiodarone, Furosemide, and Hydrochlorothiazide: &R DGPLQLVWUDWLRQ RI WROYDSWDQ GRHV QRW DSSHDU WR DOWHU WKH SKDUPDFRNLQHWLFV RI ZDUIDULQ IXURVHPLGH K\GURFKORURWKLD]LGH RU DPLRGDURQH RU LWV DFWLYH PHWDEROLWH GHVHWK\ODPLRGDURQH WR D FOLQLFDOO\ VLJQLÂ¿FDQW GHJUHH Lovastatin: 6$06&$ LV D ZHDN LQKLELWRU RI &<3 $ &R DGPLQLVWUDWLRQ RI ORYDVWDWLQ DQG 6$06&$ LQFUHDVHV WKH H[SRVXUH WR ORYDVWDWLQ DQG LWV DFWLYH PHWDEROLWH ORYDVWDWLQ È&#x2022; K\GUR[\DFLG E\ IDFWRUV RI DQG UHVSHFWLYHO\ 7KLV LV QRW D FOLQLFDOO\ UHOHYDQW change. Pharmacodynamic Interactions: 7ROYDSWDQ SURGXFHV D JUHDWHU KRXU XULQH YROXPH H[FUHWLRQ UDWH WKDQ GRHV IXURVHPLGH RU K\GURFKORURWKLD]LGH &RQFRPLWDQW DGPLQLVWUDWLRQ RI WROYDSWDQ ZLWK IXURVHPLGH RU K\GURFKORURWKLD]LGH UHVXOWV LQ D KRXU XULQH YROXPH H[FUHWLRQ UDWH WKDW LV VLPLODU WR WKH UDWH DIWHU WROYDSWDQ DGPLQLVWUDWLRQ DORQH $OWKRXJK VSHFLÂ¿F LQWHUDFWLRQ VWXGLHV ZHUH QRW SHUIRUPHG LQ FOLQLFDO VWXGLHV WROYDSWDQ ZDV XVHG FRQFRPLWDQWO\ ZLWK EHWD EORFNHUV DQJLRWHQVLQ UHFHSWRU EORFNHUV DQJLRWHQVLQ FRQYHUWLQJ HQ]\PH LQKLELWRUV DQG SRWDVVLXP VSDULQJ GLXUHWLFV $GYHUVH UHDFWLRQV RI K\SHUNDOHPLD ZHUH DSSUR[LPDWHO\ KLJKHU ZKHQ WROYDSWDQ ZDV DGPLQLVWHUHG ZLWK DQJLRWHQVLQ UHFHSWRU EORFNHUV DQJLRWHQVLQ FRQYHUWLQJ HQ]\PH LQKLELWRUV DQG SRWDVVLXP VSDULQJ GLXUHWLFV FRPSDUHG WR DGPLQLVWUDWLRQ RI WKHVH PHGLFDWLRQV ZLWK SODFHER 6HUXP SRWDVVLXP OHYHOV VKRXOG EH PRQLWRUHG GXULQJ FRQFRPLWDQW GUXJ WKHUDS\ USE IN SPECIFIC POPULATIONS: 7KHUH LV QR QHHG WR DGMXVW GRVH EDVHG RQ DJH JHQGHU UDFH RU FDUGLDF IXQFWLRQ [see Clinical Pharmacology (12.3)]. Pregnancy: Pregnancy Category C. 7KHUH DUH QR DGHTXDWH DQG ZHOO FRQWUROOHG VWXGLHV RI 6$06&$ XVH LQ SUHJQDQW ZRPHQ ,Q DQLPDO VWXGLHV FOHIW SDODWH EUDFK\PHOLD PLFURSKWKDOPLD VNHOHWDO PDOIRUPDWLRQV GHFUHDVHG IHWDO ZHLJKW GHOD\HG IHWDO RVVLÂ¿FDWLRQ DQG HPEU\R IHWDO GHDWK RFFXUUHG 6$06&$ VKRXOG EH XVHG GXULQJ SUHJQDQF\ RQO\ LI WKH SRWHQWLDO EHQHÂ¿W MXVWLÂ¿HV WKH SRWHQWLDO ULVN WR WKH IHWXV ,Q HPEU\R IHWDO GHYHORSPHQW VWXGLHV SUHJQDQW UDWV DQG UDEELWV UHFHLYHG RUDO WROYDSWDQ GXULQJ RUJDQRJHQHVLV 5DWV UHFHLYHG WR WLPHV WKH PD[LPXP UHFRPPHQGHG KXPDQ GRVH 05+' RI WROYDSWDQ RQ D ERG\ VXUIDFH DUHD EDVLV 5HGXFHG IHWDO ZHLJKWV DQG GHOD\HG IHWDO RVVLÂ¿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see Nonclinical Toxicology (13.3)]. Labor and Delivery: 7KH HIIHFW RI 6$06&$ RQ ODERU DQG GHOLYHU\ LQ KXPDQV LV XQNQRZQ Nursing Mothers: ,W LV QRW NQRZQ ZKHWKHU 6$06&$ LV H[FUHWHG LQWR KXPDQ PLON 7ROYDSWDQ LV H[FUHWHG LQWR WKH PLON RI ODFWDWLQJ UDWV %HFDXVH PDQ\ GUXJV DUH H[FUHWHG LQWR KXPDQ PLON DQG EHFDXVH RI WKH SRWHQWLDO IRU VHULRXV DGYHUVH UHDFWLRQV LQ QXUVLQJ LQIDQWV IURP 6$06&$ D GHFLVLRQ VKRXOG EH PDGH WR GLVFRQWLQXH QXUVLQJ RU 6$06&$ WDNLQJ LQWR FRQVLGHUDWLRQ WKH LPSRUWDQFH of SAMSCA to the mother. Pediatric Use: 6DIHW\ DQG HIIHFWLYHQHVV RI 6$06&$ LQ SHGLDWULF SDWLHQWV KDYH QRW EHHQ HVWDEOLVKHG Geriatric Use: 2I WKH WRWDO QXPEHU RI K\SRQDWUHPLF VXEMHFWV WUHDWHG ZLWK 6$06&$ LQ FOLQLFDO VWXGLHV ZHUH DQG RYHU ZKLOH ZHUH DQG RYHU 1R RYHUDOO GLIIHUHQFHV LQ VDIHW\ RUU HIIHFWLYHQHVV ZHUH REVHUYHG EHWZHHQ WKHVH VXEMHFWV DQG \RXQJHU VXEMHFWV DQG RWKHU UHSRUWHG FOLQLFDO H[SHULHQFH KDV QRW LGHQWLÂ¿HG GLIIHUHQFHV LQ UHVSRQVHV EHWZHHQ WKH HOGHUO\ DQG \RXQJHU SDWLHQWV EXW JUHDWHU VHQVLWLYLW\ RI VRPH ROGHU LQGLYLGXDOV FDQQRW EH UXOHG RXW ,QFUHDVLQJ DJH KDV QR HIIHFW RQ WROYDSWDQ plasma concentrations. Use in Patients with Hepatic Impairment: 0RGHUDWH DQG VHYHUH KHSDWLF LPSDLUPHQW GR QRW DIIHFW H[SRVXUH WR WROYDSWDQ WR D FOLQLFDOO\ UHOHYDQW H[WHQW 1R GRVH DGMXVWPHQW RI WROYDSWDQ LV QHFHVVDU\ Use in Patients with Renal Impairment: 1R GRVH DGMXVWPHQW LV QHFHVVDU\ EDVHG RQ UHQDO IXQFWLRQ 7KHUH DUH QR FOLQLFDO WULDO GDWD LQ SDWLHQWV ZLWK &U&O P/ PLQ DQG EHFDXVH GUXJ HIIHFWV RQ VHUXP VRGLXP OHYHOV DUH OLNHO\ ORVW DW YHU\ ORZ OHYHOV RI UHQDO IXQFWLRQ XVH LQ SDWLHQWV ZLWK D &U&O P/ PLQ LV QRW UHFRPPHQGHG 1R EHQHÂ¿W FDQ EH H[SHFWHG LQ SDWLHQWV ZKR DUH DQXULF [see Contraindications 4.5) and Clinical Pharmacology (12.3)]. Use in Patients with Congestive Heart Failure: 7KH H[SRVXUH WR WROYDSWDQ LQ SDWLHQWV ZLWK FRQJHVWLYH KHDUW IDLOXUH LV QRW FOLQLFDOO\ UHOHYDQWO\ LQFUHDVHG 1R GRVH DGMXVWPHQW LV QHFHVVDU\ OVERDOSAGE: 6LQJOH RUDO GRVHV XS WR PJ DQG PXOWLSOH GRVHV XS WR PJ RQFH GDLO\ IRU GD\V KDYH EHHQ ZHOO WROHUDWHG LQ VWXGLHV LQ KHDOWK\ VXEMHFWV 7KHUH LV QR VSHFLÂ¿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Â¿UVW VWHS $ WKRURXJK KLVWRU\ DQG GHWDLOV RI RYHUGRVH VKRXOG EH REWDLQHG DQG D SK\VLFDO H[DPLQDWLRQ VKRXOG EH SHUIRUPHG 7KH SRVVLELOLW\ RI PXOWLSOH GUXJ LQYROYHPHQW VKRXOG EH considered. 7UHDWPHQW VKRXOG LQYROYH V\PSWRPDWLF DQG VXSSRUWLYH FDUH ZLWK UHVSLUDWRU\ (&* DQG EORRG SUHVVXUH PRQLWRULQJ DQG ZDWHU à¯&#x2DC;HOHFWURO\WH VXSSOHPHQWV DV QHHGHG $ SURIXVH DQG SURORQJHG DTXDUHVLV VKRXOG EH DQWLFLSDWHG ZKLFK LI QRW PDWFKHG E\ RUDO Ã&#x20AC;XLG LQJHVWLRQ VKRXOG EH UHSODFHG ZLWK LQWUDYHQRXV K\SRWRQLF Ã&#x20AC;XLGV ZKLOH FORVHO\ PRQLWRULQJ HOHFWURO\WHV DQG Ã&#x20AC;XLG EDODQFH (&* PRQLWRULQJ VKRXOG EHJLQ LPPHGLDWHO\ DQG FRQWLQXH XQWLO (&* SDUDPHWHUV DUH ZLWKLQ QRUPDO UDQJHV 'LDO\VLV PD\ QRW EH HIIHFWLYH LQ UHPRYLQJ WROYDSWDQ EHFDXVH RI LWV KLJK ELQGLQJ DIÂ¿QLW\ IRU KXPDQ SODVPD SURWHLQ ! &ORVH PHGLFDO VXSHUYLVLRQ DQG PRQLWRULQJ VKRXOG FRQWLQXH XQWLO WKH SDWLHQW UHFRYHUV PATIENT COUNSELING INFORMATION: $V D SDUW RI SDWLHQW FRXQVHOLQJ KHDOWKFDUH SURYLGHUV PXVW UHYLHZ WKH 6$06&$ 0HGLFDWLRQ *XLGH ZLWK HYHU\ SDWLHQW [see FDA-Approved Medication Guide (17.3)]. 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 Pg-p 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 H J F\FORVSRULQH [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$06&$ >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 trademark of Otsuka Pharmaceutical Co., Ltd., Tokyo, 101-8535 Japan

UNMET NEED. FILL IT.

FREE VVATER V2

CLEARANCE

Order SAMSCA® (tolvaptan)

15 mg

30 mg

NDC: 59148-020-50

NDC: 59148-021-50

Unique oral treatment for clinically significant hypervolemic and euvolemic hyponatremia

100 %

of physicians surveyed (N=57) would recommend SAMSCA to a colleague 1 In this same survey (patient cases; N=150), physicians were satisﬁed or very satisﬁed with SAMSCA 90% of the time1

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, cirrhosis, 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, anuric patients. • 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 • 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 • Gastrointestinal bleeding in patients with cirrhosis: Use in cirrhotic patients only when the need to treat outweighs this risk • Avoid use with: CYP 3A inhibitors and CYP 3A inducers. Reduced dose of SAMSCA may be needed if used with P-gp inhibitors • Co-administration with hypertonic saline is not recommended • Monitor serum potassium in patients with levels >5 mEq/L and in those receiving drugs known to increase serum potassium Commonly observed adverse reactions: (SAMSCA vs placebo) 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%). Reference: 1. Market Rx 2010.

For more information about SAMSCA, visit samsca.com or call 1-877-726-7220.

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

March 2012

0712A-4220K

MARCH 2013 Brought to You by

REPORT Transdermal PCA in Acute Postoperative Pain Management: A Critical Evaluation of the Investigational IONSYS System Despite advances in pain manAcute postoperative pain conChair agement technology, the advent tinues to be undertreated, with of acute pain services, and proup to 75% of patients in the Eugene R. Viscusi, MD fessional practice guidelines United States failing to receive Professor of Anesthesiology aimed at improving postoperative adequate postoperative pain Director, Acute Pain Management pain management, inadequacies relief.1,2 Postoperative pain manThomas Jefferson University and treatment gaps still exist, and agement was revolutionized with improvement remains a priority.7 the introduction of patient-conPhiladelphia, Pennsylvania trolled analgesia (PCA) using IV An analgesic intervention Faculty or epidural delivery routes more that might help to mitigate clinithan 20 years ago.3 Opioids are cian concern is the fentanyl ionJohn Fanikos, RPh, MBA tophoretic transdermal system the primary treatment for acute Director of Pharmacy Business (IONSYS), a credit card–sized, pain management,4 either alone Brigham and Women’s Hospital self-contained, and preproor increasingly as part of a multiBoston, Massachusetts grammed investigational product modal analgesic strategy—charcandidate intended to provide acterized by administration of 2 Michael H. Huo, MD pain relief for adult inpatients or more drugs (eg, opioid and Professor requiring opioids following surnonopioid analgesics, used in Department of Orthopedic Surgery gery.8 It is a needle-free system combination) that act by different UT Southwestern Medical Center mechanisms, and along differthat is applied to the skin on the Dallas, Texas ent pain pathways—an approach upper arm or chest.8 A generally that is recommended by the imperceptible electrical current American Society of Anesthesithen delivers a small dose of fenologists (ASA) and the American Pain Society.5,6 However, tanyl directly through the skin and into the systemic circulation. The FDA approved IONSYS in 2006; however, it existing PCA modalities have limitations that include invawas never launched in the United States due to required sive access, challenges in titration of analgesic effect, changes in manufacturing. The enhanced design will be cumbersome pump technologies, impaired patient mobilreviewed by the FDA in the near future for use in patients ity, and limited drug preparations that have been associwith moderate to severe postoperative pain. ated with programming, medication, and dosing errors.

Supported by

REPORT

PCA Patient variables

Nurse variables Pain

Sedation Patient requests nurse Analgesia Nurse arrives

Pharmacokinetic variables

Nurse evaluates

Absorption Injection administered

Nurse readies injection

Figure 1. PCA’s influence on pain control. PCA reduces the time it takes to alleviate acute pain in patients. PCA, patient-controlled analgesia

Burden of Acute Postoperative Pain More than 48 million inpatient surgeries and roughly 35 million outpatient surgeries are performed annually in the United States, and the magnitude of unrelieved acute postoperative pain is substantial.4,9,10 Unrelieved pain can have profound implications and inadequately managed acute postoperative pain can result in negative clinical (eg, myocardial infarction, infection, pneumonia, poor wound healing, demoralization) and medical outcomes (eg, extended hospital length of stay, readmissions, patient dissatisfaction, perception of negative hospital performance, and increased health care utilization costs).4 Given the problem of insufficient pain relief, treatment regimens now include the use of multimodal analgesia to control postoperative pain and potentially improve postoperative recovery.11

Elements of Multimodal Analgesia A multimodal approach that incorporates opioid-based PCA is a principal element of acute pain management during the postoperative period.12 The 2012 ASA Practice Guidelines for Acute Pain Management in the Perioperative Setting recommend the consideration of acetaminophen, oral cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs), nonselective NSAIDs, and calcium channel α2δ antagonists (ie, gabapentin and pregabalin) as part of an acute postoperative multimodal pain management regimen.5 Patients should receive around-the-clock (ATC) doses of coxibs,

NSAIDs, or acetaminophen unless contraindicated.5 Regional anesthetic techniques, including peripheral nerve blockade, should be considered; dosing regimens, route of administration, and therapy duration should be individualized to balance considerations of effectiveness and risk for adverse events (AEs).5 Drugs with a primary indication other than analgesia (eg, anticonvulsant medications) are sometimes used as part of a multimodal strategy. While opioids remain an important part of the foundation of pharmacological management of moderate to severe pain during the postoperative period,13 opioid-reducing regimens of ATC nonopioids are considered most appropriate.5 Opioids endure as an important analgesic component for the systemic treatment of postoperative pain,12 but the best delivery route of therapeutic agents depends on many factors including the physician’s level of expertise as well as patient characteristics. Evidence shows that when compared with conventional opioid analgesia (eg, IV, subcutaneous, intramuscular), PCA with opioids provides a greater analgesic effect, even when the amount of opioids consumed is similar between the 2 methods; and it also is the preferred treatment modality among patients.14 PCA also can be used in conjunction with an opioidsparing multimodal treatment regimen.

PCA Modalities and Practices The basic tenet of PCA dictates that patients should have direct control of their pain management14 and may benefit from

REPORT doing so.15 Severe acute pain is best treated with intermittent, small doses of opioids that are delivered immediately when needed (Figure 1). This allows for rapid titration of analgesic effect and provides more effective pain relief than conventional (eg, intermittent bolus intramuscular, IV, subcutaneous) opioid regimens.14,15 The superior analgesic efficacy of IV PCA compared with intermittent intramuscular analgesia was demonstrated in a pooled-data analysis in which the incidence of moderate-severe pain with intramuscular analgesia was 67% (95% confidence interval [CI], 58.1%-76.2%) and severe pain was 29% (95% CI, 18.8%-39.4%). For PCA, the incidence of moderate-severe pain was 36% (95% CI, 31.4%-40.2%) and severe pain was 10% (95% CI, 8%-12.8%), respectively.16 Data also have shown that fewer pulmonary complications are reported with IV PCA compared with other methods of opioid delivery (eg, IV, subcutaneous, intramuscular), and the risk for oversedation is reduced.14,17 After pain control has been established with a loading dose of IV opioids, PCA is used to sustain comfort by selfadministering small amounts of analgesic medication within preset parameters.18 Staff-programmed PCA pump settings regulate medication dosing and dosing frequency, the lockout period between doses, and the maximum allowable dose per hour. Existing PCA modalities including IV PCA, patientcontrolled epidural analgesia (PCEA), and patient-controlled regional anesthesia (PCRA) have varying benefits. For example, IV PCA has an acceptable efficacy and safety profile along with reports of high patient satisfaction.3 Analgesia delivered through the epidural route (eg, PCEA, continuous infusion, bolus injection) supplies rapid analgesia and decreases systemic opioid exposure.3 PCEA also allows patients to selfadminister analgesia based on individual requisites.3 Similarly, PCRA provides analgesia without systemic exposure to opioids and it can conveniently be used in an outpatient setting.3 Similar to IV PCA and PCEA, PCRA also has the advantage of a no first-pass gastrointestinal effect but also a no first-pass hepatic effect.3 The ASA recommends the use of therapeutic options like systemic opioid PCA, central regional (ie, neuraxial) opioids, and peripheral regional techniques after carefully considering patient profiles and clinicians’ experience level, and the use of these modalities is preferred over prescribed as needed intramuscular opioids.5 PCA is a standard of postoperative pain management and current modalities allow for use of complex regimens.

Cost-Effectiveness Related to PCA Medical expenses, unintended morbidity and mo rtality costs, and overhead expenses all affect the total cost of managing pain during the postoperative period. Actual costs associated with postoperative pain management include fixed costs, which remain stable despite volume of activity (eg, IV PCA pumps), and variable costs, which fluctuate according to volume (eg, analgesics, disposable supplies). Because the inadequate treatment of postoperative pain may result in chronic pain, it may be difficult to estimate the actual cost of postoperative pain management. Unfortunately, hospitals and health care providers usually are unaware of the actual costs

associated with providing services, and actual costs do not always equate to compensation for the institution or clinician. The examination of cost-effectiveness evaluates the total benefits respective to the expenses and resources necessary for advances in pain management. For example, 1 study analyzed cost-effectiveness between PCA and intermittent intramuscular injections. In this study, PCA was the preferred modality compared with intermittent intramuscular injections because it was associated with a lower mean pain level over 24 hours and greater patient satisfaction.19 While the mean drug and equipment cost for PCA was higher per patient compared with intermittent intramuscular injections, PCA retained clinical advantages over the traditional injection such as greater pain relief and patient satisfaction.19 With regard to IV PCA, direct costs include staff time, analgesics, infusion pumps, and tubing. Likewise, intangible costs that are associated with IV PCA include restricted mobility and patient discomfort. Indirect mortality and morbidity expenses for all modalities include expenses associated with insufficient pain management, medication errors, and staff-related injuries such as needlesticks. Examples of opportunity expenses include lost nursing time for pump programming, delays in setting up equipment, and consequent delays in patient discharge from the hospital. When developing a regimen for postoperative pain management, an analysis of cost-effectiveness that scrutinizes resource utilization and labor costs related to these modalities, along with probable intangible, indirect, and opportunity costs is justified. The potential for pain relief is an important factor to consider when weighing the cost-benefits of a specific treatment modality.

Clinical and Pharmacodynamic Characteristics of Opioids in PCA Currently, opioids are the principal treatment for acute pain.4 Morphine is the most commonly employed opioid in postoperative IV PCA (usual starting dose in opioid-naive patients, 1 mg), followed in usage by hydromorphone (0.2 mg) and fentanyl (10 mcg); all are pure opioid agonists.18 Best practice dictates that approximately equianalgesic dosing of opioids is employed to minimize the impact of medication errors. Although morphine is considered the gold standard for IV PCA,18 its active metabolites—morphine-3-glucuronide and morphine-6-glucuronide—may accumulate insidiously in patients with renal impairment and have toxic effects owing to reduced excretion of the metabolite.20 Hydromorphone may be used as an alternative in morphineintolerant patients or in those with altered renal function. Compared with morphine, hydromorphone is at least 5 times more potent; initial doses should be significantly lower for hydromorphone and ordered in milligrams.15 Meperidine should be avoided for routine PCA because of an association with seizures, confusion and central nervous system stimulation, caused by its metabolism to an active form, normeperidine.15 Fentanyl has no active metabolites20 and is highly lipophilic, which facilitates crossing the blood–brain barrier. 21 Small

REPORT

Table. Patient-Controlled Modalities Used for the Management of Acute Postoperative Pain Modality

Conveniences

Limitations

Iontophoresis

Noninvasive; rapid analgesia; convenient, small in size, no required cables or pump; no programming by hospital staff required; no first-pass GI effect; limited time and resources required for administration; patient controlled

Not appropriate for patients with skin disorders or injuries that prevent application; individualization of dosing limited to frequency of dosing

IV PCA

Rapid analgesia; patient controlled; programmable

Invasive; pump apparatus, tubing, and power cables may limit patient mobility; extensive staff time and resources required for administration; requires programming by staff; potential for IV line occlusions, programming and drug errors

PCEA

Rapid analgesia; patient controlled; programmable

Invasive; pump apparatus, tubing, and power cables may limit patient mobility; extensive staff time and resources required for administration; requires programming by staff

PCRA

No first-pass hepatic effect; minimized systemic opioid requirements

Technique generally limited to orthopedic surgery patients; further development of PCRA pumps needed; efficacy and safety needs further evaluation

GI, gastrointestinal; PCA, patient-controlled analgesia; PCEA, patient-controlled epidural analgesia; PCRA, patient-controlled regional analgesia From reference 3.

positively charged molecules are ideal iontophoretic agents. Hence, fentanyl hydrochloride (HCl) is well suited for iontophoretic delivery.22 Furthermore, fentanyl exhibits a satisfactory AE profile. Hutchinson and colleagues reported that patients in the postoperative period who received IV PCA fentanyl had a low rate of common opioid-related AEs (eg, nausea, vomiting, pruritus, urinary retention, sedation).23 The same study revealed that during postoperative days 1 and 2, the IV PCA fentanyl group also had an acceptably low median pain score.23 Because the kidneys excrete metabolites of most opioids, the absence of active metabolites with fentanyl may make it a reasonable choice for patients with renal impairment.24 In critically ill patients, fentanyl has a prolonged clearance (half-life up to 25 hours) that should be taken into consideration. In addition to fentanyl, drugs with the relatively safest analgesic pharmacologic profiles for use in patients with impaired kidney function include alfentanil, ketamine, and buprenorphine.24 Drugs also used in the presence of renal failure but with special precautions—usually dose reductions—include amitriptyline, gabapentin, bupivacaine, and clonidine.24 NSAIDs and aspirin should not be used in the presence of chronic renal failure because of the risk for significant toxicity.24 In any patient population, postoperative renal function may differ markedly from preoperative renal function and clinicians should be vigilant for renal function changes.

Limitations of IV PCA When accurately prescribed and effectively monitored, PCA is an effective and safe way to control acute pain.15 However, PCA also is complex and prone to error.3 PCA is associated with numerous system-related complications and programming errors.3 In fact, device malfunction is a major cause of reported AEs with IV infusion pumps. Of 2,009 IV PCA-related events reported to the FDA’s Manufacturer and User Facility Device Experience (MAUDE) voluntary medication error reporting program during a 2-year period, 1,590 (79.1%) were classified as possible device-safety events.25 A retrospective analysis of MEDMARX, an Internet-accessible, voluntary medication error reporting program, found that PCA medication errors consequently are associated with higher relative risk for patient harm compared with non-PCA medication errors, and may occur during all phases of the medication use process.26 The increased focus on patient satisfaction in the hospital setting, led by the Centers for Medicare & Medicaid Services and the Agency for Healthcare Research and Quality, emphasizes the need for the optimal delivery of PCA. The Hospital Consumer Assessment of Healthcare Providers and Systems’ (HCAHPS) national standard survey monitors patients’ perspectives on hospital care.27 Increasingly, this survey—which includes an assessment of patient satisfaction—is being used to dictate reimbursement at risk.27 In fact, patient satisfaction with

REPORT pain management in the hospital is one of the 6 summary measurements used to determine the at-risk reimbursement under HCAHPS.28 Complications associated with PCA include a troublesome profile of common μ-agonist opioid-induced AEs including respiratory depression, nausea, vomiting, pruritus, sedation, and confusion.18 There also is the potential for complications related to the IV line itself (eg, occlusions) and catheter infiltration into subcutaneous tissue, or programming and medication errors—any of which can result in potentially serious AEs, including oversedation, respiratory depression, and under-treated pain (Table).3,15 Specific clinical disadvantages of IV PCA are that it is invasive, hinders patient mobility, requires external supplies (eg, tubing, power cables, drug cassettes) and the necessity of pump apparatus and programming, and extensive staff time and resources. In terms of patient comfort, analgesic gaps can occur while patients are waiting for medication during the transition from one analgesic modality to another. PCA delivery also requires a staff of expert clinicians including pharmacists, physicians, nurses, and physician assistants. The infrastructure must be present in order to safely and effectively deliver PCA— thus, a substantial commitment in resources is necessary. Furthermore, PCA by proxy errors, in which an unauthorized party activates the analgesic pump’s dosing mechanism, delivering analgesic medication to the patient, are another potentially serious issue within PCA delivery. PCA by proxy errors can result in serious AEs including oversedation, respiratory depression, and death.17

Limitations of PCEA and PCRA Similar to IV PCA, PCEA requires a staff-programmed pump and a highly qualified anesthesia provider to insert a catheter into the desired epidural location.3 In addition to the need for extensive hospital staff for administration, PCEA also requires manual programming, increasing the risk for serious programming and medication errors.3 PCEA’s pump, tubing, and power cables discourage patient mobility, and there also is a risk for occlusions.3 Analgesic administration via the epidural route also is associated with catheter dislodgement and migration within the epidural space; in fact, 17% of epidural catheters fail due to unexpected dislodgement.29 PCRA also possesses certain limitations. For example, in addition to being invasive, PCRA in an unmonitored setting is associated with an increased risk for complications such as leaking or dislodgement of indwelling catheters and infection.3 PCRA is usually restricted for use in orthopedic surgery patients; this modality also requires an advanced hospital staff to set up perineural catheters.3

Limitations of Other Routes of Opioid Administration While oral administration of opioids for the treatment of moderate to severe pain is both convenient and noninvasive, it is usually contraindicated in the immediate postoperative period.12 Oral opioids also possess a delayed onset of action; poor absorption in the gastrointestinal tract and a powerful first-pass effect cause a variable period of action compared with parenteral opioids.12

As such, greater doses of opioids (eg, morphine and meperidine) are required for oral administration than for the parenteral route.30 Furthermore, because the optimal analgesic dose varies among patients, overdose or the undertreatment of pain are potential risks with this route of administration. The intramuscular route is associated with painful administration10 as well as ineffective pain control compared with other modalities (ie, PCA, epidural).16 The intramuscular administration of analgesics is characterized by unpredictable absorption as there is a 30- to 60-minute lag to peak effect followed by a sudden drop in action. The intramuscular route has another troubling element—when the opioid finally peaks, patients often are alone and can experience oversedation, vomiting, and aspiration.4

Iontophoretic Transdermal Delivery Transdermal drug delivery, like parenteral delivery, avoids first-pass hepatic metabolism and obstacles associated with oral analgesics following surgery (eg, vomiting, nausea, and difficulty swallowing).31 For the delivery of analgesics, transdermal modalities operate as a drug reservoir that determines the amount of drug transfer.32 Transdermal iontophoresis is a method that employs a subtle electrical current to deliver ionized drug molecules across the skin and into the circulation.31 With iontophoresis, neutral or cationic agents are positioned below an anode and anionic agents are fixed below a cathode, and a low current density and low voltage is applied, causing ions to be repelled through and into the skin.32 The skin acts to complete the circuit as electric currents move from the anode to the cathode.31 Specifically, the anode causes cationic therapeutic agents to be moved into and through the skin, and extracts anions from the tissue beneath the skin back into the anode.32 Within the cathode, anionic buffer ions are sent through the skin and the tissues’ cations migrate into the cathode.32 As such, an active transdermal system that uses iontophoretic drug delivery offers patients control over analgesic dosing along with convenient administration and rapid analgesic delivery without some of the shortcomings associated with IV and epidural routes.31

Iontophoretic PCA IONSYS is a noninvasive device that employs iontophoretic technology and is designed for PCA via the transdermal route (Figure 2).33 IONSYS is adhered to the patient’s skin with an adhesive backing. To deliver a dose of fentanyl, the patient can press the dosing button twice within 3 seconds; an audible tone will signal the start of delivery of each dose; and a rapidly blinking green light will remain on throughout the 10-minute dosing period.33 IONSYS activation produces a small electrical voltage between the anode and cathode. This causes positively charged fentanyl molecules located in the anode hydrogel reservoir to be repelled from the positively charged anode surface and to be delivered through the skin into the systemic circulation.31 In contrast to existing PCA modalities, iontophoretic transdermal delivery does not require infusion pumps or indwelling catheters to deliver medication, which encourages patient mobility in the critically important postsurgical period.3

REPORT percentage of human-related errors reported to have inflicted patient harm was 48.1%.25 MAUDE data also indicates that the percentage of device-related errors reported to have inflicted patient harm was 0.5%.25 Furthermore, IONSYS’ compact design also eliminates the necessity for unwieldy equipment that requires nursing staff attention and may restrict patient mobility because the patient is tethered by IV tubing, an IV pole, and the IV PCA pump apparatus.

Clinical Considerations With IONSYS Pharmacokinetic (PK) evaluations of IONSYS in dosing frequency studies have demonstrated that it has a PK profile similar to that of IV PCA fentanyl, but with a slower rise, lower peak level, and less fluctuations.36,37 Systemic absorption of the fentanyl delivered by IONSYS increases as a function of time; this increase appears to be independent of dosing frequency.8 Subtherapeutic passive absorption with IONSYS is minimal compared with transdermal delivery; IONSYS leaves no significant skin depot of fentanyl with discontinuation of the system, and serum levels fall almost immediately (Figure 3).8,38 After 24 hours or 80 doses have been administered, IONSYS deactivates and cannot supply additional doses to the patient.8 IONSYS is designed to be applied to the skin on the upper arm or chest. The quantity of fentanyl HCl delivered by activation of the system has been demonstrated to be independent of patient age, sex, body mass index, or race, but is dependent on the location of the device on the body, with the ideal application sites being the upper outer arm or chest of patients.39

Figure 2. Enhanced IONSYS device. The credit card–sized, preprogrammed system delivers a small dose of fentanyl through the patient’s skin and into the systemic circulation. From reference 33.

IONSYS delivers 40 mcg of fentanyl per on-demand dose over a 10-minute period, with up to 6 doses available per hour.8 As such, IONSYS performs for as long as 24 hours or for a maximum of 80 doses, whichever takes place first; additional IONSYS systems can be used after 24 hours if needed for up to 3 days.3 The enhanced IONSYS device features an improved display, which helps clearly show to health care practitioners how many doses have been delivered. IONSYS eliminates IV line complications, which can lead to analgesic gaps, by supplying instantaneous dosing on patient demand, providing consistent analgesia and eliminating potentially painful waiting periods between requests for analgesia and drug administration. IONSYS also features preprogrammed dosing, which eliminates the potential for medication dosing errors. PCA medication errors have been the focus of hospital-directed safety alerts issued by the Institute for Safe Medication Practices and the Joint Commission, and remain a critical concern.34 For example, using MEDMARX data, the most common cause of IV PCA errors was human-related (accounting for 322.91 errors per 10,000 patients); followed by equipment-related (102.23 overall errors per 10,000 patients).35 Using MAUDE data, the

Ensuring Safe and Effective PCA Because IONSYS is intended only for use among hospitalized patients in the acute setting, the potential for misuse may be limited compared with the potential for misuse of the fentanyl transdermal patch or other opioids.3 To ensure proper usage, medical personnel are required to remove the IONSYS system prior to hospital release and dispose of it.8 Nevertheless, appropriate opioid selection can mitigate risks,40 and developing PCA patient-selection criteria (eg, evaluation of medically complicated patients, identification of patients with a need for a basal infusion, such as those who are opioid-tolerant) is one of the most overlooked but effective mechanisms to reduce risk for opioid-related AEs.15 In addition to clarifying the patient groups that are most likely to benefit from a particular PCA modality, targets for intervention in safe opioid analgesia are prescribing errors, staff training on use and protocols, monitoring, and patient education.15

Conclusion Opioids remain the most commonly used analgesics in postoperative pain management, especially for the treatment of moderate to severe pain. A multimodal approach that includes opioid-based PCA is an important tenet in managing acute postoperative pain.12 While the ideal mechanism of delivery depends on physicians’ expertise and the patient, data has shown that when compared with conventional opioid analgesia (eg, IV, subcutaneous, intramuscular), PCA with opioids is the preferred treatment modality among patients.14 However,

REPORT

Serum Fentanyl Concentration, ng/mL

3 IONSYS IV

2.5 2 1.5 1 0.5 0 23

Time, h

Figure 3. IONSYS vs IV fentanyl during last hour and at termination. Comparison of IONSYS and IV fentanyl during the last hour and at termination of the following treatment: 40 mcg of IONSYS was administered in 2 sequential doses over 20 minutes every hour for 23 hours and 20 minutes, and 80 mcg of IV fentanyl was administered over 20 minutes every hour for 23 hours and 20 minutes. From reference 8.

certain PCA modalities have disadvantages, including invasiveness (eg, IV PCA, PCRA), risk for infection (eg, PCRA), and medication or programming errors (eg, IV PCA, PCEA).3 The compact, self-contained, preprogrammed IONSYS system may limit the possibility for a number of medication and system-related events, including manual programming

errors, which have been associated with potentially serious clinical consequences.25,26 Unlike other PCA modalities, IONSYS is noninvasive, which promotes patient mobility during the postsurgical period. Within a multimodal pain management strategy, IONSYS may be a reasonable choice for analgesia in adult patients after a range of major surgical procedures.

References 1. Phillips DM. JCAHO pain management standards are unveiled. JAMA. 2000;284(4):428-429. 2. Wu CL, Raja SN. Treatment of acute postoperative pain. Lancet. 2011;377(9784):2215-2225. 3. Viscusi ER. Patient-controlled drug delivery for acute postoperative pain management: a review of current and emerging technologies. Reg Anesth Pain Med. 2008;33(2):146-158. 4. Wells N, Pasero C, McCaffery M. Chapter 17. Improving the Quality of Care Through Pain Assessment and Management. In: Hughes R, ed. Patient Safety and Quality: An Evidence-Based Handbook for Nurses. Rockville, Md: Agency for Healthcare Research and Quality; 2008. 5. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248-273. 6. Gordon DB, Dahl JL, Miaskowski C, et al. American Pain Society recommendations for improving the quality of acute and cancer

pain management: American Pain Society Quality of Care Task Force. Arch Intern Med. 2005;165(14):1574-1580. 7. Apfelbaum JL, Chen C, Mehta SS, Gan TJ. Postoperative pain experience: results from a national survey suggest postoperative pain continues to be undermanaged. Anesth Analg. 2003;97(2):534-540. 8. IONSYS (fentanyl iontophoretic transdermal system) 40 mcg*/ activation prescribing information. http://www.accessdata.fda.gov/ drugsatfda_docs/label/2006/021338lbl.pdf. Accessed January 9, 2012. 9. Cullen KA, Hall MJ, Golosinskiy A. Ambulatory surgery in the US, 2009. Natl Health Stat Report. 2009;11:1-25. 10. Centers for Disease Control and Prevention. Inpatient surgery. http://www.cdc.gov/nchs/fastats/insurg.htm. Accessed January 9, 2012. 11. Jin F, Chung F. Multimodal analgesia for postoperative pain control. J Clin Anesth. 2001;13(7):524-539.

REPORT 12. Rawal N, Langford RM. Current practices for postoperative pain management in Europe and the potential role of fentanyl HCl iontophorectic transdermal system. Eur J Anaesthesiol. 2007;24(4): 299-308.

27. National Association of Public Hospitals and Health Systems (NAPH). HCAHPS survey: patients’ perspectives of care. October 2008. http://www.naph.org/Main-Menu-Category/Publications/ Quality/hcahpsbrief.aspx?FT=.pdf. Accessed January 9, 2012.

13. Carr DB, Goudas LC. Acute pain. Lancet. 1999;353(9169): 2051-2058.

28. Consumer Assessment of Healthcare Providers and Systems (CAHPS). CAHPS hospital survey quality assurance guidelines. January 2008. http://www.hcahpsonline.org/files/HCAHPS%20 Quality%20Assurance%20guidelines%20version%203.0%20final. pdf. Accessed January 9, 2012.

14. Walder B, Schafer M, Henzi I, Tramer MR. Efficacy and safety of patient-controlled opioid analgesia for acute postoperative pain. A quantitative systematic review. Acta Anaesthesiol Scand. 2001;45(7):795-804. 15. Craft J. Patient-controlled analgesia: Is it worth the painful prescribing process? Proc (Bayl Univ Med Cent). 2010;23(4):434-438. 16. Dolin SJ, Cashman JN, Bland JM. Effectiveness of acute postoperative pain management: I. Evidence from published data. Br J Anaesth. 2002;89(3):409-423. 17. The Joint Commission. Sentinel Event Alert: Patient controlled analgesia by proxy. http://www.jointcommission.org/assets/1/18/ SEA_33.PDF. Accessed January 9, 2012. 18. Grass JA. Patient-controlled analgesia. Anesth Analg. 2005; 101(5 suppl):S44-S61. 19. Chang AM, Ip WY, Cheung TH. Patient controlled analgesia versus conventional intramuscular injection: a cost effectiveness analysis. J Adv Nurs. 2004:46(5):531-541. 20. Etches RC. Patient-controlled analgesia. Surg Clin North Am. 1999;79(2):297-312. 21. Momeni M, Crucitti M, De Kock M. Patient-controlled analgesia in the management of postoperative pain. Drugs. 2006;66(18):2321-2337. 22. Kalia YN, Naik A, Garrison J, Guy RH. Iontophoretic drug delivery. Adv Drug Deliv Rev. 2004;56(5):619-658. 23. Hutchison R, Chon E, Tucker W, Gilder R, Moss J, Daniel P. A comparison of a fentanyl, morphine, and hydromorphone patientcontrolled intravenous delivery for acute postoperative analgesia: a multicenter study of opioid-induced adverse reactions. Hosp Pharm. 2006;41(7):659-663.

29. Ready LB. Acute pain: lessons learned from 25,000 patients. Reg Anesth Pain Med. 1999;24(6):499-505. 30. Sinatra RS, Torres J, Bustos AM. Pain management after major orthopaedic surgery: current strategies and new concepts. J Am Acad Orthop Surg. 2002;10(2):117-129. 31. Power I. Fentanyl HCl iontophoretic transdermal system: clinical application of iontophoretic technology in the management of acute postoperative pain. Br J Anaesth. 2007;98(1):4-11. 32. Rawat S, Vengurlekar S, Rakesh B, Jain S, Srikati G. Transdermal delivery by iontophoresis. Indian J Pharm Sci. 2008;70(1):5-10. 33. Data on file. Incline Therapeutics; 2012. 34. Institute for Safe Medication Practices. Beware of basal opioid infusions with PCA therapy. www.ismp.org/newsletters/acutecare/ articles/20090312.asp. Accessed January 9, 2012. 35. Meissner B, Nelson W, Hicks R, Sikirica V, Gagne J, Schein J. The rate and costs attributable to intravenous patient-controlled analgesia errors. Hosp Pharm. 2009;44(4):312-324. 36. Sathyan G, Zomorodi K, Gidwani S, Gupta S. The effect of dosing frequency on the pharmacokinetics of a fentanyl HCl patient-controlled transdermal system (PCTS). Clin Pharmacokinet. 2005; 44(1 suppl):17-24. 37. Mattia C, Coluzzi F. Acute postoperative pain management: focus on iontophoretic transdermal fentanyl. Ther Clin Risk Manag. 2007;3(1):19-27.

24. Murphy EJ. Acute pain management pharmacology for the patient with concurrent renal or hepatic disease. Anaesth Intensive Care. 2005;33(3):311-322.

38. Heitz JW, Witkowski TA, Viscusi ER. New and emerging analgesics and analgesic technologies for acute pain management. Curr Opin Anaesthesiol. 2009;22(5):608-617.

25. Hankin CS, Schein J, Clark JA, Panchal S. Adverse events involving intravenous patient-controlled analgesia. Am J Health Syst Pharm. 2007;64(14):1492-1499.

39. Gupta SK, Hwang S, Southam M, Sathyan G. Effects of application site and subject demographics on the pharmcokinetics of fentanyl HCl patient-controlled transdermal system. Clin Pharmacokinet. 2005;44(1 suppl):25-32.

26. Hicks RW, Heath WM, Sikirica V, Nelson W, Schein JR. Medication errors involving patient-controlled analgesia. Jt Comm J Qual Patient Saf. 2008;34(12):734-742.

40. Smith H, Bruckenthal P. Implications of opioid analgesia for medically complicated patients. Drugs Aging. 2010;27(5):417-433.

Disclaimer: This monograph is designed to be a summary of information. While it is detailed, it is not an exhaustive clinical review. McMahon Publishing, Incline Therapeutics, Inc., 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.

SR1230

Disclosures: Dr. Fanikos reported no relevant financial conflicts of interest. Dr. Huo reported that he is a consultant for Biomet, DePuy, and Stryker. He also serves on the speakers’ bureau for Cadence Pharmaceuticals and Janssen Pharmaceuticals, Inc. Dr. Viscusi reported that he is a consultant for AcelRx Pharmaceuticals, Inc., Cubist Pharmaceuticals, Cumberland Pharmaceuticals, Incline Therapeutics, Inc., Pacira Pharmaceuticals, Inc., and Salix Pharmaceuticals. He also serves on the speakers’ bureau for Cadence Pharmaceuticals, and reported receiving honoraria from Merck.