June 2015 by McMahon Group

Te Spo ch tlig Se no ht o e pa l n ge s 3 og 6y 46

The Pharmacist’s News Source

pharmacypracticenews.com

CLINICAL

13 16

Pharmacists seek bigger role in cancer survivorship care. Hospital-based pharmacogenomics: Are we there yet?

POLICY

Transforming health care payment: IPPS in 2016

OPERATIONS & MGMT

28 30 32

How to become a powerful and intentional leader. Hospitals that save millions—and show pharmacists’ worth. Building an outpatient pharmacy for workers and patients.

TECHNOLOGY

OIG Investigates Skyrocketing Gen Drug Prices

Volume 42 • Number 6 • June 2015

The New Track and Trace Law Places Hospitals on High Alert A

s soaring prices of certain widely prescribed generic drugs continue to challenge both community and hospital outpatient pharmacies, the Department of Health and Human Services’ Office of Inspector General (OIG) has begun an investigation into the impact of the increases on the Medicare rebate program. The OIG investigation was announced in a recent letter to Sen. Bernie Sanders (I-Vt.) and Rep. Elijah E. Cummings (D-Md.), who have been waging a months-long campaign to find a solution to the generic price problem, which they told the Health and Human Services Secretary, Sylvia Burwell, in an earlier letter was “affecting the pocketbooks and health of millions of Americans.” The two lawmakers have also introduced a bill that would compel generic drug makers to increase the rebates they pay to state Medicaid programs whenever the prices of their medications exceed inflation rates.

s a metaphor for change, “a perfect storm” may be overused. Still, for health systems, it is an apt descriptor, given the flood of disruptive events on the horizon. The transition to ICD-10 diagnostic codes, the explosion of risk-sharing models of care and looming biosimilars approvals are just a few of the key trends that promise to shake up pharmacy operations. Now, crystal ballers are saying it’s time to add one more disrupter to the mix: the Drug Supply Chain Security Act (DSCSA). The legislation, which kicks into high gear this summer, is designed to protect the U.S. drug supply against counterfeiting, diversion and other criminal acts that pose a perennial threat to patient safety. DSCSA achieves some of that protection by requiring proof of an electronic transaction when a product changes ownership as it travels through the supply chain. Hospitals will have to satisfy that requirement—and that’s where some of the operational burdens come in. Beginning July 1, 2015, pharmacists must maintain all the chain of custody information

see PRICE HIKES, page 21

see TRACK AND TRACE, page 24

ADCs can help thwart drug diversion.

EDUCATIONAL REVIEW

Novel Oral Anticoagulants Strategies for Optimizing Patient Outcomes See page 8.

A coalition for compliance

Treatment delays, cost burden cited

Dusting Off Drug Libraries Yields Smarter IV Pumps

Genentech Expansion of Specialty Distribution for Ca Drugs Still Stings

Annapolis, Md.—Partnering with nurses, conducting rounds on inpatient floors and continually educating staff are all ways that hospitals can improve drug library compliance for smart pumps, panelists said at a kick-off meeting for the National Coalition for Infusion Therapy Safety. This is an initiative by the Association for the Advancement of Medical Instrumentation (AAMI) Foundation see DRUG LIBRARIES, page 36

hen Genentech announced late last year that it would begin shipping its three workhorse cancer drugs through the specialty distribution channel, hospital pharmacists worried that the move would increase their costs and the time they spent ordering and handling the products, while negatively affecting patient care. Genentech, a Roche company, said the move to deliver bevacizumab (Avastin), rituximab (Rituxan) and trastuzumab (Herceptin) through the specialty distribution channel was a proactive one to improve drug

New Product Teva introduces Argatroban Injection 250 mg/250 mL. See page 40

delivery, while ensuring that hospitals and patients received a quality product. Now, several months later, pharmacists said the move led to shortages of these important cancer drugs for the first time, as well as a host of other problems. “In the history of Genentech, there isn’t one pharmacy director who would have told you he or she experienced a shortage—not one. Now, because they have moved to the specialty distribution channel, we have actually experienced shortages,” said Niesha see DISTRIBUTION, page 26

Get the App

Si plify Now available Kabiven® and Perikabiven® Fresenius Kabi’s three-chamber bags for parenteral nutrition contain: • Amino Acids and Electrolytes • Dextrose • Lipids (Intralipid® 20% IV Fat Emulsion) www.KabivenUSA.com. To order, call 1-888-386-1300. Kabiven and Perikabiven three-chamber bags must be activated prior to infusion. For activation instructions see DIRECTIONS FOR ACTIVATING THE BAG in the prescribing information available at www.KabivenUSA.com. Neither Kabiven nor Perikabiven is recommended for use in pediatric patients < 2 years, including preterm infants because the ﬁxed content of the formulations do not meet the nutritional requirements in this age group. WARNING: DEATH IN PRETERM INFANTS

See full prescribing information for complete boxed warning • Deaths in preterm infants have been reported in literature. • Autopsy ﬁndings included intravascular fat accumulation in the lungs. • Preterm and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. Known hypersensitivity to egg, soybean proteins, peanut proteins, corn or corn products, or to any of the active substances or excipients. Monitor patient closely for signs and symptoms of infection, hypertriglyceridemia, hyperglycemia and refeeding complications. Monitor laboratory parameters for alterations in electrolytes, liver and renal impairment, ﬂuid status and coagulation parameters. Adjust rate and dose of Kabiven and Perikabiven according to clinical status. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, Vigilance & Medical Affairs at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see Brief Summary of Prescribing Information, including Boxed Warning, for Kabiven and Perikabiven on the following page.

BRIEF SUMMARY OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Kabiven and Perikabiven safely and effectively. See full prescribing information, including Boxed Warning, for Kabiven and Perikabiven available at www.KabivenUSA.com. KABIVEN® (Amino Acids, Electrolytes, Dextrose, and Lipid Injectable Emulsion), for intravenous use Initial U.S. Approval: 2014 PERIKABIVEN® (Amino Acids, Electrolytes, Dextrose, and Lipid Injectable Emulsion), for intravenous use Initial U.S. Approval: 2014 WARNING: DEATH IN PRETERM INFANTS See full prescribing information for complete boxed warning • Deaths in preterm infants have been reported in literature. • Autopsy findings included intravascular fat accumulation in the lungs. • Preterm and low birth weight infants have poor clearance of intravenous lipid emulsion and increased free fatty acid plasma levels following lipid emulsion infusion. INDICATIONS AND USAGE Kabiven and Perikabiven are each indicated as a source of calories, protein, electrolytes and essential fatty acids for adult patients requiring parenteral nutrition when oral or enteral nutrition is not possible, insufficient, or contraindicated. Kabiven and Perikabiven may be used to prevent essential fatty acid deficiency or treat negative nitrogen balance in adult patients. Limitation of Use: Not recommended for use in pediatric patients < 2 years, including preterm infants, because the fixed content of the formulation does not meet nutritional requirements in this age group.

DOSAGE AND ADMINISTRATION

WARNINGS AND PRECAUTIONS

• Kabiven is for intravenous infusion only into a central vein • Perikabiven is for intravenous infusion into a central or peripheral vein • Recommended dosage depends on clinical status, body weight and nutritional requirements • Kabiven adult dosage: 19 to 38 mL/kg/day (0.63 to 1.26 g/kg/day of amino acids, 1.85 to 3.71 g/kg/day of dextrose, 0.74 to 1.48 g/kg/day of lipid) • The maximum infusion rate for Kabiven is 2.6 mL/kg/hour (corresponding to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose, the limiting factor, and 0.1 g/kg/hour of lipid) • Perikabiven adult dosage: 27 to 40 mL/kg/day (0.64 to 0.94 g/kg/day of amino acids, 1.83 to 2.71 g/kg/day of dextrose, 0.95 to 1.4 g/kg/day of lipid) • The maximum infusion rate for Perikabiven is 3.7 mL/kg/hour (corresponding to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose, the limiting factor, and 0.13 g/kg/hour lipid) • The recommended infusion period is 12 to 24 hours

• Hypersensitivity reactions: Monitor for signs or symptoms and discontinue infusion if reactions occur • Infection, fat overload, hyperglycemia and refeeding complications: Monitor for signs and symptoms; monitor laboratory parameters

DOSAGE FORMS AND STRENGTHS • Kabiven and Perikabiven are sterile, hypertonic emulsions in a three-chamber container. The individual chambers contain one of the following: amino acids and electrolytes, dextrose, or lipid injectable emulsion, respectively • Kabiven is available in four sizes 2566 mL, 2053 mL, 1540 mL and 1026 mL • Perikabiven is available in three sizes 2400 mL, 1920 mL and 1440 mL CONTRAINDICATIONS • Known hypersensitivity to egg, soybean proteins, peanut proteins, corn or corn products, or to any of the active substances or excipients • Severe hyperlipidemia or severe disorders of lipid metabolism with serum triglycerides >1000 mg/dL • Inborn errors of amino acid metabolism • Cardiopulmonary instability • Hemophagocytic syndrome

ADVERSE REACTIONS The most common adverse reactions to Kabiven (>3%) are nausea, pyrexia, hypertension, vomiting, decreased hemoglobin, decreased total protein, hypokalemia, decreased potassium and increased gamma glutamyltransferase. The most common adverse reactions to Perikabiven (> 3%) are hyperglycemia, hypokalemia, pyrexia and increased blood triglycerides. To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC, Vigilance & Medical Affairs at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Coumarin and coumarin derivatives, including warfarin: Anticoagulant activity may be counteracted; monitor laboratory parameters USE IN SPECIFIC POPULATIONS Renal Impairment: Patients on hemodialysis or continuous renal replacement therapy may require additional supplementation to meet nutritional requirements. If required, adjust the volume of Kabiven or Perikabiven administered based on serum electrolyte levels and ﬂuid balance.

4 Up Front

Pharmacy Practice News • June 2015

Capsules

Making Med Rec More Exact

Web Exclusives

new study has shown that when clinical pharmacists add their own assessment skills to the use of widely used screening tools for detecting drug problems in older cancer patients, a high rate of polypharmacy and other drug-related safety issues are uncovered. “To our knowledge, this study is the first to combine a clinical pharmacist’s expert assessment together with validated, up-to-date criteria and screening tools used by researchers in the field,” said lead investigator Ginah Nightingale, PharmD, BCOP, an assistant professor in the Department of Pharmacy Practice, Jefferson School of Pharmacy at Thomas Jefferson University, Philadelphia. However, questions still remain about the extent of the risks posed by these medicationrelated problems, Dr. Nightingale said. “There is still a lot we don’t know about the impact of excessive and potentially inappropriate medication use for senior adults with cancer, specifically in terms of whether and how increased pill burdens might lead to compromised cancer management plans,” she explained. Dr. Nightingale is part of a multidisciplinary clinic at Jefferson that helps manage older cancer patients. The health care team, which includes a medical oncologist, geriatrician, clinical pharmacist, social worker and dietician, examined the drug regimens of 234 patients in their study. Using three standard evaluation tool surveys—the Beers Criteria list, the Screening Tool of Older Persons’ Prescriptions (STOPP) survey and the Healthcare Effectiveness Data and Information Set (HEDIS) criteria, which were designed to identify medications with a higher risk for causing (AEs) in older adults—they found that the association with potentially inappropriate medications (PIM) increased with the number of comorbid conditions requiring medication (P=0.005) and an increase in the number of medications the patients were taking (P<0.001) (J Clin Oncol 2015 Mar 23. [Epub ahead of print]). Additionally, 43% of the patients were taking more than 10 concurrent medications, and the prevalence of polypharmacy, excessive polypharmacy and PIM use was 41% (n=96), 43% (n=101) and 51% (n=119), respectively, the researchers found. “This is a vulnerable population,” said Andrew Chapman, DO, the co-director of the Multidisciplinary Senior Adult Oncology Center clinic at Jefferson. “They are prescribed complicated medical regimens that have a real risk of interfering with their cancer care.” “It’s difficult for an able-bodied adult to keep track of the dosing schedules and appropriate administration of 10 medications, much less for a senior who may have underlying functional or cognitive impairment,” Dr. Nightingale said. “This study is meant to give us a baseline, a sense of the landscape, and the risks involved in this population of cancer patients.” Now that they established a baseline, the researchers plan to develop a tool that combines the available assessments and considers cancer diagnosis, prognosis and cancer-related therapy to minimize the use of inappropriate medication in the elderly. In the meantime, they stressed, comprehensive medication assessments and monitoring plans should be implemented and completed routinely for all patients. —PPN Staff

Visit us online for Web-exclusive content. Links to all of the articles below can be found at pharmacypracticenews.com/ webex0615 or via your smartphone by scanning the adjacent 2D barcode. Be sure to check the Pharmacy Practice News site every day for late-breaking news!

Infant Antibiotic Use Linked to Adult Diseases

new study gives health care providers more reasons to educate parents against the unnecessary use of antibiotics. Researchers at the University of Minnesota, in Minneapolis, found a three-way link between antibiotic use in infants, changes in gut bacteria and disease later in life.

Yet Another Role for LipidLowerer: Rx-Resistant Anemias

generic drug used to lower cholesterol might help children with Diamond Blackfan anemia (DBA), a rare form of anemia that cannot be treated with erythropoietin (EPO), according to researchers from the Whitehead Institute for Biomedical Research in Cambridge, Mass.

Acute Kidney Injury An Underrecognized Risk In Hospitalized Patients

sudden loss of kidney function, which can lead to irreversible kidney damage, occurs in up to 10% of hospitalized patients, a new study suggests. The loss of function is often caused inadvertently during the hospital stay and thus should be high on the radar screen of pharmacists and other caregivers, the investigators warned.

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 42 • Number 6 • June 2015 • pharmacypracticenews.com

ANESTHESIOLOGY/PAIN Julie A. Golembiewski, PharmD, Chicago, IL

INTERNAL MEDICINE

EDITORIAL STAFF

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

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

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

NUCLEAR PHARMACY

David Bronstein, Editorial Director davidb@mcmahonmed.com

BIOTECHNOLOGY

Jeffrey Norenberg, PharmD, Albuquerque, NM

Indu Lew, PharmD, Livingston, NJ

ONCOLOGY

Melvin E. Liter, MS, PharmD, FASHP, Lexington, KY

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

CARDIOLOGY

Robert Ignoffo, PharmD, San Francisco, CA

C. Michael White, PharmD, Storrs, s CT CNS/PSYCHIATRY Charles F. Caley, PharmD, Storrs, CT Lawrence Cohen, PharmD, FASHP, FCCP, Fort Worth, Texas Larry Ereshefsky, PharmD, San Antonio, T Texas COMPLEMENTARY AND ALTERNATIVE MEDICINE

Marie Rosenthal, MS, Senior Editor mrosenthal@mcmahonmed.com Kevin Horty, Don Pizzi, Adam Marcus, Contributing Editors

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

James Prudden, Group Editorial Director

Cindy O’Bryant, PharmD, Aurora, CO

Robin B. Weisberg, Manager, r Editorial Services

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

Elizabeth Zhong, Associate Copy Chief

Sara S. Kim, PharmD, BCOP, New York, NY ORGAN TRANSPLANT PHARMACY

Cathy Rosenbaum, PharmD, Cincinnati, OH

Eric Tichy, PharmD, BCPS, New Haven, CT

CRITICAL CARE

PEDIATRICS

Judi Jacobi, PharmD, FCCM, Indianapolis, IN

Gretchen Brummel, PharmD, BCPS, Hudson, OH

INFECTIOUS DISEASES

REIMBURSEMENT

Steven J. Martin, PharmD, BCPS, FCCM, Toledo, OH

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

SALES David Kaplan, Group Publication Director dkaplan@mcmahonmed.com Matt Spoto, Senior Account Manager mspoto@mcmahonmed.com Lillie Onday, Account Manager londay@mcmahonmed.com

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TECHNOLOGY

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Thomas Van Hassel, RPh, Yuma, AZ

Craig Wilson, Sales Associate, Classified Advertising cwilson@mcmahonmed.com

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DYLOJECT IS AN INJECTABLE NON-OPIOID ANALGESIC NOW APPROVED BY THE FDA FOR USE IN ADULTS FOR THE: › Management of mild to moderate pain. › Management of moderate to severe pain alone or in combination with opioid analgesics.

Request a Dyloject representative at dyloject.com/rep

Avaailable soon.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS › Known hypersensitivity to diclofenac.

WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS

› History of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs.

See full prescribing information for complete boxed warning

› Perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

Cardiovascular Risk › Non-steroidal anti-inﬂ ﬂammatory drugs (NSAIDs) may increase the risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. Risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk.

› Moderate to severe renal insuﬀiciency in the perioperative period and who are at risk for volume depletion. WARNINGS & PRECAUTIONS › Serious and potentially fatal cardiovascular (CV) thrombotic events, myocardial infarction, and stroke: Patients with known CV disease or risk factors for CV disease may be at greater risk. Use for the shortest possible duration.

› Dyloject is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery.

› Serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation, which can be fatal: Use for the shortest possible duration. Use with caution in patients with prior history of ulcer disease or GI bleeding.

Gastrointestinal Risk

› Renal papillary necrosis and other renal injury with longterm administration of NSAIDs: Use Dyloject with caution in patients at greatest risk for this reaction, including the elderly; those with impaired renal function, heart failure, or liver impairment; and those taking diuretics or ACE inhibitors.

› NSAIDs increase the risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. Events can occur at any time without warning symptoms. Elderly patients are at greater risk.

› Elevation of one or more liver tests and severe hepatic reactions: Discontinue Dyloject immediately if abnormal liver tests persist or worsen.

› New onset or worsening of hypertension: Monitor blood pressure closely during treatment with Dyloject. › Fluid retention and edema: Use Dyloject with caution in patients with ﬂuid retention or heart failure. › Anaphylactic reactions in patients with the aspirin triad or in patients without prior exposure to Dyloject: Discontinue Dyloject immediately if an anaphylactic reaction occurs. › Serious skin reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. Discontinue Dyloject if rash or other signs of local skin reaction occur. ADVERSE REACTIONS › The most common adverse reactions (>5%) in controlled clinical trials include nausea, constipation, headache, infusion site pain, dizziness, ﬂatulence, vomiting, and insomnia. Please see Brief Summary of full Prescribing Information on adjacent page.

Hospira, Inc. 275 North Field Drive Lake Forest, IL 60045 P14-0277-10.5x13-Jan., 15

BRIEF SUMMARY OF PRESCRIBING INFORMATION PLEASE SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION.

Dyloject™ (diclofenac sodium) Injection, for intravenous use Rx Only WARNING: RISK OF SERIOUS CARDIOVASCULAR AND GASTROINTESTINAL EVENTS Cardiovascular Risk • Non-steroidal anti-inﬂammatory drugs (NSAIDs) may increase the risk of serious cardiovascular (CV) thrombotic events, myocardial infarction, and stroke, which can be fatal. This risk may increase with duration of use. Patients with cardiovascular disease or risk factors for cardiovascular disease may be at greater risk [see Warnings and Precautions (5.1)]. • Dyloject is contraindicated for the treatment of perioperative pain in the setting of coronary artery bypass graft (CABG) surgery [see Contraindications (4)]. Gastrointestinal Risk • NSAIDs increase the risk of serious gastrointestinal (GI) adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal. These events can occur at any time during use and without warning symptoms. Elderly patients are at greater risk for serious gastrointestinal events [see Warnings and Precautions (5.2)]. 1 INDICATIONS AND USAGE Dyloject is an NSAID indicated in adults for the management of mild to moderate pain and management of moderate to severe pain alone or in combination with opioid analgesics. 4 CONTRAINDICATIONS Dyloject is contraindicated in patients with: • known hypersensitivity (e.g., anaphylactic reactions and serious skin reactions) to diclofenac [see Warnings and Precautions (5.7, 5.8)]. • a history of asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs. Severe, rarely fatal anaphylactic-like reactions to NSAIDs have been reported in such patients [see Warnings and Precautions (5.7, 5.13)]. • perioperative pain in the setting of coronary artery bypass graft (CABG) surgery [see Warnings and Precautions (5.1)]. • moderate to severe renal insuﬃciency in the perioperative period and who are at risk for volume depletion [see Warnings and Precautions (5.3)]. 5

WARNINGS AND PRECAUTIONS

5.1 Cardiovascular Thrombotic Events Clinical trials of several COX-2 selective and nonselective NSAIDs of up to three years duration have shown an increased risk of serious cardiovascular (CV) thrombotic events, myocardial infarction and stroke, which can be fatal. All NSAIDs, both COX-2 selective and nonselective, may have a similar risk. Patients with known CV disease or risk factors for CV disease may be at greater risk. To minimize the potential risk for an adverse CV event in patients treated with an NSAID, use the lowest effective dose for the shortest duration possible. Physicians and patients should remain alert for the development of such events, even in the absence of previous CV symptoms. Patients should be informed about the signs and/or symptoms of serious CV events and the steps to take if they occur. Two large, controlled clinical trials of a COX-2 selective NSAID for the treatment of pain in the first 10-14 days following CABG surgery found an increased incidence of myocardial infarction and stroke [see Contraindications (4)]. There is no consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious gastrointestinal (GI) events [see Warnings and Precautions (5.2)]. 5.2 Gastrointestinal Effects: Risk of Ulceration, Bleeding, and Perforation NSAIDs, including Dyloject, can cause serious GI adverse events including inflammation, bleeding, ulceration, and perforation off the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with NSAIDs. Only one in five patients who develop a serious upper GI adverse event on NSAID therapy is symptomatic. Upper GI ulcers, gross bleeding, or perforation caused by NSAIDs occur in approximately 1% of patients treated for 3-6 months and in about 2-4% of patients treated for one year. These trends continue with longer duration of use, increasing the likelihood of developing a serious GI event at some time during the course of therapy. Dyloject is administered by intravenous injection and is intended for acute short term use. However, even short-term therapy is not without risk. Prescribe NSAIDs, including Dyloject, with extreme caution in those with a prior history of ulcer disease or GI bleeding. Patients with a prior history of peptic ulcer disease and/or GI bleeding who use NSAIDs have a greater than 10-fold increased risk for developing a GI bleed compared to treated patients with neither of these risk factors. Other factors that increase the risk for GI bleeding in patients treated with NSAIDs include concomitant use of oral corticosteroids or anticoagulants, longer duration of NSAID therapy, smoking, use of alcohol, older age, and poor general health status. Most reports of spontaneous fatal GI events are in elderly or debilitated patients, and therefore special care should be taken in treating this population. To minimize the potential risk for an adverse GI event in patients treated with an NSAID, use the lowest effective dose for the shortest possible duration. Patients and physicians should remain alert for signs and symptoms of GI ulcerations and bleeding during NSAID therapy and promptly initiate additional evaluation and treatment if a serious GI event is suspected. This should include discontinuation of the NSAID until a serious GI adverse event is ruled out. For high risk patients, alternate therapies that do not involve NSAIDs should be considered. 5.3 Renal Effects Use caution when initiating treatment with Dyloject in patients with considerable dehydration. Dyloject is not recommended in patients with moderate to severe renal insufficiency and is contraindicated in patients with moderate to severe renal insufficiency in the perioperative period and who are at risk for volume depletion. Acute renal decompensation was observed in 4% out of 68 patients enrolled with renal impairment and treated with Dyloject in clinical trials in the perioperative period.

incidence of borderline (less than 3 times the ULN), moderate (3-8 times the ULN), and marked (greater than 8 times the ULN) elevations of ALT or AST was observed in patients receiving diclofenac when compared to other NSAIDs. Elevations in transaminases were seen more frequently in patients with osteoarthritis than in those with rheumatoid arthritis. Almost all meaningful elevations in transaminases were detected before patients became symptomatic. Abnormal tests occurred during the first 2 months of therapy with diclofenac in 42 of the 51 patients in all trials who developed marked transaminase elevations. In postmarketing reports, cases of drug-induced hepatotoxicity have been reported in the first month, and in some cases, the first 2 months of therapy, but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation. Measure transaminases (ALT and AST) periodically in patients receiving long-term therapy with diclofenac, because severe hepatotoxicity may develop without a prodrome of distinguishing symptoms. The optimum times for making the first and subsequent transaminase measurements are not known. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 weeks after initiating treatment with diclofenac. Dyloject is not indicated for long-term treatment. However, severe hepatic reactions can occur at any time during treatment with diclofenac. If abnormal liver tests persist or worsen, if clinical signs and/or symptoms consistent with liver disease develop, or if systemic manifestations occur (e.g. eosinophilia, rash, abdominal pain, diarrhea, dark urine, etc.), discontinue Dyloject immediately. TTo minimize the possibility that hepatic injury will become severe between transaminase measurements, inform patients of the warning signs and symptoms of hepatotoxicity (e.g., nausea, fatigue, lethargy, diarrhea, pruritus, jaundice, right upper quadrant tenderness, and “flu-like” symptoms), and the appropriate action patients should take if these signs and symptoms appear. To minimize the potential risk ffor an adverse liver-related event in patients treated with diclofenac, use the lowest effective dose for the shortest duration possible. Exercise caution when prescribing Dyloject with concomitant drugs that are known to be potentially hepatotoxic (e.g., acetaminophen, certain antibiotics, anti-epileptics). 5.5 Hypertension NSAIDs, including Dyloject, can lead to onset of new hypertension or worsening of pre-existing hypertension, either of which may contribute to the increased incidence of CV events. Use NSAIDs, including Dyloject, with caution in patients with hypertension. Monitor blood pressure closely during the initiation of NSAID treatment and throughout the course of therapy. Patients taking ACE inhibitors, thiazides or loop diuretics may have impaired response to these therapies when taking NSAIDs. 5.6 Congestive Heart Failure and Edema Fluid retention and edema have been observed in some patients taking NSAIDs. Use Dyloject with caution in patients with fluid retention or heart failure. 5.7 Anaphylactic Reactions As with other NSAIDs, anaphylactic reactions may occur in patients without known prior exposure to Dyloject. Dyloject is contraindicated in patients with the aspirin triad. This symptom complex typically occurs in asthmatic patients who experience rhinitis with or without nasal polyps, or who exhibit severe, potentially fatal bronchospasm after taking aspirin or other NSAIDs [see Contraindications (4)]. 5.8 Serious Skin Reactions NSAIDs, including Dyloject, can cause serious skin adverse reactions such as exfoliative dermatitis, Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal. These serious events may occur without warning. Inform patients about the signs and symptoms of serious skin manifestations, and discontinue Dyloject at the first appearance of skin rash or any other sign of hypersensitivity [see Contraindications (4)]. 5.9 Pregnancy Starting at 30 weeks gestation, Dyloject and other NSAIDs, should be avoided by pregnant women as premature closure of the ductus arteriosus in the fetus may occur. If this drug is used during this time period in pregnancy, the patient should be apprised off the potential hazard to a fetus [see Use in Specific Populations in full prescribing information]. 5.10 Corticosteroid Treatment Dyloject cannot be expected to substitute for corticosteroids or to treat corticosteroid insufficiency. Abrupt discontinuation of corticosteroids may lead to exacerbation of corticosteroid-responsive illness. Patients on prolonged corticosteroid therapy should have their therapy tapered slowly if a decision is made to discontinue corticosteroids. 5.11 Masking Inflammation and Fever The pharmacological activity of Dyloject in reducing inflammation, and possibly fever, may diminish the utility of these diagnostic signs in detecting infectious complications of presumed noninfectious, painful conditions. 5.12 Hematological Effects Anemia may occur in patients receiving NSAIDs, including Dyloject. This may be due to fluid retention, occult or gross GI blood loss, or an incompletely described effect upon erythropoiesis. In patients on long-term treatment with NSAIDs, including diclofenac, check hemoglobin or hematocrit if they exhibit any signs or symptoms of anemia or blood loss. Dyloject is not indicated for long-term treatment. NSAIDs inhibit platelet aggregation and have been shown to prolong bleeding time in some patients. Unlike aspirin, their effect on platelet function is quantitatively less, of shorter duration, and reversible. Carefully monitor patients who may be adversely affected by alterations in platelet function, such as those with coagulation disorders or patients receiving anticoagulants. 5.13 Pre-existing Asthma Patients with asthma may have aspirin-sensitive asthma. The use of aspirin in patients with aspirin-sensitive asthma has been associated with severe bronchospasm, which can be fatal. Since cross-reactivity between aspirin and NSAIDs has been reported in such aspirinsensitive patients, including bronchospasm, Dyloject is contraindicated in patients with this form of aspirin sensitivity and should be used with caution in all patients with pre-existing asthma [see Contraindications (4)]. 5.14 Monitoring Because serious GI tract ulcerations and bleeding can occur without warning symptoms, monitor for signs or symptoms of GI bleeding. For patients on long-term treatment with NSAIDs, periodically check a CBC and chemistry profile, including liver function tests. Discontinue Dyloject if clinical signs and symptoms consistent with liver or renal disease develop, systemic manifestations occur (e.g., eosinophilia, rash), or abnormal liver tests persist or worsen. Dyloject is not indicated for long-term treatment. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling:

Long-term administration of NSAIDs has resulted in renal papillary necrosis and other renal injury. Renal toxicity has also been seen in patients in whom renal prostaglandins have a compensatory role in the maintenance of renal perfusion. In these patients, administration of an NSAID may cause a dose dependent reduction in prostaglandin formation and, secondarily, in renal blood ﬂow, which may precipitate overt renal decompensation. Patients at greatest risk of this reaction are those with impaired renal function, heart failure, liver dysfunction, those taking diuretics and ACE inhibitors, and the elderly. Discontinuation of NSAID therapy is usually followed by recovery to the pretreatment state.

• Cardiovascular thrombotic events [see Boxed Warning and Warnings and Precautions (5.1)]

5.4 Hepatic Eﬀects Elevations of one or more liver tests may occur during therapy with Dyloject. These laboratory abnormalities may progress, may remain unchanged, or may be transient with continued therapy. Borderline elevations (i.e., less than 3 times the ULN [ULN = the upper limit of the normal range]) or greater elevations of transaminases occurred in about 15% of diclofenac-treated patients in clinical trials of indications other than acute pain. Of the markers of hepatic function, ALT (SGPT) is recommended for the monitoring of liver injury.

• Hypertension [see Warnings and Precautions (5.5)]

In clinical trials of oral diclofenac, meaningful elevations (i.e., more than 3 times the ULN) of AST (SGOT) occurred in about 2% of approximately 5,700 patients at some time during diclofenac treatment (ALT was not measured in all studies).

• Serious skin reactions [see Warnings and Precautions (5.8)] Adverse reactions from clinical studies of Dyloject y j

In a large, open-label, controlled trial of 3,700 patients treated for 2-6 months, patients were monitored ﬁrst at 8 weeks and 1,200 patients were monitored again at 24 weeks. Meaningful elevations of ALT and/or AST occurred in about 4% of the 3,700 patients and included marked elevations (i.e., more than 8 times the ULN) in about 1% of the 3,700 patients. In this open-label study, a higher

• Gastrointestinal effects [see Boxed Warning and Warnings and Precautions (5.2)] • Renal effects [see Contraindications (4) and Warnings and Precautions (5.3)] • Hepatic effects [see Warnings and Precautions (5.4)]

• Congestive heart failure and edema [see Warnings and Precautions (5.6)] • Anaphylactoid reactions [see Warnings and Precautions (5.7)]

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reﬂect the rates observed in practice.

During clinical development, 1,156 patients were exposed to Dyloject in multiple-dose, controlled and open-label studies. Dyloject was administered post-surgically every 6 hours for up to 5 days. The incidence rates of adverse reactions listed in the following table are derived from multicenter, controlled clinical studies in post-operative patients comparing Dyloject to placebo in patients who may have also received morphine rescue medication. Table 1: Proportion of Patients Experiencing Common Adverse Reactions in Placebo-Controlled Clinical Studies in Patients with Acute Moderate-to-Severe Postoperative Pain occurring in greater than or equal to 3% in patients treated with Dyloject* MedDRA Preferred Term

Placebo N=126

Dyloject N=187

Any Reaction

104 (83%)

146 (78%)

Nausea

50 (40%)

45 (24%)

Constipation

14 (11%)

25 (13%)

Headache

20 (16%)

19 (10%)

Infusion Site Pain

10 (8%)

19 (10%)

Dizziness

2 (2%)

15 (8%)

Flatulence

20 (16%)

15 (8%)

Vomiting

23 (18%)

12 (6%)

Insomnia

12 (10%)

11 (6%)

Pruritus

10 (8%)

9 (5%)

Hypotension

6 (5%)

9 (5%)

Pyrexia

13 (10%)

8 (4%)

Anemia

9 (7%)

8 (4%)

Infusion Site Extravasation

1 (1%)

6 (3%)

* Intravenous morphine was permitted as rescue medication for pain management. Adverse reactions from clinical studies or spontaneous p reports p for other formulations of diclofenac and other NSAIDs In patients taking diclofenac or other NSAIDs, the most frequently reported adverse reactions occurring in approximately 1%-10% of patients are: Gastrointestinal experiences including abdominal pain, constipation, diarrhea, dyspepsia, ﬂatulence, gross bleeding/ perforation, heartburn, nausea, GI ulcers (gastric/duodenal) and vomiting.

Clinical 7

Pharmacy Practice News • June 2015

Bleeding Disorders

Controversy Impedes DOAC Bleeding Reversal Protocols

he prospect of managing bleeding in patients receiving one of the direct-acting oral anticoagulants (DOACs) likely spurs anxiety. There is no consensus guidance and no approved DOAC-specific reversal agents, and a weak body of evidence on the efficacy and safety of existing reversal agents for DOAC-related bleeding means there is a “reasonable amount of uncertainty on the choice and dose” of these medications, one expert said. “We simply do not have very much high-quality information on which to base recommendations for which of the existing reversal agents to use and how to dose them,” said Mike Boyd, PharmD, who is a specialty practice pharmacist in cardiology at Ohio State University Wexner Medical Center, in Columbus. A lack of professional association guidance on management of bleeding in DOAC recipients has left it up to

individual institutions to develop their own internal protocols. A paucity of data means these protocols are built on somewhat shaky ground, some experts noted, although prothrombin complex concentrates (PCC) are often the reversal agents of choice. Institutional recommendations for DOAC-related bleeding reversal are so contentious that experts like Michael Gulseth, PharmD, the program director for anticoagulation services at Sanford USD Medical Center, in Sioux Falls, S.D., have chosen not to share their approach. “Since we don’t truly know the risk– benefit profile of PCCs when used to see PROTOCOLS, page 15

Abnormal renal function, anemia, dizziness, edema, elevated liver enzymes, headaches, increased bleeding time, pruritus, rashes and tinnitus. Additional adverse reactions reported occasionally include: Body as a Whole: fever, infection, sepsis

Table. Management of Dabigatran-Related Bleeding Eventts

Cardiovascular System:: congestive heart failure, hypertension, tachycardia, syncope Digestive System:: esophagitis, gastric/peptic ulcers, gastritis, gastrointestinal bleeding, glossitis, hematemesis, hepatitis, jaundice

Bleeding Severity

Management Recommendationsa

Hemic and Lymphatic System:: ecchymosis, eosinophilia, leukopenia, melena, purpura, rectal bleeding, stomatitis, thrombocytopenia

Mild

Delay next dose or discontinue dabigatran

Metabolic and Nutritional:: weight changes

Moderate

Consider any of the following based on bleeding severity: • Symptomatic treatment • Mechanical compression • Surgical intervention • Fluid replacement and hemodynamic support • Blood product transfusion • Oral activated charcoal (if previous dose ingested within 2 hours); dose: liquid charcoal with sorbitol 50 g PO x 1 dose. If hemostasis is not achieved with the strategies outlined above, consider the administration of fresh frozen plasma; obtain a Hematology/Coagulation consult for further recommendations.

Severe or life-threatening

Consider any of the strategies outlined above, based on bleeding severity. In the setting of acute renal failure, initiation of hemodialysis may be considered for the purpose of facilitating drug elimination. No agent has been shown to successfully reverse the anticoagulant effects of dabigatran or treat dabigatran-related bleeding events. However, the interventions below may be considered: 1. Administer 4-factor PPC (KCentra), 50 units/kg IV x 1 (max dose, 5,000 units).b 2. For persistent refractory bleeding, pursue formal Hematology/Coagulation consult. 3. To investigate potential causes of the bleeding event, obtain the following: serum creatinine; PT, aPTT, TCT, ECT, CBC (platelets). 4. Obtain a Hematology/Coagulation consult following any of the above interventions.

Nervous System: anxiety, asthenia, confusion, depression, dream abnormalities, drowsiness, insomnia, malaise, nervousness, paresthesia, somnolence, tremors, vertigo Respiratory System: asthma, dyspnea Skin and Appendages: alopecia, photosensitivity, sweating increased Special Senses:: blurred vision Urogenital System:: cystitis, dysuria, hematuria, interstitial nephritis, oliguria/polyuria, proteinuria, renal failure Other adverse reactions, which occur rarely are: Body as a Whole:: anaphylactic reactions, appetite changes, death Cardiovascular System:: arrhythmia, hypotension, myocardial infarction, palpitations, vasculitis Digestive System:: colitis, eructation, fulminant hepatitis with and without jaundice, liver failure, liver necrosis, pancreatitis Hemic and Lymphatic System:: agranulocytosis, hemolytic anemia, aplastic anemia, lymphadenopathy, pancytopenia Metabolic and Nutritional:: hyperglycemia Nervous System:: convulsions, coma, hallucinations, meningitis Respiratory System:: respiratory depression, pneumonia Skin and Appendages:: angioedema, toxic epidermal necrolysis, erythema multiforme, exfoliative dermatitis, StevensJohnson syndrome, urticaria Special Senses:: conjunctivitis, hearing impairment Adverse reactions of special p interest Based on the analysis of the pooled data from the multi-dose, controlled clinical trials, post-operative patients treated with Dyloject had more adverse reactions related to wound healing (7.5%) compared to patients treated with placebo (4%).

There is no specific reversal agent or pharmacologic antidote for dabigatran; thus, management of hemorrhagic complications is primarily supportive. Hemodialysis is effective at removing approximately 60% of dabigatran. If patients require pharmacologic therapy to manage hemorrhagic complications, a Hematology/Coagulation consult is advised.

See dosing guide in Appendix B (http://bit.ly/1BdDDu2).

Adapted from: EN-3738; Revised 12/2014

Table adapted from van Ryn. Thromb Haemost. 2010;103(6):1116-1127. T

Manufactured for: Hospira, Inc., Lake Forest, IL 60045 USA

aPTT, activated partial thromboplastin time; CBC, complete blood count; ECT, ecanin time; TCT, thrombin clotting time

8 Clinical

Pharmacy Practice News • June 2015

Educational Review

Novel Oral Anticoagulants: Strategies for Optimizing Patient Outcomes AMANDA SCHARTEL, PHARMD Assistant Professor University of Maryland School of Pharmacy Baltimore, Maryland

CHARMAINE ROCHESTER, PHARMD, CDE, BCPS, BCACP Associate Professor Department of Pharmacy Practice and Science University of Maryland School of Pharmacy Baltimore, Maryland

here has been little advancement in the development of new oral anticoagulants since warfarin, which was approved by the FDA in 1954. Warfarin

he world remains the most widely prescribed oral anticoagulant in th for preventing thrombosis and thromboembolic disorders.1 Despite its popularity, warfarin has many shortcomings, including the he need for regular monitoring for bleeding risks and thromboembolic events; extensive drug– drug and drug–food interactions; delayed onset and long duration of action.

In 2010, the FDA approved the first novel oral anticoagulant (NOAC), dabigatran etexilate (Pradaxa, Boehringer Ingelheim).2,3 Since then, three more oral anticoagulants—rivaroxaban (Xarelto, Janssen), apixaban (Eliquis, Pfizer), and edoxaban (Savaysa, Daiichi-Sankyo)—have been approved. These agents offer new, monitoring-free options for preventing thrombosis. Although much is known about the many drug interactions associated with warfarin, there is less widespread knowledge about the potential drug interactions with the NOACs. This article will review the unique pharmacokinetic properties of these agents, the mechanism through which the reported drug interactions occur, and the prevention and management of these interactions.

and short half-life (approximately 5-17 h vs about 40 h for warfarin). In contrast to warfarin, NOACs also have a fewer number of clinically significant drug interactions, which warrants less regular monitoring of

DIRECT THROMBIN INHIBITORS Dabigatran etexilate is the only direct thrombin inhibitor currently approved in the United States for the

Table 1. Normal Dosing of NOACs Drug

Indication

Dosage

Dabigatran

Nonvalvular AF

150 mg BID

DVT and PE, treatment and prevention

150 mg BID

Nonvalvular AF

20 mg/d

DVT and PE, treatment

15 mg BID for 21 d, then 20 mg/d

DVT, prevention

20 mg/d

DVT, postoperative prophylaxis

10 mg/d

Nonvalvular AF

5 mg BID

DVT and PE, treatment

10 mg BID for 7 d, then 5 mg BID

DVT and PE, prevention

2.5 mg BID

DVT, postoperative prophylaxis

2.5 mg BID

Nonvalvular AF

60 mg/d

DVT and PE, treatment

60 mg/d

Rivaroxaban

Apixaban

Novel Oral Anticoagulants In the past 4 years, 2 new classes of oral anticoagulants have been created: the direct thrombin inhibitors and the direct factor Xa inhibitors. These agents share several similarities that make them unique and different from warfarin, including a fast onset of action (approximately 2-4 h vs 24-72 h for warfarin)

these agents.4,5

Edoxaban

AF, atrial fibrillation; BID, twice daily; D, day; DVT, deep vein thrombosis; PE, pulmonary embolism Based on references 6-9. 6 9.

prevention of stroke in patients with nonvalvular atrial fibrillation (AF) and for the treatment and prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE).6 Dabigatran etexilate is a prodrug that is converted by hepatic esterases to the active form dabigatran, which exerts its effect by inhibiting thrombin-mediated coagulation.2,5 This medication must be taken twice daily (Table 1) due to its short half-life (1217 h), and the dose must be reduced in patients with renal impairment because it is excreted extensively through the kidneys (Table 2).1-9 Dabigatran etexilate, but not dabigatran, is a known substrate of permeability glycoprotein (P-gp) transporters.2,4,5 Thus, dabigatran etexilate is vulnerable to drug interactions that affect P-gp absorption through the intestinal wall, and it should be monitored when given concomitantly with potent P-gp inhibitors and inducers (Tables 2 and 3). DIRECT FACTOR XA INHIBITORS There are currently three FDAapproved direct factor Xa inhibitors: rivaroxaban, apixaban, and edoxaban. All three agents are approved for the prevention of stroke in

Clinical 9

Pharmacy Practice News • June 2015

Educational Review Table 2. Dosage Adjustments for NOACs Based on Patient-Specific Factors

Dabigatran

Rivaroxaban

Apixaban

Indication

Creatinine Clearance

Other Considerations

Management

Nonvalvular AF

30-50 mL/min

+ Dronedarone OR + Ketoconazole

75 mg BID

15-30 mL/min

+ P-gp inhibitor

Avoid use

DVT and PE, treatment and prevention

<50 mL/min

+ P-gp inhibitor

Avoid use

—

+ Verapamil

Give dabigatran 2 h before verapamil (especially immediate-release formulation)

—

+ P-gp inducer

Avoid concomitant use

Nonvalvular AF

15-50 mL/min

—

15 mg/d

—

+ Strong combined P-gp and CYP3A4 inhibitor

Avoid concomitant use

—

Moderate to severe renal impairment

+ Moderate combined P-gp and CYP3A4 inhibitor

Use with caution

—

+ Combined P-gp and CYP3A4 inducers

Avoid concomitant use

Nonvalvular AF

—

Any 2 of the following: Age ≥80 y; Weight ≤60 kg; SCr ≥1.5 mg/dL

2.5 mg BID

+ Strong combined P-gp and CYP3A4 inhibitor

Decrease dose by 50% if already on >2.5 mg BID OR Avoid use if already on 2.5 mg BID

—

Edoxaban

—

+ Combined P-gp and CYP3A4 inducer

Avoid concomitant use

Nonvalvular AF

15-50 mL/min

—

30 mg/d

DVT and PE, treatment

15-50 mL/min

—

30 mg/d

—

+ Weight ≤60 kg

30 mg/d

—

+ Certain P-gp inhibitors (verapamil, quinidine, azithromycin, clarithromycin, erythromycin, itraconazole, ketoconazole)

30 mg/d

—

+ P-gp inducer

Avoid concomitant use

—

AF, atrial fibrillation; BID, twice daily; CYP, cytochrome P450; D, day; DVT, deep vein thrombosis; P-gp, permeability glycoprotein; PE, pulmonary embolism; SCr, serum creatinine Based on references reference es 1-9. 1 9.

patients with nonvalvular AF. Additionally, all these agents have specific indications related to DVT and PE. Rivaroxaban and apixaban are approved for the treatment and prevention of DVT and PE, including postoperative thromboprophylaxis, whereas edoxaban is approved only for the treatment of DVT and PE (Table 1).6-9 These agents work by selectively and reversibly inhibiting factor Xa in the intrinsic and extrinsic pathways of the coagulation cascade.2 By inhibiting factor Xa, these drugs directly inhibit the formation of thrombin from prothrombin. Rivaroxaban is dosed once or twice daily based on the indication, and higher doses must be taken with food to increase bioavailability.4,7 Apixaban is dosed twice daily, and the dose must be adjusted based on a combination of serum creatinine, age, and body weight.7 Edoxaban is dosed once daily, and the dose must be adjusted based on a combination of creatinine clearance, body weight, and concomitant medications (Table 2).1-9 Both rivaroxaban and apixaban are substrates of P-gp and cytochrome (CYP) enzymes (primarily CYP3A4), leaving them Text continues on page 10

Table 3. Common P-gp and CYP3A4 Inhibitors and Inducers and Their Effects on NOAC Exposure

Amiodarone

P-gp

CYP3A4

Approximate Change in Exposure, %

Inhibitor Inducer

Inhibitor Inducer (strong) (strong)

Dabigatran

Carbamazepine

X X

+40 +70-90

Erythromycin

Itraconazole

Ketoconazole

Lopinavir

Quinidine

+130-150

Verapamil

Voriconazole

+100

+50

St. John’s wort

+160

+80-90

Ritonavir

+80-90 +30

Rifampin

+40

+50

Phenytoin

Edoxaban

Diltiazema

+50

Clarithromycin

Dronedarone

Rivaroxaban Apixaban

–67

X X

+75 –50

–54

+50-150 X

Dependent on formulation

+50-60

Weak P-gp inhibitor and moderate CYP3A4 inhibitor; b Moderate CYP3A4 inhibitor; c Up to 2-fold increase in AUC.

AUC, area under the curv curve; ve; CYP, cy cytochrome ytochrome P45 P450; 50; P-gp, P gp, permeability perme eability glycoprotein glycopro otein

Based on references re eferences 1, 3, 6-9. 6 9..

10 Clinical

Pharmacy Practice News • June 2015

Educational Review Table. Home Medications Text continued from page 9

vulnerable to drug interactions that affect P-gp or CYP enzymes, while edoxaban is only a substrate of P-gp and is therefore vulnerable to drug interactions that affect P-gp (Tables 2 and 3).2,4,5,9

Pharmacokinetic Interactions The efflux transporter permeability glycoprotein 1, or P-gp, is a protein found on the surface of epithelial cells in the kidneys, liver, and small intestine.2 Its main function is to protect the body by preventing the uptake of harmful substances. As such, it plays an important role in drug disposition, which is important for the NOACs given that they are all substrates of this protein.2,4-8 In the kidneys and liver, P-gp pumps drugs out of cells into the urine and bile for clearance.11 P-gp also pumps drugs into the intestinal lumen for absorption in the small intestine. If P-gp is inhibited, it can lead to increased concentrations of NOACs, which can increase the risk for bleeding. Conversely, if P-gp is induced, it can lead to decreased concentrations of NOACs, which can then increase the risk for stroke or thromboembolism (Tables 2 and 3).2 Cytochrome P450 enzymes are responsible for the metabolism of many drugs. They are commonly found in the liver and small intestine. Both rivaroxaban and apixaban are primarily metabolized by CYP3A4 enzymes.2,4,6-8 Inhibition of CYP3A4 can increase concentrations of rivaroxaban and apixaban, which can increase the risk for bleeding. Conversely, induction of CYP3A4 can lead to decreased concentrations of these two agents, which can then increase the risk for stroke or thromboembolism (Tables 2 and 3).2 While some drugs only affect P-gp activity or CYP enzyme activity, others can affect both. This, in turn, can enhance the negative outcome of the interaction. For example, if a drug is a combined P-gp and CYP inhibitor, the inhibition of P-gp will lead to higher concentrations of the NOAC in the blood, increasing the risk for bleeding. The drug is then transported to the liver, where the inhibited CYP enzymes are unable to metabolize the NOAC, further increasing the risk for bleeding.2 These pharmacokinetic drug interactions can potentially have serious adverse outcomes. For example, a case report described a 67-year-old woman with a history of atrial fibrillation and recent hip replacement surgery, who was started on a three-month course of antibiotics for a Staphylococcus aureus

Case Study

Medication

Breakfast Lunch Dinner 150

History of Present Illness GB is a 64-year-old man who presents to the emergency room (ER) with the complaint of bleeding. He states he first noticed dark, tarry stools about 2 days ago. He then had 1 episode of hematemesis 1 day ago after eating dinner and another this morning when he tried to eat breakfast, which prompted him to come to the ER. The patient states that he recently was taken off warfarin because his INR was difficult to maintain in his goal range, and he was tired of having to go to the anticoagulation clinic so frequently. His primary care physician started him on dabigatran 150 mg twice daily 1 week before, when warfarin was discontinued. He reports that he had a colonoscopy 2 years ago, which he states was “normal.” Laboratory testing showed that the patient had a hemoglobin of 11.5 g/ dL and a hematocrit of 32% on admission.

Verapamil IR, mg

120

Aspirin, mg

Bedtime

150 120

120

Atorvastatin, mg

Loratadine, mg Fluticasone proprionate nasal spray 50 mcg

2 sprays in each nostril

Fluticasone/salmeterol diskus 100/50 mcg

1 puff

Latanoprost 0.005% ophthalmic solution

1 drop in each eye

Past Medical History • • • • •

Atrial fibrillation Myocardial infarction in 2003 Asthma Seasonal allergies Glaucoma

pronounced when immediate-release formulations of verapamil are given at the same time as dabigatran. This interaction can be averted if the doses of dabigatran and verapamil are separated by at least 2 hours. Furthermore, rates of major bleeding can be greatly increased when dabigatran is coadministered with aspirin given its antiplatelet activity.

Discussion The medical team diagnosed a gastrointestinal (GI) bleed secondary to dabigatran. The team asked the clinical pharmacist taking care of this patient to determine if there was a drug interaction that precipitated this event or if it was due to dabigatran’s initiation. After talking to the patient, the pharmacist determined that GB was taking dabigatran and immediate-release verapamil together in the morning and evening. In patients taking dabigatran, GI bleeds are the most common event. The pharmacist recognized that the GI bleed was likely due to 2 drug–drug interactions: a pharmacokinetic interaction of dabigatran with verapamil and a pharmacodynamic interaction of dabigatran with aspirin. Verapamil is a CYP450 3A4 inhibitor, and dabigatran’s exposure can be doubled with coadministration of verapamil. This effect is most

wound infection. During this time, her anticoagulant was switched from acenocoumarol to rivaroxaban due to labile international normalized ratio (INR) values. About three weeks after the change, the woman died from a PE. The fatal thromboembolism was thought to be due to low plasma concentrations of rivaroxaban caused by a drug interaction with the combined P-gp/CYP3A4 inducer rifampicin (US equivalent, rifampin), which was being used to treat her infection.10 It is important to remember that not all interactions between P-gp or CYP3A4 inhibitors and inducers and the NOACs have been studied. Despite the lack of direct evidence, caution should be used when coadministering these medications given the theoretical interactions that could occur. Furthermore, it is

Treatment The pharmacist recommended holding dabigatran and aspirin until the patient’s bleeding resolved. Also, the pharmacist suggested that when dabigatran was reinitiated, it should be given 2 hours prior to doses of immediate-release verapamil. An alternative strategy was to change verapamil to an extended-release formulation (360 mg once daily), because this does not cause the same increase in dabigatran’s area under the curve (or AUC) as the immediate-release formulation. The team also decided to give GB fluids for supportive therapy and deferred reinitiation of aspirin to the patient’s cardiologist. After 2 days, the patient’s bleeding stopped and his hemoglobin increased to 14.1 g/dL and hematocrit to 42%.

especially important when coadministering these medications in patients with renal impairment, because their decreased clearance can further increase drug exposure and magnify the significance of the pharmacokinetic reaction.2,4 Tables 2 and 3 specify the known pharmacokinetic interactions with the NOACs and the management of these interactions.

Pharmacodynamic Interactions As with other anticoagulants, increased bleeding risk is the major pharmacodynamic drug interaction of concern with the NOACs. Nonsteroidal anti-inflammatory drugs (NSAIDs) and antiplatelet drugs are common agents that can have an additive effect.2-5 In studies, the risk for major bleeding was doubled

when dabigatran was coadministered with aspirin or clopidogrel.2,6 Similarly, rates of major bleeding increased when rivaroxaban and aspirin were given concomitantly. Clopidogrel has been shown to increase bleeding time in patients receiving rivaroxaban, but not rates of clinically significant bleeding.2,3,7 Increased rates of major bleeding were seen when apixaban was coadministered with aspirin and/or clopidogrel.2,3,8 Although naproxen has been shown to increase bleeding time in patients taking apixaban, coadministration of NSAIDs and the NOACs generally has not been shown to increase clinically significant bleeding.2,3,8,12 However, in edoxaban studies, concomitant use of aspirin, thienopyridines, and NSAIDs led to increased rates of Text continues on page 12

When MH strikes,

Keep cool in the crisis with administration in

LESS THAN 1 MINUTE

ADVANCING THE STANDARD IN MALIGNANT HYPERTHERMIA (MH) TREATMENT. RYANODEX® (dantrolene sodium) for injectable suspension is changing how MH is treated. • Less time for reconstitution and administration – Less than 1 minute for a loading dose (2.5 mg/kg) of dantrolene sodium in an MH crisis1,2 • Less risk of complications with less fluid – Over 99% less sterile water for injection than other dantrolene sodium IV treatments3-5 • Less effort to stay cool in an MH crisis – 1 vial provides a loading dose for patients up to 100 kg and can be administered by 1 healthcare professional (eg, an anesthesia provider)1,3 To request that RYANODEX® be stocked in your institution or obtain ordering information, visit RYANODEX.com/ppn or call 855.318.2170. References: 1. Data on file. Eagle Pharmaceuticals, Inc. 2. Managing an MH crisis. Malignant Hyperthermia Association of the United States website. http://www.mhaus.org/healthcareprofessionals/managing-a-crisis. Accessed June 18, 2014. 3. RYANODEX [package insert]. Woodcliff Lake, NJ: Eagle Pharmaceuticals, Inc.; 2014. 4. Dantrium Intravenous [package insert]. Rochester, MI: JHP Pharmaceuticals, LLC; 2008. 5. Revonto [package insert]. Louisville, KY: US WorldMeds, LLC; 2011.

Please see Brief Summary of full Prescribing Information on the following page. © 2014 Eagle Pharmaceuticals, Inc. All rights reserved. 50 Tice Blvd, Suite 315 Woodcliff Lake, NJ 07677 (201) 326-5300 RYN14-0027-01 8/2014

INDICATION RYANODEX® (dantrolene sodium) for injectable suspension is indicated for the treatment of malignant hyperthermia in conjunction with appropriate supportive measures, and for the prevention of malignant hyperthermia in patients at high risk. IMPORTANT SAFETY INFORMATION RYANODEX® is not a substitute for appropriate supportive measures in the treatment of malignant hyperthermia (MH), including: • Discontinuing triggering • Instituting cooling when necessary anesthetic agents • Administering diuretics to prevent • Increasing oxygen late kidney injury due to myoglobinuria (the amount • Managing the of mannitol in RYANODEX® is metabolic acidosis insufficient to maintain diuresis)

12 Clinical

Pharmacy Practice News • June 2015

Educational Review Text continued from page 10

clinically relevant bleeding.9 Given these findings, it is important to be vigilant when coadministering these agents, particularly in patients with a history of, or at an increased risk for, clinically significant bleeding.

Management of Complications From Drug Interactions Unlike warfarin, the NOACs do not have specific reversal agents for bleeding complications. For minor bleeding, holding doses of the

RYANODEX® (dantrolene sodium) for injectable suspension, for intravenous use. Brief Summary of Prescribing Information. See Package Insert For Full Prescribing Information INDICATIONS AND USAGE RYANODEX® is indicated for the: • Treatment of malignant hyperthermia in conjunction with appropriate supportive measures (see Dosage and Administration) • Prevention of malignant hyperthermia in patients at high risk. DOSAGE AND ADMINISTRATION (Selected Information) In addition to RYANODEX treatment, institute the following supportive measures: • Discontinue use of malignant hyperthermia (MH)-triggering anesthetic agents (i.e., volatile anesthetic gases and succinylcholine). • Manage the metabolic acidosis • Institute cooling when necessary • Administer diuretics to prevent late kidney injury due to myoglobinuria (the amount of mannitol in RYANODEX is insufficient to maintain diuresis) Administer RYANODEX by intravenous push at a minimum dose of 1 mg/kg. If the physiologic and metabolic abnormalities of MH continue, administer additional intravenous boluses up to the maximum cumulative dosage of 10 mg/kg. If the physiologic and metabolic abnormalities reappear, repeat RYANODEX dosing by intravenous push starting with 1 mg/kg. Dosage for Prevention of Malignant Hyperthermia The recommended prophylactic dose of RYANODEX is 2.5 mg/kg administered intravenously over a period of at least 1 minute, starting approximately 75 minutes prior to surgery. Avoid agents that trigger MH. If surgery is prolonged, administer additional individualized RYANODEX doses during anesthesia and surgery. Dosage for Pediatric Patients The recommended weight-based dose of RYANODEX for pediatric patients in the treatment and prevention of MH is the same as for adults for these indications (see Dosage and Administration). Reconstitution and Administration Instructions The supplied lyophilized powder must be reconstituted prior to administration: Reconstitute each vial of RYANODEX lyophilized powder by adding 5 mL of sterile water for injection (without a bacteriostatic agent). Do not reconstitute with any other solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection). Shake the vial to ensure an orange-colored uniform suspension. Visually inspect the vial for particulate matter and discoloration prior to administration. Must use the contents of the vial within 6 hours after reconstitution. Store reconstituted suspensions at controlled room temperature (68°F to 77°F or 20°C to 25°C). (For complete Dosage and Administration Section, see full Prescribing Information)

RYANODEX has been associated with dysphasia. Assess patients for difficulty swallowing and choking. Somnolence and Dizziness Somnolence and dizziness can occur following administration of RYANODEX and may persist up to 48-hours post-dose. Patients should not be permitted to ambulate without assistance until they have normal strength and balance. Patients must not operate an automobile or engage in other hazardous activities for 48-hours post-dose. The concomitant use of sedative agents with RYANODEX may increase the risk of somnolence and dizziness. Potential for Tissue Necrosis with Extravasation Care must be taken to prevent extravasation of RYANODEX into the surrounding tissues due to the high pH of the reconstituted RYANODEX suspension and potential for tissue necrosis. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a study designed to evaluate the safety and tolerability of RYANODEX, healthy volunteers were randomly assigned to receive treatment with RYANODEX or an active comparator at doses ranging from 1 mg/kg to 2.5 mg/kg. • The RYANODEX dose was infused over the course of 1 minute for each of the doses evaluated. • The active comparator was an injectable formulation of dantrolene sodium that differed from RYANODEX in that it contained dantrolene sodium and mannitol at concentrations of 0.33 mg/mL and 50 mg/mL, respectively, when reconstituted according to the product’s prescribing information. The active comparator was infused at a rate that administered 20 mg of dantrolene per minute for each of the doses evaluated. Table 1 displays the most common adverse events in this study. These data are not an adequate basis for comparison of the types or frequencies of adverse event types between RYANODEX and the dantrolene sodium comparator. Adverse events increased in frequency with increasing doses in the trial, but did not differ in frequency between the two treatment groups. RYANODEX-treated subjects were more likely to report immediate adverse events of flushing, dystonia, and dysphagia than those receiving the active comparator. In all dose groups, hand grip strength declined after dosing. In general, the decline in hand grip strength was more pronounced and occurred more rapidly in the RYANODEX-treated subjects in the 1.0, 1.75, 2.0 and 2.25 mg/kg treatment groups. In the 2.5 mg/kg treatment group, the decline in hand grip strength both in amount and duration was similar between the two treatment groups. Table 1: Adverse Events in Healthy Volunteers Number(%) of subjects RYANODEX [N=30]

DANTROLENE SODIUM COMPARATOR [N=31]

Flushing

8 (27)

1 (3)

Somnolence

5 (17)

4 (13)

Dysphonia

4 (13)

1 (3)

Dysphagia

3 (10)

4 (13)

Nausea

3 (10)

Feeling abnormal

3 (10)

CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Muscle Weakness RYANODEX is associated with skeletal muscle weakness. The administration of RYANODEX in human volunteers has been associated with loss of grip strength and weakness in the legs. Patients should not be permitted to ambulate without assistance until they have normal strength and balance. RYANODEX has been associated with dyspnea, respiratory muscle weakness, and decreased inspiratory capacity. Monitor patients for the adequacy of ventilation.

medication may be sufficient given the short half-lives of these agents. For major bleeding, supportive measures such as blood or platelet transfusions, fluid replacement, surgical hemostasis, or mechanical compression for superficial bleeding may be required.10 Concentrates of coagulation factors, prothrombin complex concentrate, or fresh frozen plasma can also be given to patients to reverse bleeding; however, their use has not been studied in clinical trials.3,5-8,13 Hemodialysis can be used for

Headache

1 (3)

4 (13)

Vomiting

1 (3)

2 (6)

Vision blurred

1 (3)

Pain in extremity

1 (3)

Muscular Weakness/ Asthenia

1 (3)

Atrioventricular block

1 (3)

Tachycardia

1 (3)

Infusion site pain

1 (3)

Dizziness

1 (3)

those taking dabigatran because of its low protein binding.5,6,13 This is particularly useful in patients with known renal failure, given that dabigatran is eliminated renally. Activated charcoal can be used within a few hours of ingestion of rivaroxaban or apixaban (8 and 3 h, respectively) to decrease absorption of these agents.5,7,8 For patients who develop thrombotic complications as a result of a drug interaction, management includes treating the thrombosis with parenteral anticoagulants and

Postmarketing Experience The following adverse reactions have been identified during postapproval use of another formulation of dantrolene sodium for injection. 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. Pulmonaryy Edema There have been reports of pulmonary edema developing during the treatment of malignant hyperthermia crises with another dantrolene sodium dosage form. The contributory effect of the diluent volume and mannitol in these cases is not known. Thrombophlebitis p and Tissue Necrosis There have been reports of thrombophlebitis following administration of intravenous dantrolene. Tissue necrosis secondary to extravasation has been reported (see Warnings and Precautions). Hypersensitivity/Anaphylactic yp y p y Reactions There have been reports of urticaria and erythema possibly associated with the administration of dantrolene sodium for injection. Anaphylaxis has been reported. Injection j Site Reactions Injection site reactions including pain, erythema, and swelling, commonly due to extravasation, have been reported. DRUG INTERACTIONS Calcium Channel Blockers Cardiovascular collapse in association with marked hyperkalemia has been reported in patients receiving dantrolene in combination with calcium channel blockers. The concomitant use of RYANODEX and calcium channel blockers is not recommended during the treatment of malignant hyperthermia. Muscle Relaxants The concomitant administration of RYANODEX with muscle relaxants may potentiate the neuromuscular block. Antipsychotics and Antianxiety Agents The concomitant administration of RYANODEX with antipsychotic and antianxiety agents may potentiate their effects on the central nervous system (see Warnings and Precautions). USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy g y Category g yC Adequate and well controlled studies have not been conducted with RYANODEX in pregnant women. However, animal reproduction studies have been conducted with dantrolene sodium. In these studies, dantrolene sodium administered to rats and rabbits produced embryolethality (rabbits) and decreased pup survival (rats) at doses seven times the human oral dose. RYANODEX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery In one uncontrolled study, 100 mg per day of prophylactic oral dantrolene sodium was administered to term pregnant patients awaiting labor and delivery. Dantrolene readily crossed the placenta, with maternal and fetal whole blood levels approximately equal at delivery; neonatal levels then fell approximately 50% per day for 2 days before declining sharply. No neonatal respiratory and neuromuscular side effects were observed in this study.

Nursing Mothers Dantrolene is present in human milk. In one case report, low dantrolene concentrations (less than 2 micrograms per milliliter) were measured in the breast milk of a lactating woman during repeat intravenous dantrolene administration over 3 days. Because of the potential for serious adverse reactions of respiratory depression and muscle weakness in nursing infants from dantrolene, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and efficacy of RYANODEX in the treatment and prevention of malignant hyperthermia in pediatric patients is based on clinical experience with other intravenous dantrolene sodium products, which suggests adult weight-based doses are appropriate for pediatric patients. Geriatric Use Clinical studies of RYANODEX 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 reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. OVERDOSAGE Overdosage Symptoms Overdosage symptoms include, but are not limited to, muscular weakness and alterations in the state of consciousness (e.g., lethargy, coma), vomiting, diarrhea, and crystalluria. Management of Overdosage Employ general supportive measures for acute overdosage of RYANODEX. PATIENT COUNSELING INFORMATION Inform patients, their families, or their caregivers of the following: Muscle Weakness Muscle weakness (i.e. decrease in grip strength and weakness of leg muscles, especially walking down stairs) is likely to occur with the use of RYANODEX. Patients should be provided assistance with standing and walking until their strength has returned to normal (see Warnings and Precautions). Difficultyy Swallowingg Caution is indicated at meals on the day of administration because difficulty swallowing and choking have occurred with the use of dantrolene sodium products in general; dysphagia has been reported with the use of RYANODEX (see Warnings and Precautions). Dizziness and Somnolence The use of RYANODEX has been associated with dizziness and somnolence. (see Warnings and Precautions). Drivingg or Operating p g Machineryy Symptoms such as “lightheadedness” may occur. Since some of these symptoms may persist for up to 48 hours, patients must not operate an automobile or engage in other hazardous activity during this time (see Warnings and Precautions). Revised: 7/2014 Marketed by: Eagle Pharmaceuticals, Inc. Woodcliff Lake, NJ 07677

addressing the drug interaction. The drug interaction leading to the thrombosis can be eliminated by choosing a different agent in the class that does not interact with the NOAC. On the other hand, the NOAC can be changed to an alternative agent that does not interact with the patient’s medication regimen.

Conclusion While the NOACs have fewer clinically significant drug interactions than warfarin, it is important for pharmacists to be diligent in reviewing medication regimens for potential interactions with these agents. This is especially important considering that these drug interactions can lead to major bleeding or thrombotic events. Given the perception by many that the NOACs are relatively harmless compared with warfarin, pharmacists will play a key role in preventing and managing drug interactions with these agents, assessing patient adherence, and monitoring for adverse drug reactions.

References 1.

Francis CW. Warfarin: an historical perspective. Hematology Am Soc Hematol Educ Program. 2008 Jan 1:251.

2. Hellwig T, Gulseth M. Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants: what do they mean for patients with atrial ﬁbrillation? Ann Pharmacother. 2013;47(11):1478-1487. 3. Cheng JW, Barillari G. Non-vitamin K antagonist oral anticoagulants in cardiovascular disease management: evidence and unanswered questions. J Clin Pharm Ther. 2014;39(2):118-135. 4. Schulman S. Advantages and limitations of the new anticoagulants. J Intern Med. 2014;275(1):1-11. 5. Wang Y, Bajorek B. New oral anticoagulants in practice: pharmacological and practical considerations. Am J Cardiovasc Drugs. 2014;14(3):175-189. 6. Pradaxa (dabigatran) [package insert]. Ridgeﬁeld, CT: Boehringer Ingelheim Pharmaceuticals, Inc; April 2014. 7.

Xarelto (rivaroxaban) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; March 2014.

8. Eliquis (apixaban) [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; March 2014. 9. Savaysa (edoxaban) [package insert]. Parsippany, NJ: Daiichi Sankyo Co, Ltd; 2015. 10. Altena R, van Roon E, Folkeringa R, et al. Clinical challenges related to novel oral anticoagulants: drug-drug interactions and monitoring. Haematologica. 2014;99(2):e26-e27. 11. Yu DK. The contribution of P-glycoprotein to pharmacokinetic drug-drug interactions. J Clin Pharmacol. 1999;39(12):1203-1211. 12. Frost C, Shenker A, Gandhi M, et al. Evaluation of the effect of naproxen on the pharmacokinetics and pharmacodynamics of apixaban. Br J Clin Pharmacol. 2014;78(4):877-885.

13. Baglin T. Clinical use of new oral anticoagulant drugs: dabigatran and rivaroxaban. Br J Haematol. 2013;163(2):160-167.

Clinical 13

Pharmacy Practice News • June 2015

Oncology

Pharmacists Seeking Bigger Role in Survivorship Care consequences of cancer and its treatment; and coordinating among primary care providers and specialists to make sure all health needs are met, Dr. Sivik explained. “The transition of [patients] out of oncology and into primary care is one of the biggest challenges we face,” said Lew Iacovelli, PharmD, BCOP, CPP, a pharmacy manager and clinical pharmacist practitioner at Moses H. Cone Health System in Greensboro, N.C. “Many of these folks

have more than one physician; they have a cardiologist, internist, kidney doc, diabetes specialist—you need to make sure that information gets disseminated to those folks, as well.” When coordinating the transition to primary care, again the pharmacist is often forgotten, according to Dr. Scarpace, but as the provider of future medications, the community pharmacist must understand the patient’s medical history.

Therefore, the “primary care” pharmacist should be included among the professionals who receive the survivorship plan. Every treatment modality has late effects (box, page 14) and some patients see all three of these modalities before their treatment is over, compounding the possible risks, Dr. Sivik said. Many institutions have developed a template for the survivorship plan, but see SURVIVORSHIP, page 14

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Austin, Texas—Health care professionals need guidance about how to manage cancer survivors because these patients have unique issues and toxicities—weeks, months and years after treatment—that other patients do not necessarily experience. These issues affect every aspect of the cancer survivor’s life and include physical and mental health, psychosocial and financial health, professional and personal identity, as well as sexual function, experts pointed out at the 11th Annual Hematology/Oncology Pharmacy Association (HOPA) Conference. Helping cancer survivors was less of an issue when Richard Nixon declared a War on Cancer in the 1970s, because only 3 million patients survived their disease. By 2012, that number rose to 13.7 million and will reach 18 million by 2020, according to the American Cancer Society. The National Comprehensive Cancer Network and the American Society of Clinical Oncology are among the groups that have put together survivorship panels to offer guidance about developing plans for cancer survivors. An assortment of oncology professionals, from the patient advocate to the physician, sits on these panels. Yet, one professional is starkly absent—the pharmacist. “On these survivorship panels, we have a wide representation of health care professionals, but no pharmacists,” said Jeffrey Sivik, PharmD, BCOP, an adult oncology clinical pharmacy specialist, Penn State Hershey Medical Center in Hershey, Pa. “Yet, we can answer drug information questions, provide comprehensive medication profile reviews, evaluate drug therapies and interactions, and help manage some of the late toxicities.” A consensus report from the Institute of Medicine (IOM), “From Cancer Patient to Cancer Survivor: Lost in Transition” (National Academies Press, 2015) only mentions pharmacists once in 535 pages, according to Sarah L. Scarpace, PharmD, MPH, an associate professor at the Albany College of Pharmacy and Health Sciences, in Albany, N.Y. Physicians are currently administering 73% of survivorship care, added Dr. Scarpace, which takes them away from their other important roles. “What is disturbing is that pharmacists are missing from [the IOM’s] list of professionals [who] could help cancer survivors,” she said. This is an opportunity for clinical pharmacists to be part of the treatment team and complement the work of the oncologist. Survivorship care centers around the prevention of new or recurrent cancers; surveillance for cancer spread, recurrence or second cancer; intervention for the

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14 Clinical

Pharmacy Practice News â&#x20AC;˘ June 2015

Oncology

SURVIVORSHIP continued from page 13

experts at the HOPA meeting questioned whether that template provides enough information. For instance, is there just a check box for chemotherapy or is there space to include names and amounts of the systemic agents that were given, as well as the end date of treatment? â&#x20AC;&#x153;Pharmacists are the detail-oriented ones,â&#x20AC;? Dr. Scarpace said, â&#x20AC;&#x153;and for certain drugs, you want to make sure the important detail is there.â&#x20AC;?

Education has always been a big part of the pharmacistâ&#x20AC;&#x2122;s role and that does not change when talking to survivors about their cancer journey, noted Dr. Iacovelli. Pharmacists educate patients about drugs, their toxicities and managing those toxicities. â&#x20AC;&#x153;That could be a role for pharmacists as we move into this survivorship planning. Maybe before discharge, we should be reviewing their medications again and telling them the things to look out for in terms of relapses, etc.â&#x20AC;? Dr. Scarpace said that holding survivorship clinics could be a role for phar-

macists. Because there is a general lack of information about such clinics, but clearly a need, pharmacists can help develop and run them at their facilities, she said. Another gap that pharmacists could help fill is the need for more data, said Dr. Scarpace, who recommended several areas of research that could be valuable, starting with whether cancer survivors are adherent to survivorship plans. Other areas would be the long-term toxicities of new oral chemotherapies, use of complementary and alternative medicine and behavior modification, and whether

Table. Late Effects Of Adult Cancer Treatment Increased Risk for Secondary Cancers Psychosocial and Physical Problems â&#x20AC;˘ General anxiety and depression â&#x20AC;˘ Fear of cancer returning â&#x20AC;˘ Cognitive decline â&#x20AC;˘ Pain â&#x20AC;˘ Sexual dysfunction â&#x20AC;˘ Sleep disorders

Late Toxicities From Chemotherapy Major Organ Problems

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â&#x20AC;˘ Cardiotoxicity â&#x20AC;˘ Hepatotoxicity â&#x20AC;˘ Pulmonary issues â&#x20AC;˘ Neurotoxicities

Hormonal Issues â&#x20AC;˘ Early menopause â&#x20AC;˘ Infertility â&#x20AC;˘ Osteoporosis

Part 3: A Multidisciplinary Approach to

2SWLPL]LQJ 6DIHW\ DQG (IÂżFLHQF\ Case Study Brenda is a 78-year-old woman undergoing open abdominal surgery to correct symptomatic pelvic organ prolapse. Current Symptoms Â&#x2021; Pelvic organ prolapse failing conservative therapy Vital Signs Â&#x2021; Height: 175 cm Â&#x2021; Weight: 85 kg 6LJQLÂżFDQW 0HGLFDO +LVWRU\ Â&#x2021; Dyslipidemia Â&#x2021; Type 2 diabetes mellitus Â&#x2021; Glaucoma &XUUHQW 0HGLFDWLRQV Â&#x2021; Ezetimibe Â&#x2021; Glyburide Â&#x2021; Insulin glargine Â&#x2021; Pravastatin Anesthesia is induced with fentanyl 100 mcg, propofol 150 mg, and rocuronium 50 mg and maintained with GHVĂ&#x20AC;XUDQH LQ DLU R[\JHQ $PSLFLOOLQ VXOEDFWDP 3 g is given intravenously as well. At 90 minutes after induction, the surgeon reports tension in the surgical ÂżHOG DQG UHTXHVWV DGGLWLRQDO UHOD[DWLRQ 1R PRQLWRULQJ of neuromuscular function is performed.

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Global Education Group and Applied Clinical Education are pleased to introduce part 3 of a 3-part interactive CME series featuring challenging cases LQ 10% (DFK DFWLYLW\ SUHVHQWV D FOLQLFDO VFHQDULR that you face in your daily practice. After reading the introduction to the case, consider the challenge TXHVWLRQV DQG WKHQ YLVLW ZZZ &0(=RQH FRP QPE WR ÂżQG RXW KRZ \RXU DQVZHUV VWDFN XS DJDLQVW WKRVH of our multidisciplinary faculty panel. Access the activities on your desktop, laptop, or tablet WR H[SORUH WKH LVVXHV VXUURXQGLQJ VDIH HIIHFWLYH 10% UHYHUVDO YLD D XQLTXH PXOWLPHGLD OHDUQLQJ H[SHULHQFH and earn 1.0 AMA PRA Category 1 Creditâ&#x201E;˘ or 1.0 $$1$ &( FUHGLW IRU HDFK &RPSOHWH WKH ZKROH VHULHV and earn a total of 3.0 credits.

Late Toxicities From Radiation Therapy Major Organ Problems â&#x20AC;˘ Cardiovascular â&#x20AC;˘ Pulmonary disease â&#x20AC;˘ Gastrointestinal

Hormonal Issues â&#x20AC;˘ Hypothyroidism â&#x20AC;˘ Infertility â&#x20AC;˘ Osteoporosis

Other â&#x20AC;˘ Dental problems â&#x20AC;˘ Lymphedema â&#x20AC;˘ Cognitive deficits (memory) â&#x20AC;˘ Skin changes

Late Effects of Surgery Surgery specific â&#x20AC;˘ Increased risk for infection â&#x20AC;˘ Physical disabilities â&#x20AC;˘ Phantom pain â&#x20AC;˘ Adhesions/scar tissue â&#x20AC;˘ Disfigurement â&#x20AC;˘ Lymphedema

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having a pharmacist onboard improves patient care. â&#x20AC;&#x153;Lots of work needs to be done in this area,â&#x20AC;? Dr. Scarpace said. â&#x20AC;&#x153;There are some real opportunities for us to make a contribution.â&#x20AC;? â&#x20AC;&#x201D;Marie Rosenthal Drs. Iacovelli and Sivik reported no relevant ďŹ nancial conďŹ&#x201A;icts of interest. Dr. Scarpace received consulting fees from Eli Lilly, Merck and PďŹ zer.

7ULFLD 0H\HU 3KDUP' 06 )$6+3 Departments of Pharmacy and Anesthesiology Scott and White Memorial Hospital Texas A&M University System HSC College of Medicine Temple, Texas

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This activity is jointly provided by Global Education Group and Applied Clinical Education. Supported by an educational grant from Merck.

Web Extra Although every cancer survivor deals with a variety of issues, the experience for children is often starkly different. To access story, scan the adjacent QR code.

Clinical 15

Pharmacy Practice News • June 2015

Bleeding Disorders

PROTOCOLS

DOAC-related bleeds will likely subside, and the current debate on reversal protocols will similarly abate. “This may all be moot by this time next year,” Dr. Boyd said.

continued from page 7

reverse DOAC bleeding, and we know there is a risk of thrombosis with these agents, many of us will not want to share our specific recommendations without having some kind of data to validate them,” said Dr. Gulseth, noting that most bleeding management approaches are based on data from healthy volunteers or are extrapolated from other uses of PCCs. In contrast to Drs. Gulseth and Boyd, who shied away from disclosing their institution’s internal recommendations, Stephan Moll, MD, professor of medicine in the Division of Hematology-Oncology at the University of North Carolina (UNC), Chapel Hill, and a co-founder of Clot Connect (www.clotconnect.org), has made the antithrombotic drug reversal guidance document developed at his institution available on the Internet (http://bit.ly/1BdDDu2). “The reversal protocol from UNC was developed collaboratively by a group of specialists involved in the care of patients with bleeding on anticoagulation, which makes it comprehensive,” Dr. Moll stated. The protocol suggests using the fourfactor PCC, KCentra (CSL Behring), for reversal of DOAC-related bleeding. Dr. Moll said the document provides guidance based on existing knowledge of DOAC reversal, but the protocol also includes the caveat that no agents have been shown to successfully reverse the anticoagulant effects of dabigatran (Pradaxa, Boehringer Ingelheim) or factor Xa inhibitors or to reverse major bleeding in patients receiving these drugs. “Both activated and nonactivated PCCs and recombinant factor VIIa drugs reversed DOAC-related anticoagulation in vitro, but no agent has been appropriately studied in vivo in patients receiving DOACs,” Dr. Moll noted. (For more details on a dabigatran reversal protocol, see Table, page 7; protocols for reversing Factor Xa inhibitors, apixaban, rivaroxaban and fondaparinux can be accessed at http:// bit.ly/1BdDDu2). In contrast to the UNC recommendations, Dr. Boyd’s institution uses FEIBA (Baxter) for reversal of DOACrelated bleeding. Part of the reason for the choice is that KCentra simply is not on his hospital’s formulary, he noted. Another is that “there may be a slight difference in favor of FEIBA for dabigatran-related bleeding, although both KCentra and FEIBA are likely interchangeable for factor Xa inhibitor–related bleeding,” he said. As DOAC-specific reversal agents make their way through the FDA approval pipeline, anxiety over not knowing exactly how to manage

—David Wild Dr. Boyd reported no relevant conﬂicts of interest. Dr. Gulseth reported serving as a consultant and speaker for BristolMyers Squibb, Janssen and Pﬁzer and as a consultant for Boehringer Ingelheim, Daiichi Sankyo and Portola. Dr. Moll reported serving as a consultant for Portola.

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16 Clinical

Pharmacy Practice News • June 2015

Pharmacogenomics

New PGx Clinic a ‘Model’ for Burgeoning Field W

hen Kathy Mangold, PhD, developed a blood clot in her leg after surgery in January 2014, her doctors had potentially lifesaving information at hand. A pharmacogenomics (PGx) test had identified mutations that Dr. Mangold carried that could prolong the time warfarin lingers in her body. The

NorthShore’s Pharmacogenomics Clinic currently uses a third-party assay—a 15-gene panel (PGXL Laboratories; Table) that covers drug metabolism enzymes and transporters related to treatment for cardiovascular problems as well as cancer, pain management and psychiatric disorders. Such

testing is far more comprehensive than what Dr. Mangold underwent years ago. “Now, you don’t have to know your family history to utilize it,” she said. “With one fell swoop, you can look at the pharmacogenomics of many drugs at the same time.”

will impact the health system’s overall costs or care. Among the 10 patients visiting the clinic in its first month, however, he highlighted promising anecdotes. One woman had undergone two years of unsuccessful treatments before finally finding a pain management regimen that worked well. “Based

‘The community told us there was this need [for pharmacogenomics services]. And we have the expertise here to do it.’ —Mark Dunnenberger, PharmD

NorthShore University HealthSystem, in Chicago environs, has invested in state-ofthe-art genomic sequencing technology to provide onsite testing for patients.

test was prompted by an earlier genetics test, which had confirmed a hunch inspired by her family’s history: She had inherited a high risk for blood clots. “That pharmacogenomics information sat in a medical file waiting for an opportunity to be used,” said Dr. Mangold, who was tested and treated through the Chicago area’s NorthShore University HealthSystem, where she also works as director of the biospecimen repository. An opportunity had arrived: Her doctors used the results to ensure they did not overshoot appropriate levels of the drug, which could have put her at risk for internal bleeding. In other words, her medicine was personalized. In March, NorthShore took its personalized medicine efforts a step further, launching the first PGx clinic in the Chicago area. It’s one of a small yet growing fleet of similar programs across the country. In its “Pharmacy Forecast 2015-2019,” the Center for Health-System Pharmacy Leadership, a collaboration of the American Society of HealthSystem Pharmacists (ASHP) and the ASHP Research and Education Foundation, reported that 79% of experts surveyed predicted “at least one academic medical center in their region will have a formal pharmacy-based pharmacogenetic information/consultation service for health professionals and patients within the next five years.”

Mark Dunnenberger, PharmD, heads the clinic, which is housed within the Center for Medical Genetics. He noted that the launch came in response to requests from both patients and clinicians. “The community told us there was this need,” said Dr. Dunnenberger, who is also a senior clinical specialist and the lead pharmacogenomist for the health system. “And we have the expertise here to do it.” It’s too early to predict how the clinic

on her genetic results, I would’ve recommended a similar regimen,” Dr. Dunnenberger said. “The clinicians got it right. But had we had results up front, perhaps she could’ve skipped two or three steps. “Pharmacogenomics can narrow the scope of trial-and-error in medicine,” he said. “But it’s almost impossible to use it as a crystal ball to say that medication A at dose X is definitely going to work for you the first time, every time.”

Table. Pharmacogenomic Testing Companies Below is a sample of U.S. companies that market pharmacogenomic tests and services. “Each one has a different panel, and each one reports results in a different way,” said Mark Dunnenberger, PharmD, a senior clinical specialist and lead pharmacogenomist for NorthShore University HealthSystem. “Each has a niche, so you have to evaluate and determine what is best for your patient population.”

PGx Lab

Website

Tests and Services

ARUP Laboratories

https://www.aruplab. com/genetics/tests/ pharmacogenetics

ARUP offers test panels to help clinicians identify appropriate treatments and to monitor efficacy and toxicity of drugs in areas such as oncology, cardiology, pain management and HIV/AIDS.

AssureRx Health

http://assurexhealth.com AssureRx Health specializes in tests that match patients with the best psychiatric drugs for their genetic makeup. AssureRx recently added tests for ADHD and pain medications. Turnaround can be as fast as 36 h.

Genelex

http://genelex.com/ pharmacogenetic-tests/

Genelex provides test panels relevant for treatment of ADHD, psychiatric disorders, cardiovascular disease and pain. Genelex’s system pairs pharmacogenomic testing with medication management software.

Millennium Health

http://www.millenniumhealth.com/services/ pgt-testing/

Millennium Health offers support for medication decisions covering >40 commonly prescribed drugs across 13 classes, including pain management and mental health. The company also provides access to genetics scientists and clinical pharmacists for live discussions.

PGXL Laboratories

http://www.pgxlab.com

PGXL’s testing panel covers areas including oncology, psychotropics, cardiology and pain management. (NorthShore University HealthSystem’s Pharmacogenomics Clinic is currently contracting with PGXL.)

Well Med RX

https://www.wellmedrx. com

Well Med RX provides genetic tests that cover up to 150 FDAflagged cardiovascular, pain management and psychiatric drugs, as well as a system that integrates with most electronic health records to identify patients who may qualify for testing. The company also offers tools such as template letters, forms and personalized patient prescription reports.

ADHD,, atte attention-deficit/hyperactivity t o de c t/ ype act v ty d disorder so o de

Clinical 17

Pharmacy Practice News • June 2015

Pharmacogenomics

Meeting the Challenge of Big (Genetic) Data Boston—For the past 20 years, companies have been developing technology to produce the $1,000 genome, and researchers have been hyping its potential to improve health care. At the recent Bio-IT World Conference & Expo, researchers discussed some of the challenges and promise of the explosive growth of genomic data.

Oracle Health Sciences in London. He pointed out that 50% of all treatments in early clinical development rely on biomarker data, and 155 pharmacogenomics biomarkers already are included on FDAapproved drug labels. According to research conducted at Vlerick Business Center, based in Belgium, when women with breast cancer

vertical dedicated processing power.” Dr. van Rooyen said advances in graphics processing unit (GPU)-accelerated computing is helping. (GPUaccelerated computing is the use of a GPU together with a central processing unit to increase the speed of scientific, analytics, engineering, consumer and enterprise applications.)

Table. All-in-One-Day Technology for Genomics at the Hospital Morning

Afternoon

Within 24 Hours

Primary analysis sequencing

Secondary analysis to find relevant variants/mutations

Clinical decision support

• Next-generation sequencers • Computing, storage, networking clusters • Imaging • Algorithms and genomic workflows

• Massively scalable, high throughput genomic workflows • Optimized hardware clusters and software for private and public cloud

• Knowledge database of clinically actionable variants • Machine learning • Data-driven associations and correlations • Drug sensitivity analysis

Currently, a consumer can get his or her genome sequenced for about $5,000. The massive amount of genomic data creates immense hurdles in terms of managing that information throughout the testing life cycle, from generation to analysis to storage. “Currently, less than 0.1% of the U.S. population has had their genome sequenced, but this number is expected to rise exponentially in the coming years,” said Pieter van Rooyen, PhD, the president and CEO of San Diego-based Edico Genome. “We are only at the beginning of this. Specifically for whole-genome sequencing, there are only on the order of 50,000 to 60,000 people who have been sequenced.” To get an idea of the future benefits of personalized medicine, one only has to look at the benefits that have already been realized, said Ketan Patel, PhD, a product strategist at Precision Medicine,

receive genetic testing of their tumor prior to treatment, there is a 34% reduction in chemotherapy (“It’s Time to Invest More In Our Health,” 2014; www.vlerick. com). The researchers concluded that roughly 17,000 strokes could be prevented annually if a genetic test is used to properly dose the blood thinner warfarin. A slew of companies are feverishly working to create hardware and software to handle the explosion of genomic information. “Big data is growing faster than general processors can keep up,” Dr. van Rooyen said. “As we move from research to clinical applications, where we have to look at tumor samples and normal samples to get a wide range of genomic data sequenced, all the way from the epigenome/microbiome to whole genome sequences, it is clear that the amount of data that is being generated is far outpacing the processing power. We need more

Speakers at the conference seemed optimistic that the challenges would be overcome. Ketan Paranjape, general manager of life sciences, Intel Corp., discussed the “all-in-one-day goal by 2020,” where within a 24-hour period, a patient would get his or her genome sequenced and analyzed, and have a discussion with the doctor about precision medicine options (Table). Partnering with Dell and Translational Genomics Research Institute, the group has been able to reduce RNA-Seq data analysis from seven days to four

For some other patients, the clinic team identified genetic variants in the metabolism of clopidogrel, much like the warfarin information that proved helpful for Dr. Mangold. (Because of variants in CYP2C19, he explained, these patients can’t effectively metabolize clopidogrel. Thus, they are less likely to receive its therapeutic benefits. Better alternatives would be prasugrel and ticagrelor, he noted.)

erate some great data,” he said of the new program. But Dr. Empey also noted that reimbursement remains a significant challenge to widespread adoption of PGx, especially pre-emptive tests. The key to overcoming that obstacle, he added, is to prove the return on investment to payors. “You need to understand what to measure to make sure that you’re demonstrating the value of these services,” he said. Dr. Empey suggested that institutions determine how likely their patients are to suffer the related event or take the relevant medication. Comorbidities and other medications could enter the equation. Older patients who have undergone high-risk procedures or who already have a history of bleeding,

for example, may be ideal candidates for clopidogrel-related tests. Dr. Dunnenberger’s team is considering the optimal end points to make their case. He noted that they are tracking the number of genetic variants per patient, as well as looking into other variables such as the number of high-risk drugs currently prescribed to their patients. Still, the highest priority, he emphasized, is directly helping patients— turning the increasing bounty of pharmacogenomics data into actionable information. “I can put data into a medical record all day long, but unless we educate clinicians and provide context for how the data should be used, it will be a waste of resources,” said Dr. Dunnenberger,

Kudos to NorthShore Philip Empey, PharmD, PhD, BCPS, an assistant professor of pharmacy at University of Pittsburgh’s School of Pharmacy, expressed his excitement about NorthShore’s launch and the broader emergence of PGx. “I think they’ll gen-

Software companies also face formidable challenges. “EMRs [electronic medical records] are not capable of handling genomic data,” Dr. Patel said. “Even image data storage is dwarfed by whole genomes.”

Positive Outlook

hours. “The need to collaborate and share best practices within the life sciences ecosystem is even more crucial as we look to taking precision medicine mainstream,” Mr. Paranjape said. Research efforts are focused not only on fast data, but slow data. “Fast data comes from the processing technologies. Slow data is how you get back knowledge from many years of informatics. They are both extremely important,” said Sanjay Joshi, Life Sciences chief technology officer, EMC Emerging Technology Division, in Seattle. “Most countries are realizing that you have to do population-scale genomics and its integration with population-scale health care. Ultimately, you have to create a container of [health] information that we call a ‘data lake.’” Mr. Joshi pointed out that Iceland keeps health care data on people for 10 years after they die. Lakes of data are springing up around the United States. The Wellderly Study, for example, is a joint initiative between the Scripps Translational Science Institute in La Jolla, Calif., and scientists at the J. Craig Venter Institute in Rockville, Md. Through this study, researchers are sequencing the genomes of 1,300 individuals over age 80 years who have never had any serious disease. “The race to N has started, increasing sample sizes to produce credible answers for clinical questions,” said Shawn Dolley, health and life science big data expert at Cloudera, in Palo Alto, Calif. “It is a wonderland out there.” —Kate O’Rourke

adding that maximizing the power of pharmacogenomics “takes a team.” The NorthShore University HealthSystem’s pharmacogenomics program hosts a committee of 30 members including nurses, physicians, counselors, geneticists, informatics specialists and billing experts. “This is a perfect space for pharmacists,” he added. Dr. Empey agreed. “This is a model of what we all need to do,” he said. “It’s a great example of a pharmacist-led initiative in which we’re pushing new discoveries for the benefit of patients.” —Lynne Peeples The sources reported no relevant ﬁnancial conﬂicts of interest.

18 Clinical

Pharmacy Practice News • June 2015

Nutrition

Gut Bacteria May Inﬂuence ICU Outcomes Long Beach, Calif.—How well a patient fares in the hospital may depend largely on the health of the bacterial communities that person hosts, according to research presented at the American Society for Parenteral and Enteral Nutrition’s (A.S.P.E.N.) annual conference. “A large part of what makes us human is not human,” said Paul Wischmeyer, MD, the director of Nutrition Therapy Services at the University of Colorado School of Medicine. In fact, bacteria cells outnumber human cells in the body by a factor of 10-to-1. “Because of that, a lot of things about how we respond to stress and illness—or just things in everyday life—are determined by bacteria,” he said. As Dr. Wischmeyer and other researchers explained to A.S.P.E.N. attendees, a hospitalized patient’s resident bacteria—known as the microbiome—often face a range of insults, from bombardment by antibiotics to the withholding of nutrition vital for the survival of “good” bacteria, or the microbes that keep their pathogenic peers in check. A resulting decline in microbial diversity in the gut can then trigger a cascade of trouble throughout the body, even reducing the effectiveness of drug treatments. In the end, although a care team may succeed in saving a patient from a traumatic injury or infection in the short term, there may well be longterm repercussions. Dr. Wischmeyer shared a case in point: “We’ve halved mortality from heart disease, but sepsis deaths are skyrocketing.” Thanks to research such as the National Institutes of Health’s (NIH) Human Microbiome Project, evidence continues to mount that this vast non-

‘We found dramatic changes in the appearance of bacteria in ICU patients, [where] healthy bacteria begin to go away and pathogens begin to overgrow.’ —Paul Wischmeyer, MD human ecosystem plays a powerful role in human health. Yet science is “just scratching the surface,” according to Dr. Wischmeyer, when it comes to the role of the microbiome in disease. If researchers could gain a better understanding of the normal changes in the microbiome for, say, patients being treated in the ICU, he added, then clinicians might better optimize care and perhaps even “resod the lawn with normal bacteria to improve recovery.”

More on the Microbiome Project The ICU Microbiome Project is one such effort toward that goal. Researchers hope to define changes in the microbiomes of patients in the ICU, the role of nutrition in those changes and how such fluctuations affect patient outcomes, explained Dr. Wischmeyer. In one study being conducted as part of the project, researchers obtained stool, mouth and skin samples from patients shortly after the subjects were admitted to the ICU and then again seven to 10 days later. The samples were obtained from 149 patients at four sites in the United States and Canada. Results were then compared over time as well as with healthy controls in the American Gut Project, an open-source project that is helping to characterize the microbial diversity in the American population.

“We found dramatic changes in the appearance of bacteria in ICU patients,” said Dr. Wischmeyer, noting that his team is currently writing up a first publication of the data. “We saw healthy bacteria begin to go away and pathogens begin to overgrow.” Compared with the healthy cohort, the researchers identified a rise of Bacteroidetes, Staphyloccus aureus and Enterobacteriaceae, as well as a drop in Firmicutes and Faecalibacterium prausnitzii among the critically ill. Among their other initial findings was an association between greater bacterial diversity and a shorter length of stay. However, Dr. Wischmeyer also noted that it is difficult to draw any “specific conclusions” from the data just yet. Some patients had already been treated in the hospital before coming to the ICU, for example, whereas others had suffered acute injuries—such as in car accidents—and therefore arrived with their natural gut microbiome still largely intact. Dr. Wischmeyer noted that the next study would focus solely on trauma patients to help tease out those differences.

Bugs and Drugs Gail Cresci, PhD, RD, a gastroenterology and hepatology scientist at the Cleveland Clinic, in Ohio, also spoke at A.S.P.E.N. about the significant role of

Is Autism a Gastrointestinal Spectrum Disorder?

ome autism spectrum disorders (ASDs) could be caused by imbalanced gut microbiota composition, according to recently published proceedings from the 1st International Symposium on the Microbiome in Health and Disease with a Special Focus on Autism, held at Arkansas Children’s Hospital, in Little Rock. “There are several lines of research that suggest that specific changes in the [gut microbiome] could be causative or highly associated with driving core and associated ASD symptoms,” the workshop attendees wrote in the proceedings. Among other topics, the group of clinicians, researchers and parents of children with ASD discussed how to design and conduct clinical trials among children with ASD, how to define subgroups of ASD patients, and what possible treatments for ASD warrant investigation. In addition to antibiotics and antifungals, they discussed: • Fecal microbiota transplantation (“the attendees felt that this approach is still in need of refinement, particularly in understanding the type of transplant, the delivery system to use, dosage and duration of treatment as well as the need for pretreatment use of antibiotics and bowel-cleansing regimens”) • Helminthic therapy y (there is currently at least one clinical trial underway) • Probiotics (“there is growing excitement” following a study that showed Bacteroides fragilis improved metabolic, enteric microbiome and behavioral abnormalities in mice with ASD-like characteristics) • Unprocessed foods (“some interesting preliminary studies suggest some benefit of camel’s milk in children with ASD”) • Fermented foods (“although there are reasons to believe that [fermented foods] could be useful, at least in some children with ASD, further research is needed to determine whether there is any true benefit.”) • Dietary treatments (“clearly this is an interesting area of clinical research that is still very preliminary”) • Digestive enzymes (“clinical treatment studies using digestive enzymes report mixed results”) and vitamins (“children with ASD may have low amounts of the gut microbiome bacteria that produce biotin and may benefit from biotin supplements”) The group concluded that microbiome-focused therapies are promising and may benefit some children with ASD. —PPN Staff

Animal studies suggest that intestinal health that is disrupted by broad-spectrum antibiotics could be normalized via supplementation with Lactobacillus GG.

the microbiome in the treatment and outcomes of critically ill patients. “Gut microbiota not only possesses enzymes to break down food, but it also metabolizes medications,” Dr. Cresci said. “If we think about giving an oral medication in an ICU setting, and there’s a change in the microbiome, then that could potentially greatly affect the outcome of that drug or dosing.” Her research has also underscored the role of butyrate, a fermentation byproduct of the commensal gut microbiota, in suppressing inflammation, as well as in helping the body absorb water and electrolytes. If that molecule is depleted due to changes in the microbiome, then these benefits may, too, be lost, she said. However, in mouse models, her research team also found that if a probiotic containingg Lactobacillus GG or a form of butyrate is given during antibiotic delivery, then the integrity of intestinal tightjunction proteins persisted and the animals fared better ((J Parenter Enteral Nutr 2013;37[6]:763-74). Dr. Cresci noted that a review published in 2012 underscored the potential benefits of probiotics in reducing infectious complications such as ventilator-associated pneumonia, as well as lowering ICU mortality (Crit Care Med 2012;40[12]:290-302). Still, the data remain inconsistent. Another review published that same year suggested that probiotics do not actually benefit patients who are mechanically ventilated (Chest 2012;142[4]:859-868). “A lot of future work needs to be done,” she said, noting that the use of both preand probiotics may be most ideal. “If the gut microbiota is already altered, then we should give back probiotics to try to restore the microbial balance but see GUT BACTERIA, page 20

Trusted to take a bite out * of G-CSF acquisition costs GRANIX X® has gained >3 34% share of the t US short-actting G-CSF hospita al marrket in its first 17 monthss1 » A 71% red duction in duration of severe e neutrropenia vs placebo (1.1 days vs 3.8 days, p<0.000 01)2 – Efficacy was evaluated in a mu ultinattional, m multi ltice t center, random mizzed e , co c ntrolllled ed d, Ph P a asse IIIII st stu udy of che h mo moth th her erap apyap y-na naïv ïve e pati patien ents ts V bo olu us))/d /doc occet etax axel ax el (75 mg/ g/m m2)2 with high h-risk breast cancer re eceivin ng doxo orubicin n (60 mg/m2 IV » The safetyy of GRANIX was esttab blish hed in 3 Ph Phasse II III trria alss, wi with th 680 80 pat atie ie ent ntss re recce ceivin ceiv ivving g ch hem emo othera othe rapy py for eithe herr br breast cancer,, lung cance er, or non-Hodgkin lyym mpho oma ma (NH NH HL)2 » Offering a prese entatio i n fo for se elf--a adm dmin nisstr trat atio at io on

Indication » GRAN GRANIX X is a le eukkoc o yt yte e gr grow owth ow th fa acto ac t r indi to d ca cate ted te d fo forr re redu duct ctio ion n in the durat atio ion of severe neutropeniia in patients with nonmyeloid malilign ma g a gn an nci c es es rec ecei eivi ei ving vi ng mye yelo losu lo supp pre r sssive an anti tica canc ncer er dru rugs gs ass ssoc o ia ated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Sp Sple leni le nicc ru ni upt ptur ure: ur e: Spl e: p en e ic rup uptu turre e, in incl clu udin ng fatal ca c ses, can occur following the administration of human granulocyte colonystim st imul im ulat ul atin at ing in g fa fact c or ct o s (h ( GG-CS CSFs Fs). ). Dis isco ont ntinue GRANIX and evaluate for an enlarged spleen or splen nic rupture in patients who repo re port po rt upp pper abd b om omin inal al or sh s ou ould der pain a after receiving GRANIX. » Ac Acut ute ut e re resp spiirrat sp ator orry di dist stre ress ss syn y drom me (A ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and an d lu lung ng g inf n ililtr trat ates es or re resp spir irat atory distresss after receiving GRANIX, for ARDS. Discontinue GRANIX in n patients with ARDS. » Al Alle lerg le rgic ic react eactio ionss: Ser eriouss allerrgic reactions, including anaphylaxis, can occur in patients receivving hG-CSFs. Reactions can occu oc cu ur on ini niti tial al exp xpos o urre. Perrma anently discontinue GRANIX in patients with serious allergic reacctions. Do not administer GRAN GR ANIX IX to pa pati tien ents t wit ith h a hi h st sto oryy of se erious allergic reactions to filgrastim or pegfilgrastim. » Us U e in pattie ient ntss wi with th sickl kle ce c ll diseasse: Severe and sometimes fatal sickle cell crises can occurr in patients with sickle cellll dis ce isea easse s rec ecei eivi ving n hG-CSFs F . Consid der the p potential risks and benefits prior p to the administrattion of GRANIX in patients with sick si ckle le cel elll di dise seas ase. e Dissco c ntinue GRANIX X in patients undergoing a sickle cell crisis. » Capi Capilllar ary y le leak ak syndr d ome (CLS):: CLS ca an occur in patients receiving hG-CSFs and is characte erize ed by hypotension, hypo hy poal albu b mi m ne emi mia, ede ema and h hemoco oncentration. Episodes vary in frequency, severity and may be life-threatening if treatment is del elay ayed ed d. Pati t ents who develo op symp ptoms of CLS should be closely monitored and receive sta andard symptomatic treatmen e t, whic wh ich h ma mayy includ de a need for in ntensive e care. » Pote Po ent ntia al for tumor growth stim mulatory effects on malignant cells: The granulocyte colony-stim mulating factor (G-CSF) receptor, thro th roug gh wh which GR RANIX X acts, hass been found f on tumor cell lines. The possibility that GRANIX act c s as a growth factorr for any tumor type ty p , in nclu u uding myeloi myeloid o d maligna ancies and myelodysplasia, diseases for which GRANIX is not apprroved, cannot be excluded. »M Most s com mmon treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in n pattientss treated wi w th GRANIX X at the e recommended dose with an incidence of at least 1% or greater and tw wo times more freq fr e ue ent n than in the placebo gro oup wa as bone pain. Plea Pl e se e see e brief summary of Fulll Prescribing Information on adjacent page.

For more information, visit GRANIXhcp.com. *Ba Base sed d on o who ole lesa ale e acquisiition n cost (WA AC) of all short-acting G-CSF products as of March 2015. WAC represents pub blished catalogue or list prices and mayy no ma nott re repr pre e en es nt actual tra ans nsactional p prices. Ple ease contact your supplier for actual prices. ease prices R fe Re fere renc nces es: 1. Th Thiss inf nfo orma mati tion n iss an a estim mate de derived from the use of information under license from the following IMS S Health Information Service: IMS Nati Na t on ti onal al Sal ales es Per ersp spec ecti tive ve, GR GRAN ANIX X mic i rro ogr g ams byy non-federal hospital channel March 2015. IMS expressly reserves all rights, including right h s of copying, d st di stri ribu b ti bu t on on, an nd re epu publ b ic icat atio on (m mic icro rogr gram ams ca alcul ullate ed as eaches x strrength). 2. GRANIX® (tbo-filgrastim) Inje j ction Presccribing Information. North Wales, PA A: Teva Te va Pha harm rmac a euti ac eutica cals ls;; 20 2014 14..

©2015 ©201 5 Ce Ceph phal alon on,, In Inc. c , a wh w olllyy-o -owned e sub u sidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered t ad tr adem emar arkk of Tev eva a Ph Phar arma m ce ceut utic iccal a Ind ndustrries Ltd. All rights reserved. GRX-40681 May 2015.

20 Clinical

Pharmacy Practice News • June 2015

Nutrition

GUT BACTERIA

‘If we think about giving an oral medication in an ICU setting, and there’s a change in the microbiome, then that could potentially greatly affect the outcome of that drug or dosing.’

continued from page 18

also give the bacteria its preferential food source at the same time,” added Dr. Cresci, who is currently studying the use of probiotics for prevention of antibiotic-induced Clostridium difficile, and how aging affects the microbiome.

—Gail Cresci, PhD, RD

Judicious Use of Antibiotics Daniel Teitelbaum, MD, a professor of surgery at C.S. Mott Children’s Hospital in the University of Michigan Health Sys-

tem, in Ann Arbor, and another A.S.P.E.N presenter, is less optimistic about the promise of probiotics. Yet he agreed with

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colonystimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: UÊ -« i VÊ,Õ«ÌÕÀiÊQsee Warnings and Precautions (5.1)] UÊ VÕÌiÊ,iÃ« À>Ì ÀÞÊ ÃÌÀiÃÃÊ-Þ `À iÊQsee Warnings and Precautions (5.2)] UÊ -iÀ ÕÃÊ iÀ} VÊ,i>VÌ ÃÊQsee Warnings and Precautions (5.3)] UÊ 1ÃiÊ Ê*>Ì i ÌÃÊÜ Ì Ê- V iÊ i Ê Ãi>ÃiÊQsee Warnings and Precautions (5.4)] UÊ >« >ÀÞÊ i> Ê-Þ `À i [see Warnings and Precautions (5.5)] UÊ * Ìi Ì > Êv ÀÊ/Õ ÀÊ À ÜÌ Ê-Ì Õ >Ì ÀÞÊ vviVÌÃÊ Ê > } > ÌÊ i ÃÊQsee Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of *10,000 x 106/L after nadir was reached.

Dr. Cresci about the need for clinicians and pharmacists to be more “judicious” with the use of antibiotics, as well as

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-USapproved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40581 January 2015 This brief summary is based on TBO-004 GRANIX full Prescribing Information.

more proactive in the administration of nutrients preferred by beneficial bacteria. “Continually flooding patients with antimicrobials destroys the least aggressive bacteria,” Dr. Teitelbaum said, adding that a lack of adequate nutrition in the gut can produce similar results. “More aggressive virulent strains of bacteria tend to survive in these unfavorable gastrointestinal environments, and these can lead to a breakdown in the epithelial barrier of the gut.” Furthermore, if the survival of aggressive bacteria also is compromised in a malnourished gastrointestinal tract, then they may end up in the bloodstream and cause dangerous conditions such as sepsis. “It’s all about creating an environment that is desirable for favorable bacteria to live in,” he said. Dr. Teitelbaum described his team’s latest work on the role of nutrient deprivation to A.S.P.E.N. attendees ((J Parenter Enteral Nutr 2014;38[3]:392-399). In the study, a series of small-bowel specimens were obtained from pediatric and adult patients undergoing small-intestine resection. The investigators found a strong correlation between suboptimal feeding, gut diversity and postoperative complications. The complications included anastomotic problems (some with complete disruption), abdominal wound infections ((Klebsiella pneumioniae, Candida albicans and methicillin- sensitive Staphylococcus aureus), s central venous line infection ((Klebsiella pneumioniaee) and recurrent enterocolitis. “For patients who are not receiving enteral nutrition, we saw shifts toward a very poorly diverse [gut bacteria] population,” Dr. Teitelbaum explained. “With this loss of diversity, we also saw an increased number of surgical complications with these patients. It’s worrisome.” The investigators agreed that research funding and a general consideration of the microbiome in the care of critically ill patients should be prioritized. “We need to embrace the microbiome as a future diagnostic and therapeutic tool—and embrace probiotics, stool transplants and pills as primary therapeutics for patients,” Dr. Wischmeyer said. “The NIH invested over $150 million in the human microbiome, to understand what is normal. Now, we need to make that investment pay off and help people.” —Lynne Peeples Drs. Wischmeyer, Cresci and Teitelbaum reported no relevant ﬁnancial conﬂicts of interest.

Next issue: More reports from A.S.P.E.N., including soy beans and other nutritional components that, when added to parenteral feeding, may boost clinical oucomes.

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Over the last few years, surging generic drug prices have resulted in an all-toofamiliar scenario for hospital outpatient pharmacies: The pennies-per-pill price they had been accustomed to paying suddenly and inexplicably shoots up by 10 or even 100 or more times. The pharmacy, knowing that the current reimbursement rate won’t cover the drug’s cost, scrambles to meet the patient’s need with a less expensive substitute that works as well. Sometimes there is no substitute. “Generics have always increased in price along with other pharmaceuticals, but we never saw this type of increase before,” said Frederick Cassera, BSPharm, MBA, the director of pharmacy at Maimonides Medical Center, in Brooklyn, N.Y. “It is far outpacing other price increases.” The increases can be staggering. Pricing data for a list of 10 widely prescribed medications gathered by the Healthcare Supply Chain Association show costs for individual drugs surging by as much as 8,281% between 2013 and 2014. The average market price for a single drug— doxycycline hyclate—rose from $20 for a 500-count bottle of 100 mg tablets in October 2013 to $1,849 the following April (Figure). The price list was released in October 2014 by Sen. Sanders and Rep. Cummings in connection with their ongoing investigation into the reasons behind the steeply inflated prices. Stephen Schondelmeyer, PharmD, PhD, a professor and the head of pharmaceutical care and health systems at the University of Minnesota College of Pharmacy, in Minneapolis, and who testified at a November 2014 hearing held by the lawmakers, told Pharmacy Practice News that no single reason can account for the widespread generic price rises that are happening “suddenly and dramatically.” But a key factor, he said, has been “the rapid rise of single-source generics over the last five to six years,” driven in part by rock-bottom prices that have forced out weaker competitors and created a “functional monopoly” for companies left standing, as well as by industry consolidation. In addition, Dr. Schondelmeyer said, it was “not unusual” that a year or two after a drug has been in shortage, one manufacturer will re-emerge in the marketplace with the drug price tripled. “So there is a connection between generic pricing, consolidation in the market and shortages,” he said.

Reimbursement Hit The interval between the increases and adjusted reimbursements from various payors has been an ongoing headache for outpatient pharmacies that have long relied on low generic prices and fairly predictable, moderate price inflation to

$20 October 2013 A 500-count bottle of 100-mg doxycycline tablets increased in price from a mean of $20 to a mean of $1,849 in a recent six-month period.

manage their drug acquisition costs. Richard Ptachcinski, PharmD, FCCP, the president of American Pharmacotherapy LLC, a firm that provides health systems with monthly updates on drug pricing, costs and utilization rates via the company’s BenchmaRx monitoring service, said clients were experiencing the severe effects of delayed reimbursement increases. “The lag that you see in ASP [average sales price]-based reimbursements from quarter to quarter is creating significant challenges for organizations,” he said.

For pharmacies, the solutions are limited, but Dr. Schondelmeyer suggested “pushing for the payment agencies to recognize how dynamic the market is,” as well as getting them to recognize the economic impact of price hikes and keeping the reimbursement from going up at the same time and rate. “That really is an unfair cost to the pharmacies,” he said. Dr. Ptachcinski said his firm advises its clients to monitor drug prices diligently. “These changes occur so quickly that you may not know they’re happening,” see PRICE HIKES, page 23

for complicated intra-abdominal infections (cIAI), in A new IV antibiotic treatment—AVYCAZ™—is now available combination with metronidazole, and complicated urinary for complicated intra-abdominal infections (cIAI), in tract infections (cUTI), including pyelonephritis, caused combination with metronidazole, and complicated urinary by designated susceptible microorganisms. As only limited tract infections (cUTI), including pyelonephritis, caused clinical safety and efﬁcacy data for AVYCAZ are currently by designated susceptible microorganisms. As only limited available, reserve AVYCAZ for use in patients who have clinical safety and efﬁcacy data for AVYCAZ are currently limited or no alternative treatment options.1 (See full available, reserve AVYCAZ for use in patients who have Indications and Usage below.) limited or no alternative treatment options.1 (See full Indications and Usage below.)

Now available Now Now available available Ordering information1 • AVYCAZ for injection is supplied in a single-use, clear glass vial for constitution • Available in cartons of ten 2.5 g vials – Carton of 10 vials (NDC# 0456-2700-10) – Individual 2.5 g vial (NDC# 0456-2700-01) Vial not shown actual size.

INDICATIONS AND USAGE Complicated Intra-Abdominal Infections (cIAI) AVYCAZ (ceftazidime-avibactam), in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca, and Pseudomonas aeruginosa in patients 18 years or older. As only limited clinical safety and effi ficacy data for AVYCAZ are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options. Complicated Urinary Tract Infections (cUTI), including Pyelonephritis AVYCAZ is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri, Enterobacter aerogenes, Enterobacter cloacae, Citrobacter freundii, Proteus spp., and Pseudomonas aeruginosa in patients 18 years or older. As only limited clinical safety and efficacy fi data for AVYCAZ are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options. Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used to treat r only indicated infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are r available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Reference: 1. AVYCAZ™ (ceftazidime-avibactam) [prescribing information]. Cincinnati, OH: Forest Pharmaceuticals, Inc.; 2015.

Please see Brief Summary of full Prescribing Information on the following pages. Actavis™ and its design are trademarks of Actavis, Inc. or its affiliates. fi AVYCAZ™ and its design are trademarks of Actavis, Inc. or its affiliates. fi ©Actavis 2015. All rights reserved. AVY28263 04/15

Discover more at AVYCAZ.com, and see below for Discover more at AVYCAZ.com, and see below for the information you need to stock AVYCAZ today. Discover more at AVYCAZ.com, and see below for the information you need to stock AVYCAZ today. the information you need to stock AVYCAZ today IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS AVYCAZ is contraindicated in patients with known serious hypersensitivity to AVYCAZ, avibactam-containing products, ceftazidime, or other members of the cephalosporin class. WARNINGS AND PRECAUTIONS • In a Phase 3 complicated intra-abdominal infections (cIAI) trial, clinical cure rates were lower in a subgroup of patients with baseline creatinine clearance (CrCL) of 30 to 50 mL/min compared to those with CrCL greater than 50 mL/min. The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCL 30 to 50 mL/min. Monitor CrCL at least daily in patients with changing renal function and adjust the dosage of AVYCAZ accordingly. • Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with AVYCAZ is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established. Discontinue the drug if an allergic reaction to AVYCAZ occurs. • Clostridium difficile fi -associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs. If CDAD is suspected or confi firmed, antibacterials not directed against C. difficile fi should be discontinued, if possible. • Seizures, nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment. Adjust dosing based on creatinine clearance. • Prescribing AVYCAZ in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit fi to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS • The most common adverse reactions (incidence of ≥10% in either indication) were vomiting, nausea, constipation, and anxiety.

AVYCAZTM (ceftazidime-avibactam) for injection, for intravenous use Brief Summary of full Prescribing Information Initial U.S. Approval: 2015 INDICATIONS AND USAGE: Complicated Intra-Abdominal Infections (cIAI) AVYCAZ (ceftazidime-avibactam), in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia stuartii, Enterobacter cloacae, Klebsiella oxytoca, and Pseudomonas aeruginosaa in patients 18 years or older. As only limited clinical safety and efﬁcacy data for AVYCAZ are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options [see Clinical Studies in the full Prescribing Information]. Complicated Urinary Tract Infections (cUTI), including Pyelonephritis - AVYCAZ (ceftazidime-avibactam) is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis caused by the following susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter koseri,i Enterobacter aerogenes, Enterobacter cloacae, Citrobacter freundii,i Proteus spp., and Pseudomonas aeruginosa in patients 18 years or older. As only limited clinical safety and efﬁcacy data for AVYCAZ are currently available, reserve AVYCAZ for use in patients who have limited or no alternative treatment options [see Clinical Studies in the full Prescribing Information]. Usage - To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used to treat only indicated infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy [see Dosage and Administration in the full Prescribing Information]. CONTRAINDICATIONS: AVYCAZ is contraindicated in patients with known serious hypersensitivity to AVYCAZ, avibactam-containing products, ceftazidime, or other members of the cephalosporin class [see Warnings and Precautions]. WARNINGS AND PRECAUTIONS: Decreased Clinical Response in Patients with Baseline Creatinine Clearance of 30 to 50 mL/min - In a Phase 3 cIAI trial, clinical cure rates were lower in a subgroup of patients with baseline CrCL of 30 to 50 mL/min compared to those with CrCL greater than 50 mL/min (Table 3). The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCL 30 to 50 mL/min. Monitor CrCL at least daily in patients with changing renal function and adjust the dosage of AVYCAZ accordingly [see Dosage and Administration in the full Prescribing Information, and Adverse Reactions]. Table 3. Clinical Cure Rate at Test of Cure, by Baseline Renal Function – mMITT Population1

Normal function / mild impairment (CrCL greater than 50 mL/min) Moderate impairment (CrCL 30 to 50 mL/min)

AVYCAZ + Metronidazole % (n/N)

Meropenem % (n/N)

85% (322/379)

86% (321/373)

45% (14/31)

74% (26/35)

Microbiological modiﬁed intent-to-treat (mMITT) population included patients who had at least one bacterial pathogen at baseline and received at least one dose of study drug.

Hypersensitivity Reactions - Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with AVYCAZ is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established. Discontinue the drug if an allergic reaction to AVYCAZ occurs. Clostridium difficile-associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD.

Hypertoxin producing strains of C. difficilee cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficilee may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated. Central Nervous System Reactions - Seizures, nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment. Adjust dosing based on creatinine clearance [see Dosage and Administration in the full Prescribing Information]. Development of Drug-Resistant Bacteria Prescribing AVYCAZ in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage]. ADVERSE REACTIONS: The following are discussed in greater detail in the Warnings and Precautions section: Decreased Clinical Response in Patients with Baseline CrCL of 30 to 50 mL/min; Hypersensitivity Reactions; Clostridium difficile-Associated Diarrhea; Central Nervous System Reactions; Development of Drug-Resistant Bacteria [see Warnings and Precautions]. Clinical Trial Experience - Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. AVYCAZ was evaluated in two active-controlled Phase 2 clinical trials, one each in cIAI and cUTI, including pyelonephritis. The Phase 2 trials included a total of 169 adult patients treated with AVYCAZ and 169 patients treated with comparators. Complicated p Intra-Abdominal Infections - The Phase 2 cIAI trial included 101 adult patients treated with AVYCAZ (2 grams ceftazidime and 0.5 grams avibactam) administered intravenously over 30 minutes every 8 hours plus 500 mg metronidazole administered intravenously over 60 minutes every 8 hours and 102 patients treated with meropenem. The median age of patients treated with AVYCAZ was 41 years (range 18 to 79 years). Patients were predominantly male (69.3%) and Caucasian (55.4%). Patients with an estimated baseline CrCL 50 mL/min or less were excluded. Serious adverse reactions occurred in 9/101 (8.9%) of patients receiving A AVYCAZ (with metronidazole) and 11/102 (10.8%) of patients receiving meropenem. The most common adverse reactions leading to discontinuation in patients receiving AVYCAZ were skin and subcutaneous tissue disorders (3%). Adverse reactions occurring in 10% or more of patients receiving AVYCAZ were vomiting and nausea. Increased Mortality - In a Phase 3 cIAI trial, death occurred in 2.5% (13/529) of patients who received AVYCAZ/metronidazole and in 1.5% (8/529) of patients who received meropenem. Among a subgroup of patients with baseline CrCL 30 to 50 mL/min, death occurred in 25.8% (8/31) of patients who received AVYCAZ/metronidazole and in 8.6% (3/35) of patients who received meropenem. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCL 30 to 50 mL/min [see Dosage and Administration in the full Prescribing Information and Warnings and Precautions]. In patients with normal renal function or mild renal impairment (baseline CrCL greater than 50 mL/min), death occurred in 1.0% (5/498) of patients who received AVYCAZ/ metronidazole and in 1.0% (5/494) of patients who received meropenem. The causes of death varied and contributing factors included progression of underlying infection, baseline pathogens isolated that were unlikely to respond to the study drug, and delayed surgical intervention. Complicated p Urinaryy Tract Infections,, Includingg Pyelonephritis y p - The Phase 2 cUTI trial included 68 adult patients treated with AVYCAZ (0.5 grams ceftazidime + 0.125 grams avibactam) administered intravenously over 30 minutes every 8 hours and 67 patients treated with imipenem-cilastatin (0.5 grams intravenously every 6 hours). The dose of AVYCAZ in this trial was lower than the recommended dose [see Dosage and Administration in the full Prescribing Information]. Median age of patients treated with AVYCAZ was 47.5 years (range 18 to 85 years). Patients were predominantly female (75%) and Caucasian (58.8%). Patients with CrCL less than 70 mL/min were excluded. Serious adverse reactions occurred in 6/68 (8.8%) of patients receiving AVYCAZ and 2/67 (3.0%) of patients receiving imipenem-cilastatin. Two patients prematurely discontinued treatment with AVYCAZ: one due to an accidental overdose and one due to atrial fibrillation. Adverse reactions occurring in 10% or more of patients receiving AVYCAZ were constipation and anxiety. Table 4 lists adverse reactions occurring in 5% or more of patients receiving AVYCAZ in the Phase 2 cIAI trial or the Phase 2 cUTI trial.

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Table 4. Incidence of Selected Adverse Drug Reactions Occurring in 5% or more of Patients Receiving AVYCAZ in the Phase 2 cIAI Trial or the Phase 2 cUTI Trial Phase 2 cIAI Trial Phase 2 cUTI Trial AVYCAZ plus Meropenem b AVYCAZ c ImipenemCilastatin d Metronidazole a (N = 102) (N = 68) (N = 67) (N = 101) Gastrointestinal disorders Vomiting 14% 5% 0% 0% Nausea 10% 6% 2% 5% Constipation 4% 1% 10% 3% Abdominal pain 8% 3% 7% 5% Upper abdominal pain 1% 0% 7% 2% Investigations Increased blood 9% 7% 3% 2% alkaline phosphatase Increased alanine 8% 13% 3% 6% aminotransferase Nervous system disorders Dizziness 0% 2% 6% 0% Psychiatric disorders Anxiety 5% 1% 10% 8% a

2.5 grams (2 grams/0.5 grams) intravenously over 30 minutes every 8 hours (with metronidazole 500 mg intravenously every 8 hours) b 1 gram intravenously over 30 minutes every 8 hours c 0.625 grams (0.5 grams/0.125 grams) intravenously over 30 minutes every 8 hours d 0.5 grams intravenously over 30 minutes every 6 hours

Other Adverse Reactions of AVYCAZ and Ceftazidime - The following selected adverse reactions were reported in AVYCAZ-treated subjects at a rate of less than 5% in the Phase 2 trials and are not described elsewhere in the labeling. Blood and lymphatic disorderss - Eosinophilia, Thrombocytopenia; Investigationss - Increased gamma-glutamyltransferase, Prolonged prothrombin time; Metabolism and nutrition disorderss - Hypokalemia; Renal and urinary disorderss - Acute renal failure, Renal impairment; Skin and subcutaneous tissue disorderss - Rash. Additionally, adverse reactions reported with ceftazidime alone that were not reported in AVYCAZ clinical trials are listed below: Blood and lymphatic disorders - Agranulocytosis, Hemolytic anemia, Leukopenia, Lymphocytosis, Neutropenia, Thrombocytosis; General disorders and administration site conditions - Infusion site inﬂammation, Injection site hematoma, Injection site phlebitis, Injection site thrombosis; Hepatobiliary disorders - Jaundice; Infections and infestations - Candidiasis; Investigations - Increased blood lactate dehydrogenase; Nervous system disorders - Dysgeusia, Paresthesia; Renal and urinary disorders - Tubulointerstitial nephritis; Reproductive and breast disorders - Vaginal inﬂammation; Skin and subcutaneous tissue disorders - Angioedema, Erythema multiforme, Pruritis, Stevens-Johnson syndrome, Toxic epidermal necrolysis, Urticaria. Laboratoryy Changes g - Seroconversion from a negative to a positive direct Coombs’ test result occurred in 6/82 (7.3%) of patients receiving AVYCAZ plus metronidazole and 2/84 (2.4%) of patients receiving meropenem in the cIAI trial. Seroconversion from a negative to a positive direct Coombs’ test result occurred in 1/52 (1.9%) of patients receiving AVYCAZ and 5/60 (8.3%) of patients receiving imipenem cilastatin in the cUTI trial. No adverse reactions representing hemolytic anemia were reported in any treatment group. DRUG INTERACTIONS: Probenecid - In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake from the blood compartment, and thereby its excretion. As a potent OAT inhibitor, probenecid inhibits OAT uptake of avibactam by 56% to 70% in vitro o and, therefore, has the potential to decrease the elimination of avibactam when co-administered. Because a clinical interaction study of AVYCAZ or avibactam alone with probenecid has not been conducted, co-administration of AVYCAZ with probenecid is not recommended [see Clinical Pharmacology in the full Prescribing Information]. Drug/Laboratory Test Interactions - The administration of ceftazidime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used. USE IN SPECIFIC POPULATIONS: Pregnancy - Pregnancy Category B Animal reproductive toxicity studies have been conducted with ceftazidime and with avibactam. However, there are no adequate and well-controlled studies of AVYCAZ, ceftazidime, or avibactam in pregnant women. Because

animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed. Ceftazidime Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and showed no evidence of harm to the fetus due to ceftazidime. Avibactam - Avibactam was not teratogenic in rats or rabbits. In the rat, intravenous studies showed no embryofetal toxicity at doses of 1000 mg/kg/day, approximately 9 times the human dose based on exposure (AUC). In a rat pre- and postnatal study at up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), there were no effects on pup growth and viability. A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weanling pups that was not associated with pathological changes to renal parenchyma or renal function, with renal pelvic dilatation persisting after female weanling pups became adults. Reproductive studies performed during early pregnancy in rabbits showed no effects on embryofetal development at doses of 100 mg/kg, twice the human exposure (AUC). At higher doses, increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies were observed. Nursing Mothers Ceftazidime is excreted in human milk in low concentrations. It is not known whether avibactam is excreted into human milk, although avibactam was shown to be excreted in the milk of rats in a dose dependent manner. Exercise caution if AVYCAZ is to be administered to a nursing woman. Pediatric Use - Safety and effectiveness in patients less than 18 years of age have not been established. Geriatric Use - Of the 169 patients treated with AVYCAZ in the Phase 2 cIAI and cUTI trials, 18 (10.7%) were 65 years of age and older. Because of limited data, differences in outcomes or specific risks with AVYCAZ cannot be ruled out for patients 65 years of age and older. Ceftazidime and avibactam are excreted primarily by the kidney, and the risk of adverse reactions may be greater in patients with renal impairment. Because elderly patients are more likely to have renal impairment, care should be taken in dose selection in this age group and it may be useful to monitor renal function. Healthy elderly subjects had 17% greater exposure relative to healthy young subjects when administered the same single dose of avibactam, which may have been related to decreased renal function in the elderly subjects. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration and Clinical Pharmacology in the full Prescribing Information]. Renal Impairment - Dosage adjustment is required in patients with moderately or severely impaired renal function (CrCL 50 mL/min or less). For patients with changing renal function, CrCL should be monitored at least daily and dosage of AVYCAZ adjusted accordingly. Both ceftazidime and avibactam are hemodialyzable; thus, AVYCAZ should be administered after hemodialysis on hemodialysis days [see Dosage and Administration and Clinical Pharmacology in the full Prescribing Information]. OVERDOSAGE: In the event of overdose, discontinue AVYCAZ and institute general supportive treatment. Ceftazidime and avibactam can be removed by hemodialysis. In subjects with ESRD administered 1 gram ceftazidime, the mean total recovery in dialysate following a 4-hour hemodialysis session was 55% of the administered dose. In subjects with ESRD administered 100 mg avibactam, the mean total recovery in dialysate following a 4 hour hemodialysis session started 1 hour after dosing was approximately 55% of the dose. No clinical information is available on the use of hemodialysis to treat AVYCAZ overdosage [see Clinical Pharmacology in the full Prescribing Information]. Distributed by: y Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, LLC Cincinnati, Ohio 45209 Manufactured by: y GlaxoSmithKline Manufacturing S.p.A. Verona, 37135 Italy AVYCAZTM is a trademark of Actavis, Inc. or its affiliates.

he said. “Second, as soon as you’re aware of them, make sure your medical staff and senior leadership know what is happening. Nobody likes to be blindsided.”

A Coping Strategy Grows In Brooklyn At Maimonides Medical Center, the outpatient pharmacy fills approximately 300 to 400 prescriptions weekly, not only for discharge patients but also walk-ins from the surrounding Borough Park section of Brooklyn. “We’ve adopted a philosophy here,” Mr. Cassera said, “that we want to fill the discharge prescriptions for the patient before they leave the hospital.” Under a program called “meds to beds,” the outpatient pharmacy delivers the medications to the inpatient pharmacist, who takes them to the patient’s bedside and provides education on their use. When the price of a generic exceeds the reimbursement rate, he said, “we work with the patient and the pharmaceutical company. Sometimes we prescribe something that’s more affordable, and sometimes we just have to bite the bullet and fill the script.”

Inpatient Drugs Also on the Rise Rising prices are not just creating budgetary problems for outpatient pharmacies. The impact is also being felt on the inpatient side. Erin Fox, PharmD, the director of the Drug Information Service at University of Utah Health Care, told Pharmacy Practice News that this year’s increases in just two critical cardiac care drugs, Nitropress (nitroprusside) and Isuprel (isoproterenol), both marketed by Valeant Pharmaceuticals International, would have resulted in a $2.86 million budget hit had the pharmacy not taken steps to reduce the cost. The price of a single ampule of Isuprel alone, Dr. Fox said, rose from $180 in 2014 to $2,700 this year. “That is a huge cost,” she said. The pharmacy began looking for ways to reduce the impact. One solution was to cut back on the number of emergency crash carts stocked with Isuprel. There are more than a hundred at the university. “And so that’s what we’re working to do,” Dr. Fox said. It was a “little trickier” for Nitropress, she said, “because we had already gone to a leaner inventory.” She said alternative products are used whenever possible, “but the problem with those drugs is that there aren’t any alternatives. They have been around for years. There could be generic products, but there just aren’t any.” —Bruce Buckley More coverage online: Gary M. Abrams, BSPharm, on the cost-versus-care equation in transplant medicine. www. pharmacypracticenews.com/GAbrams.

24 Policy

Pharmacy Practice News • June 2015

Supply Chain What Is Suspect?

TRACK AND TRACE

Under the DSCSA, a suspect product is defined as a product that is believed to be:

continued from page 1

(inbound and outbound) that will enable product tracing. These tracking data will center around the transaction information (TI), transaction history (TH) and transaction statement (TS), called the 3Ts (box: Minding the 3Ts). “Recordkeeping will be a key component of this [process],” said Raymond Lake, RPh, MS, a pharmacist at MedStar Health, a health system serving the Baltimore-Washington region, headquartered in Columbia, Md., during an American Society of Health-System Pharmacists (ASHP) webinar about the new law. Unless specifically exempted, each entity in the supply chain must provide the 3Ts information to the subsequent owner who must capture and maintain it for each transaction for six years (box: Tracking Requirements Exceptions). Additionally, they must be able to respond to requests for this information by the FDA or vendor if there is a recall or investigation into a product. Joseph Hill, MA, the director of Federal Legislative Affairs at ASHP, underscored the need for pharmacists to insist upon having tracking information on hand before adding drugs to inventory. “We cannot accept a product from an authorized trading partner without the transaction history, information and statements, unless it is exempted,” Mr. Hill said, “and we must provide any subsequent owner with the 3Ts.”

Two-Year Rollout DSCSA should not be completely unknown to health systems: The law was passed in 2013, and as of Jan. 1, 2015, all trading partners, including pharmacists, are required to notify the FDA and several key players in the drug supply

Minding the 3Ts The following product tracing information must be maintained under the law: TI (Transaction information): Includes the name of the product, strength and dosage form; National Drug Code; container size; name and address of seller and purchaser; and other DSCSA-specified information. TH (Transaction history): Paper or electronic statement that includes the transaction information for each prior transaction back to the manufacturer. TS (Transaction statement): Paper or electronic attestation by the entity transferring ownership of the product that it is authorized under DSCSA; received the product from an authorized party; and other specified information. All information must be kept for 6 years.

• Counterfeit, diverted or stolen • Intentionally adulterated • Subject of a fraudulent transaction • Otherwise unfit for distribution Dispensers will be required to quarantine suspect product, notify FDA and vendors within 24 hours and be able to produce the 3Ts information for all products.

A worker tracks medications at a McKesson Distribution Center.

chain if they believe a product is suspect or illegitimate—no later than 24 hours after making that determination. Additionally, a suspect product must be quarantined and pharmacists are required to assist in the investigation to determine if there is indeed a problem. “We as dispensers must have systems in place to [isolate] products whose integrity may have been compromised,” Mr. Hill said. A suspect product, he noted, would be any drug whose integrity has been called into question and thus would be inappropriate to give to a patient.

Technology Can Help Compliance with the track-and-trace law will generate a mountain of data, industry experts warned. In the beginning, paper transactions will suffice as a documentation tool, but eventually the paper trail will end and the informa-

tion must be stored digitally. This might require that hospitals increase network server space or look to cloud-based storage. As a partial solution, Mr. Hill recommended that pharmacists talk with their distributors to see if they offer cloud storage for 3Ts information. Hospitals also will need barcode scanners that can capture the unique parameters of the product transaction. Scanning systems need to play well with the hospital pharmacy database and potentially the electronic medical record. Additionally, software must be able to scan inbound and outbound products and flag received products that should not be shipped or products scanned multiple times in multiple places. A case might have a two-dimensional barcode or a linear barcode, but each package must have a two-dimensional barcode.

‘We cannot accept a product from an authorized trading partner without the transaction history, information and statements, unless it is exempted.’ —Joseph Hill, MA

Some hospitals give their drug and related products inventory a proprietary number, which will need to be addressed for better interoperability, according to Siobhan O’Bara, senior vice president, industry engagement, of GS1 US, a nonprofit standards organization that has been collaborating with industry stakeholders to address DSCSA requirements through the usage of GS1 Standards. (The law preempts state tracing laws and regulations, including any recordkeeping and pedigree requirements.) “Effective compliance requires [using] a standard identifier across the supply chain,” Ms. O’Bara said. Such an identifier “may create a need to move away from proprietary numbering, or at the very least be able to cross reference a pharmaceutical’s global identifier created by the manufacturer.” Pharmacists must have systems in place to handle this information, Mr. Lake reiterated, not the least of which is making sure that all vendors are authorized trading partners. “Is your vendor familiar to you? Is he providing unsolicited offers by email, fax or phone? What is his reputation? Is he hesitant to provide you with the transaction history? Is the price too good to be true?” These are all questions, Mr. Lake stressed, that pharmacists must ask before ordering from a vendor.

Pharmacy-Unique Issues Beyond the technology upgrades, there are several concerns with the implementation of DSCSA that are unique to pharmacists, according to Mr. Hill, including managing the complexities of the federal 340B drug discount program, drug shortages and selling excess inventory or returning it to the distributor. Before the law went into effect, 340B purchases often shipped directly to the contract pharmacy, but the covered entity actually owns the product, Mr. Hill explained. The FDA has not made clear if this practice can continue under DSCSA, or if the product has to be shipped to the covered entity, which then must ship it to the contract pharmacy. Both entities would have to store that 340B product’s 3Ts information.

Policy 25

Pharmacy Practice News • June 2015

Reimbursement Matters

Transforming Health Care Payment: IPPS in 2016 M

edicare operates its Inpatient Prospective Payment System (IPPS) on a fiscal year (FY) basis beginning Oct. 1 and recently released the proposed payments for comment; final rules will be published later this summer. There is no question that the steady march toward payment reform is continuing at a very rapid pace, with the overarching mantra being “spend less and improve more rapidly” in an effort to shift the focus from volume to value. This presents an increasing dilemma for pharmacy departments, as they see the cost of drugs rising with no end to this trend in sight. Although this column touches on a few highlights, the IPPS rule itself is extremely complex, with myriad opportunities to participate in cost containment efforts at your facility. Nothing that pharmacy routinely or traditionally does should be held sacred and all should be up for discussion. The IPPS pays hospitals for services provided to Medicare beneficiaries using a national base payment rate, adjusted for a number of factors that affect hospitals’ costs, including the patient’s condition and local market conditions. The Centers for Medicare & Medicaid Services (CMS) generally sets payment rates prospectively for inpatient stays based on the patient’s diagnosis and severity of illness. This approach is based on the traditional diagnosis-related group (DRG) model. But when severity is added to the cal-

“A dispenser or any authorized trading partner under the new law is unable to accept product that does not contain one of the 3Ts,” he said. “That presents us with a potential problem with the current replenishment model under the 340B contract pharmacy arrangements.” ASHP said it has asked for clarification and recommended that the product and its 3Ts information be sent directly to the contract pharmacy. Drug shortages are another important track-and-trace consideration. They are a fact of life at every hospital and many facilities have had to beg, borrow and barter from area health systems to obtain much-needed short-supply medications. There were concerns about these practices under the new law, which does make specific exemptions, such as distributing product among members of health care entities under common control or during an emergency. DSCSA is not trying to keep any pharmacist from obtaining medications from a legitimate source, including borrow and loan programs or the purchase of medications from a hos-

culus, payments are made under Medicare Severity DRGs (MS-DRGs). Under the IPPS, a hospital receives a single payment for the case based on the MS-DRG payment. The proposed rules set measurable goals and a timeline to move the Medicare program, and the health care system at large, toward paying providers based on the quality, rather than the quantity, of care they give patients. As discussed in the April 2015 column (http://goo.gl/5xFEPK), effective Oct. 1, 2015, the 10th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10) codes will replace the older ICD-9 codes to begin a full year of more detailed and accurate patient condition descriptions that capture severity and complexity. CMS projects that the proposed rate increase, together with other proposed changes to IPPS payment policies, will increase IPPS operating payments by approximately 0.3%. However, other payment adjustments will include continued penalties for preventable hospital readmissions, a continued 1% penalty for hospitals in the worst-performing quartile under the Hospital Acquired Condition Reduction Program, and continued bonuses and penalties under the Hospital Valued-Based Purchasing (VBP) program. Sections of the extensive IPPS rule include several provisions that will determine your hospital’s rate of reim-

bursement for a wide range of conditions and procedures; below are some highlights to keep in mind when assessing your facility’s readiness.

Bundled Payments for Care Improvement Initiative: It’s Expanding! In 2011, CMS launched the Bundled Payments for Care Improvement (BPCI) initiative. This initiative combines payments for multiple services during an episode of care into a bundled payment. BPCI episodes start with either an inpatient stay or post-acute services following a qualifying inpatient stay. CMS is continuing to implement the initiative, which is testing four models of care with hundreds of providers across the country.

Hospital VBP Program The Hospital VBP Program was established by the Affordable Care Act and adjusts payments to hospitals for inpatient services based on the facilities’ performance on an announced set of measures. CMS is proposing to continue updates to the Hospital VBP Program and to expand the number of measures, including a care coordination measure, to the FY 2018 program year and a 30-day mortality measure for chronic obstructive pulmonary disease to the FY 2021 program year. CMS also proposes to remove two measures, effective with the FY 2018 program

Tracking Requirement Exceptions • Intracompany distribution of any product between members of an affiliate or within a manufacturer • Distribution of product among hospitals or health care systems under common control • Distribution of product for emergency medical reasons, which includes a public health emergency, but excludes a drug shortage unless caused by a public health emergency • Distribution of minimal quantities by a licensed retail pharmacy or licensed practitioner for office use • Distribution of IV product intended for fluid or electrolyte replenishment • Distribution of IV product to maintain equilibrium of water and minerals in the body • Product intended for irrigation or sterile water • Distribution of medical gas • Drugs compounded in compliance with Section 503A or 503B Source: ASHP

pital that has excess inventory, Ms. O’Bara pointed out. “In a drug shortage, you will seek an alternative supply,” she said. “The law is not trying to take away that activity or impede your ability to sell off excess inventory or

to find inventory at a lower cost,” she said. “But as these transactions move the product around, they have to be recorded. If you are a hospital that has excess inventory, and you sell it to another hospital or back to the dis-

“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

year, and signals future policy changes that will affect certain National Healthcare Safety Network measures beginning with the FY 2019 program year.

New Technology Add-on Payments These payments are of special interest to pharmacy departments because they represent the only opportunity for a separate DRG payment for a drug or biological. The request for a product to be considered for this special category is begun by the manufacturer and, after intensive review, may be allowed or denied. The proposed changes for FY 2016 include: 1. Creating a new component within ICD-10 PCS (Procedure Coding System) codes, labeled Section “X” (analogous to outpatient C codes), that will be used to identify and describe new technologies and services (e.g., drugs, biologicals and see IPPS in 2016, page 32

tributor, it has to be registered.” In fact, DSCSA specifies that wholesale distributors “may accept dispenser returns only if they can associate the returned product with the transaction information associated with that product,” explained Anita T. Ducca, the senior vice president of regulatory affairs at the Healthcare Distribution Management Association, in Arlington, Va. The FDA recognizes the complexity of this new law, and it is being phased in over 10 years. “July 1 is the initial phase-in for dispensers,” Mr. Hill said. “They have to collect and store the 3T information and [quarantine suspect] products that come through their door.” Eventually, they will need to affix the barcode to the smaller cases and be able to track the product throughout the hospital. “This is a work in progress.” “If you haven’t already talked to your wholesale distributor [about the law’s implementation],” Ms. Ducca said, “we can’t urge you strongly enough to get in touch with them.” —Marie Rosenthal

26 Policy

Pharmacy Practice News • June 2015

Specialty Pharmacy Speak Up!

DISTRIBUTION continued from page 1

Griffith, RPh, MS, FASHP, the administrator of Oncology Pharmacy and Infusion Services at the Arthur G. James Cancer Hospital at Ohio State University in Columbus. “If the drug can’t get to the patient—that’s a shortage.” However, Genentech said that, except for “limited instances,” facilities are receiving their supplies. “The majority of hospitals are successfully purchasing Avastin, Herceptin and Rituxan through the specialty distribution model,” said Edward Lang, a spokesperson for Genentech in South San Francisco, Calif. In a 2014 interview, Genentech told Pharmacy Practice News that a 2012 incident involving counterfeit bevacizumab was cause for company concern. However, a new federal track-and-trace law enacted to enhance the security of the entire U.S. pharmaceutical supply chain makes this concern a non-issue, according to William H. Woodward, RPh, MS, the senior director of pharmacy contract services at Novation LLC, a group purchasing organization representing more than one-third of all the hospitals in the country (Related story, page 1). Novation was one of many groups that met with the company to discuss their concerns, but Genentech said it was not hearing widespread complaints. Therefore, Novation surveyed its membership to find out what they were experiencing. In February 2015, the survey went to 1,440 facilities and received more than 200 responses (15% response rate). Results showed that the change in distribution model significantly impacted the facilities’ bottom lines (81%) and 28% of respondents indicated the change affected patient care, with 88% of those saying that some patients experienced a delay in treatment (WSJ Pharmalott 2015 Mar 2.). See our website for more survey results (goo.gl/VYziw3). “If it is true patients are not getting these life-saving medicines, we are deeply concerned. We are not hearing about it directly from hospitals,” Mr. Lang said. “We’ve only received three reports of patient-access concerns directly from hospitals and can only resolve issues if we know where they are occurring.” Mr. Woodward said the direct financial impact resulted in about a $68 million loss among all Novation members from cost-minus discounts that were not available through the specialty distribution channel. However, hospitals also took other indirect financial hits, including treatment delays that meant they could not turn over an infusion suite as quickly; extra staff time to order products; increased waste disposal charges; and having to maintain higher inventories. Hospitals also reported issues with 340B compliance

because specialty distributors do not have the software that interfaces with the split-billing software needed for 340B, according to Mr. Woodward. “All of these things are added financial impacts, and we don’t have a way to aggregate those costs, but for the cost-minus discounts, it was a $68 million loss. It is a tremendous amount of money,” he said. The problem is that these three drugs are the workhorses of cancer infusion medicines, Mr. Woodward explained. Bevacizumab and rituximab are indicated to treat multiple cancer types. Trastuzumab is a leading breast cancer therapy. The three drugs are among the top 5 cancer treatments in the world.

distributors. The delivery is handled by the wholesaler and delivered in a refrigerated container right to the pharmacy. When the new order is filled, the delivery person takes the empty refrigerated containers. Pharmacists can schedule patient treatments around a delivery time, which is pretty much the same time every day. There are roughly 80 distribution centers around the country, so if there is a disruption for any reason—say bad snow storms—another distribution center can ensure delivery, they said. In some cases to order through the specialty channel, pharmacists must go outside their routine ordering system interface. Often, they order by phone

The Genentech Effect A Novation survey asked pharmacists how finances were affected by the move to the specialty distribution chain. (They were asked to select all that apply.) Loss of cost-minus discounts causing higher drug purchasing cost

Increased inventory expense

Additional unreimbursed expense

Increased copayments for patients (increased collection risk)

18 8

Extra freight charges for emergency deliveries

5 59

Other

20%

40%

60%

80%

100%

Source: Novation survey released in Feb. 2015. An independent third party, Market Strategies International, certified the survey results and methodology.

“Among our members, the total purchase volume is $1.4 billion for these three products alone,” Mr. Woodward said. (According to a Roche press release, rituximab, trastuxumab and bevacizumab were the company’s topselling pharmaceuticals in 2014, earning almost $8 billion in U.S. sales alone.) Patient care was also affected, according to Ms. Griffith. Pharmacists can no longer depend on their wholesaler’s daily delivery for these drugs, and if they haven’t accounted for this in their inventory, treatments could be delayed. “We are fortunate, because we did account for these delays by increasing our inventory, but [this winter] we were down to counting vials after not receiving a delivery for three days,” she said. To understand why these issues are occurring, one must understand how the product was delivered before and after the change. With a normal wholesaler, pharmacists place an order in the evening and it is delivered by truck the next day, Mr. Woodward said. Much of the product ordering is automated for many larger

so they can talk with the specialty distributor. The drugs are delivered by a commercial carrier like FedEx or United Parcel Service (UPS) to a loading dock, not the pharmacy, Mr. Woodward said. Because it does not go directly to the pharmacy department, the pharmacist must wait until it is processed like any other stock and delivered to the department, which increases the delays. Delivery times change based on what other packages are on the truck and the commercial carriers don’t take the empty packaging. Instead, pharmacy has to dispose of the waste, Ms. Griffith said. Additionally, most specialty distributors only have one main distribution hub. If there is a storm or some other event, deliveries are delayed, sometimes for days. “When Tennessee was hammered with several storms in late winter this year, there were no deliveries coming out of there for a few days,” Mr. Woodward said. Ms. Griffith said there were several times when specialty drug deliveries were delayed or lost, and because many of these products require refrigeration, a late delivery could mean an expired

Edward Lang, a Genentech spokesperson, explained that the best way for the company to resolve any operational issues is to work directly with affected hospitals. The company has a dedicated hotline and email to contact them.

800-551-2231 (M-F, 6 am-5 pm PST) distribution-questions@gene.com

product. She said one shipment took four days to arrive at her pharmacy. “We knew the integrity of the drug was compromised, so we returned it without even opening the package,” Ms. Griffith said. “I find it ironic that the things they wanted to avoid are now happening, but they never happened before,” she added. “These are scenarios I honestly never imagined.” Mr. Long said that when hospitals reported problems obtaining medication, Genentech worked directly with them to resolve the issue. “During the unprecedented winter storms earlier this year, our distributors informed us that there were limited interruptions in service,” he noted. One exception was during the storms in Memphis, Tenn., and Louisville, Ky., which delayed specialty distributions for one day. “Shipments resumed the following day and UPS/FedEx prioritized pharmacy deliveries,” he said. In addition, “in emergency situations, Genentech can also support customers through drop shipments at no extra charge. No requests for any of these options were received from customers related to the storms earlier this year.” Pharmacists want Genentech to reverse its decision, but after several meetings with company officials that appears unlikely. Ms. Griffith recommended that pharmacists start contacting Genentech directly about problems (See box). “They keep telling us they aren’t hearing about these issues. They don’t know if no one tells them,” she said. “When you don’t get your delivery, you should contact them. “People are really frustrated,” Ms. Griffith said. “They went from a seamless, reliable process to something that is costing more money and resources, and we are adding risk to our patients with shortages and delivery issues.” —Marie Rosenthal

Video Exclusive Cindy O’Bryant and Niesha Griffith talk about limited distribution. Visit www.pharmacypracticenews. com/LDN or scan the adjacent QR code.

Kcentra

WHEN PATIENTS NEED URGENT WARFARIN REVERSAL…

plex m o C n i hromb l t o r P r ersa -Facto v 4 e R y l n n i arfar and O W t s t r i n F e a—the -PCC) for Urg r t n e c K (4F e t a r t n Kcentra—Ready When You Need It Conce Important Safety Information Kcentra is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA—eg, warfarin) therapy in adult patients with acute major bleeding or the need for urgent surgery or other invasive procedure. Kcentra is for intravenous use only. WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS Patients being treated with Vitamin K antagonist therapy have underlying disease states that predispose them to thromboembolic events. Potential benefits of reversing VKA should be weighed against the risk of thromboembolic events, especially in patients with history of such events. Resumption of anticoagulation therapy should be carefully considered once the risk of thromboembolic events outweighs the risk of acute bleeding. Both fatal and nonfatal arterial and venous thromboembolic complications have been reported in clinical trials and postmarketing surveillance. Monitor patients receiving Kcentra, and inform them of signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra might not be suitable for patients with thromboembolic events in the prior 3 months. Kcentra is contraindicated in patients with known anaphylactic or severe systemic reactions to Kcentra or any of its components (including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin). Kcentra is also contraindicated in patients with disseminated intravascular coagulation. Because Kcentra contains heparin, it is contraindicated in patients with heparin-induced thrombocytopenia (HIT). Hypersensitivity reactions to Kcentra may occur. If patient experiences severe allergic or anaphylactic type reactions, discontinue administration and institute appropriate treatment. In clinical trials, the most frequent (≥2.8%) adverse reactions observed in subjects receiving Kcentra were headache, nausea/vomiting, hypotension, and anemia. The most serious adverse reactions were thromboembolic events, including stroke, pulmonary embolism and deep vein thrombosis. Kcentra is derived from human plasma. The risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated. The safety and efficacy of Kcentra in pediatric use have not been studied, and Kcentra should be used in women who are pregnant or nursing only if clearly needed. Please see brief summary of full prescribing information on reverse.

The ﬁrst and only non-activated 4F-PCC for urgent warfarin reversal in adult patients with: – Acute major bleeding or – Need for an urgent surgery/invasive procedure Mean infusion time ~7x faster than plasma Room temperature storage for 36 months

Kcentra has over 15 years of clinical experience as Beriplex® outside the US. www.Kcentra.com Kcentra Hotline: 1-855-4KCENTRA (1-855-452-3687)

Urgent Warfarin Reversal Kcentra is manufactured by CSL Behring GmbH and distributed by CSL Behring LLC. Kcentra® and Beriplex® are registered trademarks of CSL Behring GmbH. ©2015 CSL Behring LLC 1020 First Avenue, PO Box 61501, King of Prussia, PA 19406-0901 USA www.CSLBehring-us.com www.Kcentra.com KCT15-01-0006 3/2015

28 Operations & Management

Pharmacy Practice News • June 2015

Leadership in Action

Are You Intentional? Y

ou are a busy pharmacy manager. You have people pulling at you from every direction. Your employees need your help. Your boss has made demands that you desire to fulfill. There is the new renovation project for the pharmacy that you finally received approval to complete. The budget is due soon and you haven’t really started working on it yet. And oh, by the way, you have to cut $1 million in drug

expenses from next year’s budget. Sound familiar yet? And this is just the work side of life. Add to this your home life, juggling the kid’s soccer and softball games, school parent-teacher organization meetings and events, piano lessons for your youngest child and the regularly scheduled orthodontist appointments for your oldest. Your spouse goes in one direction and you go in the other to cover all the bases. When you finally roll

into bed at night, you’re exhausted but your mind is still racing, thinking about all the items that didn’t get checked off that day’s to-do list, not to mention all of the appointments on your schedule tomorrow. You wonder when you’ll get time to work on anything. You feel stressed and reactionary. As Greg Hicks describes in his book, “Leader Shock … and How to Triumph over It, Eight Revolutionary Rules for

“Leadership in Action” is authored by Ernest R. Anderson Jr., MS, RPh, of Brockton, Mass. Mr. Anderson welcomes your input on leadership issues, at ernestanderson1130 @gmail.com

Ernest R. Anderson Jr., MS, RPh

Becoming a Powerful and Exhilarated Leader” (McGraw-Hill, 2004), leaders are overwhelmed by the complexity of their responsibilities, overloaded by the volume of information and data, and overstressed by the pace of crisis management and the demands of difficult people. This is what Hicks has coined “leader shock.” The good news is that there is a way out. Over the next several months, we will look at leadership behaviors that can help you gain more control over your personal and professional life. These practices can be learned and are attainable by everyone who decides to put them into practice.

Attitude Is Everything

KCENTRA® (Prothrombin Complex Concentrate [Human]) For Intravenous Use, Lyophilized Powder for Reconstitution Initial U.S. Approval: 2013 BRIEF SUMMARY OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use Kcentra safely and effectively. See full prescribing information for Kcentra. WARNING: ARTERIAL AND VENOUS THROMBOEMBOLIC COMPLICATIONS Patients being treated with Vitamin K antagonists (VKA) therapy have underlying disease states that predispose them to thromboembolic events. Potential beneﬁts of reversing VKA should be weighed against the potential risks of thromboembolic events, especially in patients with the history of a thromboembolic event. Resumption of anticoagulation should be carefully considered as soon as the risk of thromboembolic events outweighs the risk of acute bleeding. • Both fatal and non-fatal arterial and venous thromboembolic complications have been reported with Kcentra in clinical trials and post marketing surveillance. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. • Kcentra was not studied in subjects who had a thromboembolic event, myocardial infarction, disseminated intravascular coagulation, cerebral vascular accident, transient ischemic attack, unstable angina pectoris, or severe peripheral vascular disease within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. ---------------------------------INDICATIONS AND USAGE-----------------------------------Kcentra, Prothrombin Complex Concentrate (Human), is a blood coagulation factor replacement product indicated for the urgent reversal of acquired coagulation factor deﬁciency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with: • acute major bleeding or • need for an urgent surgery/invasive procedure. -----------------------------DOSAGE AND ADMINISTRATION--------------------------------For intravenous use only • Kcentra dosing should be individualized based on the patient’s baseline International Normalized Ratio (INR) value, and body weight. • Administer Vitamin K concurrently to patients receiving Kcentra to maintain factor levels once the effects of Kcentra have diminished. • The safety and effectiveness of repeat dosing have not been established and it is not recommended. • Administer reconstituted Kcentra at a rate of 0.12 mL/kg/min (~3 units/kg/min) up to a maximum rate of 8.4 mL/min (~210 units/min.).

Pre-treatment INR

2–<4

4–6

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

Maximum dose‡ (units of Factor IX)

Not to exceed 2500

Not to exceed 3500

Not to exceed 5000

* Dosing is based on body weight. Dose based on actual potency as stated on the carton, which will vary from 20-31 Factor IX units/mL after reconstitution. Nominal potency is 500 or 1000 units per vial, approximately 25 units per mL after reconstitution. † Units refer to International Units. ‡ Dose is based on body weight up to but not exceeding 100 kg. For patients weighing more than 100 kg, maximum dose should not be exceeded.

--------------------------------DOSAGE FORMS AND STRENGTHS-------------------------• Kcentra is available as a single-use vial containing coagulation Factors II, VII, IX and X, and antithrombotic Proteins C and S as a lyophilized concentrate. -------------------------------------CONTRAINDICATIONS ------------------------------------Kcentra is contraindicated in patients with: • Known anaphylactic or severe systemic reactions to Kcentra or any components in Kcentra including heparin, Factors II, VII, IX, X, Proteins C and S, Antithrombin III and human albumin. • Disseminated intravascular coagulation. • Known heparin-induced thrombocytopenia. Kcentra contains heparin. --------------------------------WARNINGS AND PRECAUTIONS-----------------------------• Hypersensitivity reactions may occur. If necessary, discontinue administration and institute appropriate treatment. • Arterial and venous thromboembolic complications have been reported in patients receiving Kcentra. Monitor patients receiving Kcentra for signs and symptoms of thromboembolic events. Kcentra was not studied in subjects who had a thrombotic or thromboembolic (TE) event within the prior 3 months. Kcentra may not be suitable in patients with thromboembolic events in the prior 3 months. • Kcentra is made from human blood and may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. ------------------------------------ADVERSE REACTIONS--------------------------------------• The most common adverse reactions (ARs) (frequency *2.8%) observed in subjects receiving Kcentra were headache, nausea/vomiting, hypotension, and anemia. • The most serious ARs were thromboembolic events including stroke, pulmonary embolism, and deep vein thrombosis. To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring at 1-866-9156958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. -----------------------------USE IN SPECIFIC POPULATIONS---------------------------------Pregnancy: No human or animal data. Use only if clearly needed. Based on March 2014R version.

Several years ago, one of my elder mentors taught me that “attitude is everything.” I owe a great debt of gratitude to this friend and mentor, because his simple yet profound message to me was this: We are in control of our attitudes. In that same vein, Thomas Jefferson once stated, “Nothing can stop the man with the right mental attitude from achieving his goals; nothing on earth can help the man with the wrong mental attitude.” I made a choice many years ago to embrace that sensibility and have a positive attitude—to be both an optimist and a realist. I recognized that I was in control of my attitudes and I couldn’t blame them on my circumstances or external forces. Hicks’s first rule, to “activate intentions,” touches on this concept. As he states in his book, “our intentions are 100% within our control.” The recommendation is to first set our intention before every event, and secondly, state it to the people with whom you are engaging. That deliberate, proactive approach requires that you understand the difference between responding and reacting. Responding is the split second when you make a decision on your intention by determining your attitude and your behavior. Reacting, in contrast, is usually a more emotional—and far less effective—response to a triggering event. Self-awareness is an important part of this journey. We often hear, for example, the saying, “check your attitude,” and that sage advice can be a great tool for becoming more aware of whether your attitudes are working for or against you. Are you defensive, hostile or apathetic? Will these attitude types get the response you are intending to obtain? Probably not. Even though you may have little control of the circumstances, you do have control of your attitude. What is

Operations & Management 29

Pharmacy Practice News • June 2015

Leadership in Action the intended outcome that you are looking for? Your attitude determines your speech and actions. It’s also important to choose a behavior that will optimize the results you desire. For instance, should you demonstrate, via good listening, that you have an empathetic ear? Do you offer your full support? Or do you just gather the facts? By determining your intentions up front, you will determine your attitude and behavior toward that interaction.

You’re in Charge As you think about the multiple interactions that you have in the course of the day, you are in charge of your intentions. Think about those intentions and the desired outcomes. You make choices that increase the likelihood of the desired outcome for each one of those interactions. Making this a habit will keep you in check and in control, versus reactionary and out of control. As an example, most of us probably know the desired outcome of a meeting in which we are in charge, but we may not be thinking sufficiently about the multiple steps that are required to get to the desired outcome, as well as what our intentions should be during each of those steps. As you set your attitudes and behaviors consciously, this empowers you to be in control and not in the “leader shock” reactionary mode. Another example is an employee whom you sense is having an issue that is interfering with his or her focus and performance. You could ignore the issue or intentionally face it head-on, going in with the attitude of listening to determine the issue, communicating to address the issue and putting the employee at ease with a desired outcome of understanding and next steps. A third example is the presentation that you are scheduled to make in front of the Quality Committee in the hospital. You know that the chairperson of the committee is hard to please. Rather than approach the meeting with fear and trepidation, you approach it with confidence as the medication expert who knows more about drug therapy than anyone else in the room. You approach the meeting intentionally confident as the medication expert with the appropriate data to tell your story. This is a matter of attitude driven by the facts. You articulate these facts with confidence and experience a positive outcome, as you desired. A fourth example is the contentious meeting you anticipate. Rather than feed into emotional hostility, your intention is to choose not to be offended by anything said during the meeting and your behavior is to listen with understanding, reflecting back what you perceive. These actions increase the desired meeting outcome graciously. I invite you to make a list of those

than tear them down • Taking criticisms as constructive feedback opportunities • Selling our profession of pharmacy at every opportunity of change in the health care system

Creating Trust and Respect

intentions that will become a part of your character, such as: • Having a positive attitude • Choosing to build people up rather

Stating our intentions at the beginning of a conversation or a meeting invokes unequivocally clear communication. It clearly establishes that there are no hidden agendas. This creates trust and respect. This evening I will be

in a meeting that has the potential to be contentious. My intention is to go into the meeting with a positive attitude, listen well, and state at the beginning my desire to learn and understand and walk out of the meeting with a mutually agreeable plan of action. Clarity and unity yield better results. Openness yields trust. Decided intention yields respect. Action based on those intentions yields integrity. Next month, we’ll talk further about taking full responsibility and owning it all. ■

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30 Operations & Management

Pharmacy Practice News • June 2015

Finance

Saving Millions—And Showing Worth in the Process F

rom inpatient discharge medication reconciliation to ambulatory virtual medical record reviews, pharmacists continue to show that they are an indispensable part of hospital care and cost containment.

being used in, that limitation precludes applying any rounding rules at all. “We’re looking for a program [that would] allow us to apply several rounding rules to one agent, depending on the specific regimen,” he said.

Savings With Dose Rounding

Medication Reconciliation

By applying dose-rounding rules for only eight of the roughly 105 oncology drugs used at their outpatient clinic, a team at Beth Israel Deaconess Medical Center in Boston has reduced the cost of waste for these agents by 35%. Zaven Norigian, PharmD, a clinical pharmacy coordinator in oncology at the medical center, outlined some of the reasons why chemotherapy and biotherapy drugs were being wasted before the initiative. “Not all vials contain preservatives, which means meeting USP <797> requirements for sterility is an issue, and it is difficult to schedule groups of patients receiving the same drug,” Dr. Norigian explained. “And because billing for waste is complicated, we thought an initiative like ours was necessary.” Dr. Norigian and his colleagues scoured the dose-rounding literature on agents used in their hospital’s outpatient oncology clinic. They analyzed dosing, vial size and concentrations of the 105 chemotherapeutic and biotherapeutic agents in use at the clinic and also took into consideration the units of measurement used by their hospital’s pharmacy. “After considering those criteria and selecting nine agents, we held discussions with our physicians and nurses to make sure they were comfortable with the rounding rules,” Dr. Norigian said. Such consensus was needed, he noted, because “the rules are 100% required and prescribers can’t alter or override the rounding.” (Table 1 lists the selected agents and rounding rules.) To document cost savings, the team compared the cost of waste for the nine drugs during a nine-month period beginning August 2013. For the comparison, they chose the same nine-month calendar period in 2012, which was before they incorporated the new rules into their computerized prescriber order entry (CPOE) system. They found that rounding the doses reduced waste by $205,199, from $571,298 to $366,099 (Table 2). “The program has been well received and we recently added three more agents to the list; we will continue to look for additional drugs to round,” Dr. Norigian said. One limitation of the current oncology CPOE system is that it can only apply one rounding rule per agent, Dr. Norigian noted. For an agent such as methotrexate, which is dosed differently depending on the regimen it is

During a 12-month pilot period, pharmacists at Mount Carmel West Hospital in Columbus, Ohio, detected and prevented more than 330 serious or life-threatening drug errors through medication reconciliation, optimizing patients’ health and avoiding roughly $584,800 in health care expenses. Every day, inpatient pharmacists at the hospital identify patients scheduled for discharge, according to Virginia Ruef, PharmD, a pharmacy clinical coordinator at the hospital. Although they attempt to meet with all patients, some

are prioritized according to the number of newly initiated medications they have received, their specific diagnosis (congestive heart failure, acute myocardial infarction and pneumonia top the list), and their slated time for discharge. During discharge medication list reviews, pharmacists ensure that written instructions are clear and the prescribed medications are the most affordable of the suitable options, Dr. Ruef noted. During a typical meeting with a patient, pharmacists verify there are no discrepancies between home and newly initiated medications, and also highlight any potential drug and food interactions. Additionally, pharmacists educate patients regarding their newly initiated medications and, in some cases, share information on the general management of their condition. Finally, within one week of discharge, pharmacists call patients to address any questions, to confirm they have started newly prescribed regimens and also to identify any potential adverse events. To assess the efficacy of these interventions, hospital pharmacists assessed, counseled and attempted to follow up with 1,251 patients discharged between June 2013 and June 2014, Dr. Ruef noted. Of these individuals, 31.5% (393) required a total of 714 interventions, and 334 of these averted potentially serious or life-threatening errors. Assuming each of these 334 serious errors would have required an additional $2,200 in health care spending, the potential cost-avoidance thanks to the pharmacist medication reconciliation service during the 12-month study period was roughly $734,800, Dr. Ruef said. Subtracting the $150,000 cost for a 1.5 full-time equivalent pharmacist salary, the net cost avoidance would have added up to roughly $584,800.

Savings at Sentara

Month (2013-2014)

Pre-Dose Rounding ($)

Post-Dose Rounding ($)

Cost Savings ($)

August

82,688

51,237

31,454

September

57,089

48,038

9,051

October

64,443

58,103

6,340

November

80,587

38,803

41,784

December

48,911

35,632

13,279

January

69,584

38,252

31,332

February

40,422

26,051

14,371

Ambulatory care pharmacists at Sentara Medical Group in Norfolk, Va., are saving one insurer big bucks by virtually (and scrupulously) monitoring their elderly Medicare Advantage patients’ drug therapy. Data from 2014 showed that two ambulatory clinical pharmacists assigned to perform virtual chart and prescription reviews issued cost-cutting recommendations that saved Optima Health an estimated $176,442. “We wanted to have a dynamic, behindthe-scenes impact on this patient population,” Candace Minter, PharmD, an ambulatory clinical pharmacy specialist at Sentara Medical Group, said of the impetus that drove her and her colleagues to develop the virtual ambulatory pharmacy review project. In January 2014, they parlayed that lofty intention into concrete actions: They began reviewing charts for Optima Health’s Medicare Advantage patient population before each visit to any of the medical group’s ambulatory primary care or specialist physicians as well as after discharge from a Sentara hospital or emergency department. They also reviewed prescriptions after they were entered through the CPOE system. Between Jan. 1 and Sept. 30, 2014, two Sentara ambulatory clinical pharmacists reviewed charts and prescription orders for 396 patients, and conducted 2,171 direct clinical recommendations, or 4.3 clinical recommendations per patient. Those interventions included, among others, suggestions for medication starts, stops or dose adjustments; lower-cost formulary and generic alternatives; and immunizations and laboratory tests the patients might have needed. According to Dr. Minter, physicians accepted 79% of these recommendations. Extrapolating from the cost data over the eight-month period of study, the savings from medication discontinuations and generic switches alone would have added up to an estimated $176,442 annually, she said. Sentara’s integrated EPIC electronic medication record (EMR) has been essential to the program’s success. Using the system, Dr. Minter noted, “We document our recommendations and interventions in EMR progress notes and we can also send notes directly to providers through the EMR.”

March

50,842

38,856

11,986

—David Wild

April

76,732

31,127

45,605

Total

571,298

366,099

205,199

Table 1. Selected Agents Approved For Rounding Agent

Rounding Increment

Bendamustinea

25 mg

Bevacizumab

100 mg

Brentuximab vedotina

50 mg

Cetuximab

100 mg

Gemcitabine

200 mg

Ipilimumab

50 mg

Pertuzumab

210 mg b

Pembrolizumab

50 mg

Rituximab

100 mg

Rounding initiated June 16, 2014

Rounding ou d g initiated t ated Octob October be 1,, 2014 0

Table 2. Monthly Reported Drug Waste

None of the sources reported any relevant financial conflicts of interest. The research was first presented at the 2014 ASHP Midyear Clinical Meeting in Las Vegas.

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32 Operations & Management

Pharmacy Practice News • June 2015

Finance

Is It Time To Build an Outpatient Pharmacy? T

he idea of opening an on-site outpatient pharmacy for employees and patients at Peninsula Regional Medical Center (PRMC), a 275-bed acute care hospital on Maryland’s Eastern Shore, first came up in the C-suite in 2010. The timing wasn’t right then, but in 2012, facing mounting pressure from the state’s Health Services Cost Review Commission (HSCRC) to reduce readmissions, PRMC decided that it was time to move forward with its own outpatient pharmacy. After about 18 months of development, PRMC Home Scripts opened its doors in December 2013, serving the hospital’s approximately 3,000 employees and their families, as well as providing first-fill prescriptions for patients about to be discharged. “We had two primary goals,” said Dennis Killian, PharmD, PRMC’s director of pharmacy. “We wanted to improve continuity of care for our patients, and combat rising prescription drug benefit costs.” PRMC is one of a growing number of hospitals and health systems that are providing on-site outpatient pharma-

cies for their employees and patients, according to Ernest R. Anderson Jr., MS, FASHP, a pharmacy consultant who helped establish an outpatient pharmacy serving employees and families as vice president of system pharmacy for Steward Health Care, an 11-hospital system with corporate offices in Boston, Mr. Anderson now guides other hospitals and hospital systems through the same process. “With most health systems now selfinsured, they [assume] the whole risk for the employee benefits program,” Mr. Anderson said. “So it makes a lot of sense for them to keep that program internally rather than to have their employees fill their scripts at Walgreens or CVS or wherever. They’ll pay the cost of the drug rather than a marked-up fee. It’s a big savings to the hospital or health system.” How big? Hospitals can typically save between 8% and 12% simply on the “buy side” when they establish their own outpatient pharmacy, according to Gregory Shaeffer, MBA, RPh, FASHP, the vice

‘When PBMs indicate that they would renegotiate reimbursement rates if the hospital had an on-site outpatient pharmacy, that can be eye-opening!’ —Gregory Shaeffer, MBA, RPh, FASHP

president of consulting for AmerisourceBergen’s Pharmacy Healthcare Solutions (PHS), which helped PRMC establish its outpatient pharmacy. “That’s the difference between contract pricing in an acute care marketplace versus the retail marketplace,” Mr. Shaeffer said. “And if you have employees who meet the 340B criteria and you are a covered entity, that savings can be double the 8% to 12%. The most expensive place a hospital employee can get a prescription filled is anywhere but their hospital pharmacy, if the hospital has one.” Capturing employee and family pre-

scriptions through an onsite pharmacy also helps decrease utilization, Mr. Shaeffer noted. “Hospital employees are high utilizers of medications,” he explained. “They are knowledgeable consumers and have access to medical staff, and they know about the latest and greatest drug therapies—which may or may not be appropriate for them. That definitely drives up cost and utilization. An in-house [outpatient] pharmacy allows you to trace and track employee utilization in a more channeled and controlled environment, see OUTPATIENT, page 35

POLICY

Reimbursement Matters

IPPS in 2016 continued from page 25

newer medical devices being tested in clinical trials). Section X will also assist in identifying and tracking new technologies and related inpatient services for add-ons. More information is available on CMS’ website at http://goo.gl/k4pLdh. 2. Denied extension requests for existing drug-specific add-on technologies: • Glucarpidase (Voraxaze, BTG) treats toxic methotrexate concentrations as a result of renal impairment; • Zilver PTX Drug Eluting Peripheral Stent (Cook Medical), used in the treatment of peripheral artery disease (PAD) affecting above– the-knee femoropopliteal arteries (superficial femoral arteries). 3. Successful requests for continuing drug-specific existing add-on technologies: • Kcentra (CSL Behring), a prothrombin complex concentrate replace-

ment therapy for fresh frozen plasma for patients with an acquired coagulation factor deficiency due to warfarin and who are experiencing a severe bleed (ICD-10 code: 30283B1). 4. New drug-specific applications for FY 2016: • Blincyto (blinatumomab, Amgen), a bispecific T-cell engager used for the treatment of Philadelphia chromosome–negative relapsed or refractory B-cell precursor acute lymphoblastic leukemia; • Avycaz (ceftazidime-avibactam, Actavis) treats adults with complicated urinary tract infections, including pyelonephritis and complicated intraabdominal infections; • Cresemba (Isavuconazonium sulfate, Astellas), an IV and oral broad-spectrum antifungal used for the treatment of adults with severe invasive and life-threatening fungal infections, including invasive aspergillosis and mucormycosis; • Idarucizumab (Boehringer Ingel-

heim), a humanized fragment antigen-binding molecule that specifically binds to dabigatran etexilate (Pradaxa), the company’s oral direct thrombin inhibitor, to deactivate Pradaxa’s anticoagulant effect; • Lutonix (Bard) and IN.PACT Admiral (Medtronic), both of which are paclitaxel-coated percutaneous transluminal angioplasty balloon catheters and are used to reopen blocked or narrowed arteries in the thigh and knee caused by PAD. CMS Fact Sheets are available on the CMS website at http://goo.gl/jl5kkO, and the entire IPPS proposed rule as published in the Federal Register is at https://www.federalregister.gov/public-inspection.

Adding to Your E-library Last month, this column introduced the concept of maintaining an e-library of important documents and references that you’ll need to structure your reimbursement systems and fall back on

when defending decisions or answering questions. This month’s suggestion is the wealth of information available from the Agency for Healthcare Research and Quality (AHRQ). When starting a new project or revamping one that needs some tweaking, take advantage of the work the agency has already done. It’s easy to put yourself on their email update distribution list at https://goo.gl/Q5Jvel. You can even watch their new YouTube videos (box) or use them to stimulate discussion with your staff (see box for their latest announcement). ■

More on Web To access the AHRQ’s YouTube channel featuring patient safety videos, visit pharmacypracticenews. com/AHRQ or scan the adjacent QR code.

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To place your order, call your wholesaler or distributor today. Please see brief summary of prescribing information on adjacent page.

12226

BRIEF SUMMARY OF PRESCRIBING INFORMATION Argatroban Injection in 0.9% Sodium Chloride, for intravenous infusion only 250 mg argatroban in 250 mL sodium chloride solution (1 mg/mL) SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Heparin-Induced Thrombocytopenia Argatroban Injection is indicated for prophylaxis or treatment of thrombosis in adult patients with heparin-induced thrombocytopenia (HIT). 1.2 Percutaneous Coronary Intervention Argatroban Injection is indicated as an anticoagulant in adult patients with or at risk for HIT undergoing percutaneous coronary intervention (PCI). 4 CONTRAINDICATIONS Argatroban is contraindicated in: • Patients with major bleeding, • Patients with a history of hypersensitivity to argatroban. Airway, skin, and generalized hypersensitivity reactions have been reported [see Adverse Reactions (6.4)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Hemorrhage Hemorrhage can occur at any site in the body in patients receiving argatroban. An unexplained fall in hematocrit or hemoglobin or a fall in blood pressure should lead to consideration of a hemorrhagic event. Argatroban Injection should be used with extreme caution in disease states and other circumstances in which there is an increased danger of hemorrhage. These include severe hypertension; immediately following lumbar puncture; spinal anesthesia; major surgery, especially involving the brain, spinal cord, or eye; hematologic conditions associated with increased bleeding tendencies such as congenital or acquired bleeding disorders and gastrointestinal lesions such as ulcerations. Concomitant use of argatroban with antiplatelet agents, thrombolytics, and other anticoagulants may increase the risk of bleeding. 5.2 Use in Hepatic Impairment Use caution when administering argatroban to patients with hepatic impairment by starting with a lower dose and carefully titrating until the desired level of anticoagulation is achieved. Upon cessation of argatroban infusion in the hepatically impaired patient, full reversal of anticoagulant effects may require longer than 4 hours due to decreased clearance and increased elimination half-life of argatroban. Use of argatroban in PCI patients with clinically significant hepatic disease or AST/ALT levels * 3 times the upper limit of normal should be avoided. 5.3 Laboratory Tests Anticoagulation effects associated with argatroban infusion at doses up to 40 mcg/kg/min correlate with increases of the activated partial thromboplastin time (aPTT). Although other global clot-based tests including prothrombin time (PT), the International Normalized Ratio (INR), and thrombin time (TT) are affected by argatroban, the therapeutic ranges for these tests have not been identified for argatroban therapy. In clinical trials in PCI, the activated clotting time (ACT) was used for monitoring argatroban anticoagulant activity during the procedure. The concomitant use of argatroban and warfarin results in prolongation of the PT and INR beyond that produced by warfarin alone. 6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse event rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.1 Adverse Events in Patients with HIT (With or Without Thrombosis) The following safety information is based on all 568 patients treated with argatroban in Study 1 and Study 2. The safety profile of the patients from these studies is compared with that of 193 historical controls in which the adverse events were collected retrospectively. Adverse events are separated into hemorrhagic and non-hemorrhagic events. Major bleeding was defined as bleeding that was overt and associated with a hemoglobin decrease * 2 g/dL, that led to a transfusion of * 2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. Minor bleeding was overt bleeding that did not meet the criteria for major bleeding. Table 4 gives an overview of the most frequently observed hemorrhagic events, presented separately by major and minor bleeding, sorted by decreasing occurrence among argatroban-treated patients with HIT (with or without thrombosis). Table 4. Major and Minor Hemorrhagic Adverse Events in Patients With HIT*

Major Hemorrhagic Eventsa Argatroban-Treated Patients Historical (Study 1 and Study 2) Controlc (n = 568) (n = 193) % % 5.3 6.7

Overall bleeding Gastro2.3 1.6 intestinal Genitourinary 0.9 0.5 and hematuria Decrease in 0.7 0 hemoglobin and hematocrit Multisystem 0.5 1 hemorrhage and DIC Limb and 0.5 0 BKA stump 0.5 Intracranial 0b hemorrhage Minor Hemorrhagic Eventsa Argatroban-Treated Patients Historical (Study 1 and Study 2) Controlc (n = 568) (n = 193) % % Gastro14.4 18.1 intestinal Genitourinary 11.6 0.8 and hematuria Decrease in 10.4 0 hemoglobin and hematocrit Groin 5.4 3.1 Hemoptysis 2.9 0.8 Brachial 2.4 0.8 *with or without thrombosis a Patients may have experienced more than 1 adverse event. b One patient experienced intracranial hemorrhage 4 days after discontinuation of argatroban and following therapy with urokinase and oral anticoagulation. c The historical control group consisted of patients with a clinical diagnosis of HIT (with or without thrombosis) that were considered eligible by an independent medical panel. DIC = disseminated intravascular coagulation. BKA = below-the-knee amputation. Table 5 gives an overview of the most frequently observed non-hemorrhagic events sorted by decreasing frequency of occurrence (* 2%) among argatroban-treated HIT/HITTS patients. Table 5. Non-hemorrhagic Adverse Events in Patientsa With HITb Argatroban-Treated Patients Historical (Study 1 and Study 2) Controlc (n = 568) (n = 193) % % Dyspnea 8.1 8.8 Hypotension 7.2 2.6 Fever 6.9 2.1 Diarrhea 6.2 1.6 Sepsis 6 12.4 Cardiac arrest 5.8 3.1 Nausea 4.8 0.5 Ventricular 4.8 3.1 tachycardia Pain 4.6 3.1 Urinary tract 4.6 5.2 infection Vomiting 4.2 0 Infection 3.7 3.6 Pneumonia 3.3 9.3 Atrial 3 11.4 ﬁbrillation Coughing 2.8 1.6 Abnormal renal 2.8 4.7 function Abdominal pain 2.6 1.6 Cerebrovascular 2.3 4.1 disorder a Patients may have experienced more than 1 adverse event. b with or without thrombosis

The historical control group consisted of patients with a clinical diagnosis of HIT (with or without thrombosis) that were considered eligible by an independent medical panel. 6.2 Adverse Events in Patients with or at Risk for HIT Patients Undergoing PCI The following safety information is based on 91 patients initially treated with argatroban and 21 patients subsequently re-exposed to argatroban for a total of 112 PCIs with argatroban anticoagulation. Adverse events are separated into hemorrhagic (Table 6) and non-hemorrhagic (Table 7) events. Major bleeding was deﬁned as bleeding that was overt and associated with a hemoglobin decrease * 5 g/dL, that led to a transfusion of * 2 units, or that was intracranial, retroperitoneal, or into a major prosthetic joint. The rate of major bleeding events in patients treated with argatroban in the PCI trials was 1.8%. Table 6. Major and Minor Hemorrhagic Adverse Events in Patients With HIT Undergoing PCI Major Hemorrhagic Eventsa Argatroban-Treated Patients (n = 112)b % Retroperitoneal 0.9 Gastrointestinal 0.9 Intracranial 0 Minor Hemorrhagic Eventsa Argatroban-Treated Patients (n = 112)b % Groin 3.6 (bleeding or hematoma) Gastrointestinal 2.6 (includes hematemesis) Genitourinary 1.8 (includes hematuria) Minor Hemorrhagic Eventsa Argatroban-Treated Patients (n = 112)b % Decrease in hemoglobin 1.8 and/or hematocrit CABG 1.8 (coronary arteries) Access site 0.9 Hemoptysis 0.9 Other 0.9 a Patients may have experienced more than 1 adverse event. b 91 patients who underwent 112 interventions. CABG = coronary artery bypass graft. Table 7 gives an overview of the most frequently observed non-hemorrhagic events (> 2%), sorted by decreasing frequency of occurrence among argatroban-treated PCI patients. Table 7. Non-hemorrhagic Adverse Eventsa in Patients With HIT Patients Undergoing PCI Argatroban Proceduresa (n = 112)b % Chest pain 15.2 Hypotension 10.7 Back pain 8 Nausea 7.1 Vomiting 6.3 Headache 5.4 Bradycardia 4.5 Abdominal pain 3.6 Fever 3.6 Myocardial infarction 3.6 a Patients may have experienced more than 1 adverse event. b 91 patients who underwent 112 interventions. There were 22 serious adverse events in 17 PCI patients (19.6% in 112 interventions). Table 8 lists the serious adverse events occurring in argatrobantreated patients with or at risk for HIT undergoing PCI. Table 8. Serious Adverse Events in Patients With HIT Undergoing PCIa Argatroban Proceduresb Coded Term (n = 112) Myocardial infarction 4 (3.5%) Angina pectoris 2 (1.8%) Coronary thrombosis 2 (1.8%)

Myocardial ischemia 2 (1.8%) Occlusion coronary 2 (1.8%) Chest pain 1 (0.9%) Fever 1 (0.9%) Retroperitoneal 1 (0.9%) hemorrhage Aortic stenosis 1 (0.9%) Arterial thrombosis 1 (0.9%) Gastrointestinal (0.9%) hemorrhage Gastrointestinal 1 (0.9%) disorder (GERD) Cerebrovascular 1 (0.9%) disorder Lung edema 1 (0.9%) Vascular disorder 1 (0.9%) a Individual events may also have been reported elsewhere (see Tables 6 and 7). b 91 patients underwent 112 procedures. Some patients may have experienced more than 1 event. 6.3 Intracranial Bleeding in Other Populations Increased risks for intracranial bleeding have been observed in investigational studies of argatroban for other uses. In a study of patients with acute myocardial infarction receiving both argatroban and thrombolytic therapy (streptokinase or tissue plasminogen activator), the overall frequency of intracranial bleeding was 1% (8 out of 810 patients). Intracranial bleeding was not observed in 317 subjects or patients who did not receive concomitant thrombolysis [see Drug Interactions (7.4)]. The safety and effectiveness of argatroban for cardiac indications other than PCI in patients with HIT have not been established. Intracranial bleeding was also observed in a prospective, placebo-controlled study of argatroban in patients who had onset of acute stroke within 12 hours of study entry. Symptomatic intracranial hemorrhage was reported in 5 of 117 patients (4.3%) who received argatroban at 1 to 3 mcg/kg/min and in none of the 54 patients who received placebo. Asymptomatic intracranial hemorrhage occurred in 5 (4.3%) and 2 (3.7%) of the patients, respectively. 6.4 Allergic Reactions One hundred ﬁfty-six allergic reactions or suspected allergic reactions were observed in 1,127 individuals who were treated with argatroban in clinical pharmacology studies or for various clinical indications. About 95% (148/156) of these reactions occurred in patients who concomitantly received thrombolytic therapy (e.g., streptokinase) or contrast media. Allergic reactions or suspected allergic reactions in populations other than patients with HIT (with or without thrombosis) include (in descending order of frequency): • Airway reactions (coughing, dyspnea): 10% or more • Skin reactions (rash, bullous eruption): 1 to < 10% • General reactions (vasodilation): 1 to 10% Limited data are available on the potential formation of drug-related antibodies. Plasma from 12 healthy volunteers treated with argatroban over 6 days showed no evidence of neutralizing antibodies. No loss of anticoagulant activity was noted with repeated administration of argatroban to more than 40 patients. 7 DRUG INTERACTIONS 7.1 Heparin If argatroban is to be initiated after cessation of heparin therapy, allow sufﬁcient time for heparin’s effect on the aPTT to decrease prior to initiation of argatroban therapy. 7.2 Oral Anticoagulant Agents Pharmacokinetic drug-drug interactions between argatroban and warfarin (7.5 mg single oral dose) have not been demonstrated. However, the concomitant use of argatroban and warfarin (5 to 7.5 mg initial oral dose, followed by 2.5 to 6 mg/day orally for 6 to 10 days) results in prolongation of the prothrombin time (PT) and International Normalized Ratio (INR). 7.3 Aspirin/Acetaminophen No drug-drug interactions have been demonstrated between argatroban and concomitantly administered aspirin or acetaminophen. 7.4 Thrombolytic Agents The safety and effectiveness of argatroban with thrombolytic agents have not been established [see Adverse Reactions (6.3)]. 7.5 Glycoprotein IIb/IIIa Antagonists The safety and effectiveness of argatroban with glycoprotein IIb/IIIa antagonists have not been established. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B

continued

35 Operations & Management

Pharmacy Practice News • June 2015

Finance

OUTPATIENT continued from page 32

which also translates into better management of chronic therapies.”

A Good Fit for All? Can all hospitals benefit from an inhouse outpatient pharmacy? It generally depends on the number of employees, Mr. Anderson said, adding that if a facility is big enough to call itself a health system, it probably has enough employees to warrant investing in an outpatient pharmacy. “But if you have a 100-bed hospital and only about 300 employees, it may not be worth the investment, because it will take you longer to recoup the cost,” he said. “You have to decide—do you want to invest in an outpatient pharmacy or a new MRI machine?” In the middle, of course, are larger hospitals that aren’t quite the size of a health system. What’s the tipping point? Mr. Anderson advised health systems to gather data from their human resources department, analyze the annual costs of scripts filled and then estimate what an annual 8% to 12% savings on that cost will yield. Mr. Shaeffer said that PHS’ strategy for guiding a new hospital or health system through the process of opening an outpatient pharmacy has three preliminary phases: 1) A detailed economic assessment to determine the potential profitability of the pharmacy; 2) Design of a business and project plan; and 3) Implementation—from getting the goahead to the pharmacy’s opening day. “On the short side, that [implementation] can take six months, but more reasonably, it’s about nine to 12 months,

The outpatient pharmacy at Peninsula Regional Medical Center, on Maryland’s Eastern Shore, has helped the health system boost revenue and employee satisfaction.

including getting the space, renovation, acquiring license and permits, selecting IT [information technology] and contracting with a PBM [pharmacy benefits manager],” Mr. Shaeffer said. “It required some pretty heavy lifting.” Dr. Killian can attest to that. “We already had a space designated for the outpatient pharmacy, so at least it wasn’t a total demo to get that ready,” he said. “Most of the costs were in the shelf work. Between that, and getting the computer systems in, the total cost was probably about half a million dollars. The software systems were a challenge because they are very difficult from a typical inpatient pharmacy. Relatively few hospital inpatient pharmacy computer systems could fill outpatient orders. On the inpatient side, when you’re processing orders on a daily basis and usually using automation to take medications from a Pyxis machine, that’s very different than giving a patient a 30-day or 90-day supply

There are no adequate and well-controlled studies of argatroban use in pregnant women. Developmental studies performed in rats with argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the maximum recommended human dose, based on body surface area) and in rabbits at intravenous doses up to 10.8 mg/kg/day (0.2 times the maximum recommended human dose, based on body surface area) have revealed no evidence of impaired fertility or harm to the fetus. Because animal reproductive studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers It is not known whether argatroban is excreted in human milk. Argatroban is detected in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from argatroban, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of argatroban, including the appropriate anticoagulation goals and duration of therapy, have not been established among pediatric patients. 8.5 Geriatric Use Of the total number of subjects (1340) in clinical studies of argatroban, 35% were 65 and over.

in a prescription bottle.” The licensure process added another hurdle. “Our facility was already in the middle part of 2013, but we had to wait to open until we could get all the approvals done—inspections, state-controlled drug licenses, the federal DEA [Drug Enforcement Administration],” Dr. Killian said. “And it’s all sequential—you can’t do these processes simultaneously. I knew it would take a long time, but I didn’t know it was going to be that long!”

PBM Partnership Is Key A key element for the new hospital outpatient pharmacy is selecting the right PBM partner. Indeed, Mr. Shaeffer said, many hospitals are reluctant to make changes and open an outpatient pharmacy for their employees because of longstanding relationships with their current PBM. “They don’t want to disrupt the employee population by changing plans. But when PBMs indicate that they would renegotiate reimbursement rates if the

In the clinical studies of adult patients with HIT (with or without thrombosis), the effectiveness of argatroban was not affected by age. No trends were observed across age groups for both aPTT and the ACT. The safety analysis did suggest that older patients tended to have an increased incidence of events compared to younger patients; however, older patients had increased underlying conditions, which may predispose them to events. The studies were not sized appropriately to detect differences in safety between age groups. 8.6 Hepatic Impairment Dose reduction and careful titration are required when administering argatroban to patients with hepatic impairment. Reversal of anticoagulation effect may be prolonged in this population [see Warning and Precautions (5.2)]. Manufactured In Hungary By: Teva Pharmaceutical Works Ltd. Hungary H-2100 Gödöllö Táncsics M. út 82 Hungary Manufactured For: TEVA PHARMACEUTICALS USA, INC North Wales, PA 19454 Brief summary based on Prescribing Information Iss. 11/2014

hospital had an on-site outpatient pharmacy, that can be eye-opening!” PRMC began negotiations with a handful of PBMs in mid-2013, in anticipation of the new benefit year beginning in January 2014. “We wanted to realign our PBM strategy to really drive business to the ambulatory pharmacy,” Dr. Killian said. “Under bigger PBMs, they want a mail-order business, and we knew from our employee surveys that mail order was a [negative] for our employees and dependents. Doing away with mail order and having the pharmacy in-house was a staff satisfier.” Then came discussion of benefit structure strategy. Would PRMC incentivize employees and their families to come to the pharmacy by reducing copays, or “deincentivize” going outside by increasing those copays? Ultimately, the medical center chose to keep its previous copay structure if beneficiaries used its pharmacy, while doubling copays for prescriptions filled elsewhere. So copays at its ambulatory pharmacy remained $10 for generic drugs, $20 for brand-name drugs and $50 for non-formulary drugs—and $20, $40 and $100, respectively, at outside pharmacies. “Some pharmacy benefit designs will require employee and dependents to use their in-house pharmacy, but that is not the message we want to send,” Dr. Killian said. Mr. Anderson took a similar approach at Steward. “We had a system where if you filled the prescription at our pharmacy, you got a three-month supply for one month’s copay,” he said. “But after I left, they implemented a mandatory program for all employees—all maintenance medications had to be filled there.” Rather than building multiple pharmacies in the same system, a health system could set up its own mail-order pharmacy, Mr. Anderson added. “That is what we did at Steward and what I have seen others do. When you do that, it may only be for employee maintenance medications and not for first fills.” Only 18 months after opening, PRMC’s outpatient pharmacy has been so successful that the medical center is now in the process of launching two additional full outpatient retail operations, approximately 30 minutes from the hospital in two different directions. One is slated to open in June and the other in August. “I don’t know why a facility would not opt to set this up both for their employees and dependents, and for patients,” Dr. Killian said. “There of course is a certain break-even point depending on facility size, but I would definitely say that any institutions our size or bigger should consider this.” —Gina Shaw None of the sources reported any relevant ﬁnancial conﬂicts of interest.

36 Spotlight on Technology

DRUG LIBRARIES continued from page 1

and industry partners to develop and promote solutions that improve infusion therapy–related patient outcomes. Steps such as these enabled Western Maryland Health System, in Cumberland, to achieve 100% drug library compliance, said Christine Ruhl, BSN, MBA, the medical center’s director of critical care services.

Pharmacy Practice News • June 2015

errors. “If you can make it impactful to the staff, they’ll be more likely to follow through and remember” to comply.

Wireless Pumps Create Better Compliance At the University of North Carolina (UNC) Hospitals, an 803-bed academic medical center in Chapel Hill, implementing wireless pumps led to a 97% drug library compliance rate since mid-2013, according to Ashley Pappas,

‘We had to teach staff that basic infusion was not acceptable, and if they used basic infusion, they needed to tell us why, like if a drug was not in the library.’ —Jacquelyn McClary, PharmD, BCPS The hospital installed more than 400 IV smart pumps (BBraun Outlook ES) throughout the system in 2011. Pharmacists, physicians and bedside nurses worked together to develop the drug libraries. They added doublechecks to high-risk medications such as insulin and heparin, and instituted soft-max and hard-max limits to help prevent errors. Next, they established a target of 95% compliance with metrics such as dose rate and correct location of the pump. Six weeks later, they had achieved a compliance rate that ranged between 49% and 93% among patient units. Studying clinician responses to alerts, including some overrides and corrections, the project leaders kicked things up a notch. With support from hospital and nursing leadership, they communicated “good catches” and averted errors to staff to promote buy-in, distributed a newsletter discussing errors related to smart pumps, conducted weekly audits and directly observed nurses in action to document compliance and identify barriers. By July 2012, drug library compliance with all metrics reached 100%. “It is a challenge to maintain that [high rate],” Ms. Ruhl said, noting that she and her colleagues have ongoing processes in place, such as monthly audits of all inpatient units, real-time feedback to staff, regular data reports to nurse managers, and continuing education for new staff and for any issues with new medications. Using monitoring tools from the pump manufacturer, they can track the number of alerts coming from any one unit, which is shared with nurse managers. Not only is it important to have the right champions involved in developing drug libraries, but it also is imperative to have strong leadership support at the C-suite level, Ms. Ruhl pointed out. In addition, she said, keep communication with staff ongoing, and bring them realtime mentions of averted medication

PharmD, BCPS, a clinical assistant professor at the UNC Eshelman School of Pharmacy. The hospital had been using one pump vendor for several years, but when it was time to renew in 2013, hospital leaders wanted a change, Dr. Pappas said. The pumps that the hospital was using, which were not wireless,

had some recalls. Additionally, clinicians needed to manually press a pump screen key to opt in to the drug library, so it was easy for nurses to program infusions without it. Partly as a result of these issues, drug library compliance was only 17%. Furthermore, staff only updated the libraries twice a year because the process was cumbersome; all 2,000 pumps had to be collected and transported to an update area, where the new library would be manually transferred to each pump and activated, and then returned to patient floors. The hospital formed a multidisciplinary group representing pharmacy, nursing and anesthesiology to search for a new pump and an easier process to program and update drug libraries. They brought in three vendors and let nurses examine sample pumps, and spent multiple days developing a drug library with nurses, asking what drugs they use, what doses and what medications were missing from the existing library. The newer pumps (SIGMA Spectrum Infusion System, Baxter), installed in March 2013, are wireless and automatically default to the drug library, Dr.

Pappas said. Library updates, which happen once a month, are automatically delivered to and activated by all pumps. If a pump is in use, it stores the updated drug library and activates it after the current infusion is completed and cleared. Even pumps not in use but plugged in will power on periodically, search for and load any drug library update on the wireless network. The overall compliance goal was 95% within three months of going live, Dr. Pappas said, but they exceeded that, hitting 97% compliance. The percentage has stayed around that target. Continuous data tracking allows the committee to evaluate compliance across care areas, and to easily identify areas where improvements can be made. “Ensure it’s a collaborative process,” she advised. “Nursing should be involved in which pump to purchase and through the build of the library, because they’re the end users.” The group is now looking at developing best practices for infusion pump use, including what to do when a soft or hard limit fires and when it is appropriate to bypass alerts, she said.

An Online Forum for Pump Improvement

ant more inspiration to improve drug library compliance? Try an evidence-based community forum. Since 2010, Purdue University’s Regenstrief Center for Healthcare Engineering has run Information Pump Informatics, an evidence-based online resource for clinicians who use smart pumps manufactured by Implemented CareFusion, Hospira and Baxter. There project to improve is no fee for the service, but members, compliance invited by word of mouth, are asked to share their infusion pump compliance data with the group. By logging on to a website called CatalyzeCare, members can promote best practices for alert management and drug library compliance management, and compare their performance against others. There are currently 20 hospital systems onboard, representing a total of 65 hospitals in Indiana, Iowa, Kentucky, Michigan, Nebraska, Utah and Wisconsin, said Richard Zink, MBA, CatalyzeCare development and implementation manager, speaking at the National Coalition for Infusion Therapy Safety meeting. “We try to give them the tools they need to make better decisions,” he said. A community hospital in northeastern Indiana, noting that its compliance was below others in the group, was inspired to implement a project to improve, Mr. Zink said. Its compliance increased from 78% in March 2014 to 98% in August 2014 (top Figure). “Call it what you want—‘peer pressure’ or the ‘power of community’—but it works,” Mr. Zink said. A second group created in March, called Drug Limit Library Compliance for Smart Pumps, is open to anyone and serves as a collaborative space to share information related to the appropriate use of smart pump drug limit libraries (bottom Figure). For more information, go to catalyzecare.org. —K.B.

Spotlight on Technology 37

Pharmacy Practice News • June 2015

How To Make Smart Pump Alarms More Discerning Annapolis, Md.—Taking a few extra seconds to slowly prime the IV and warming refrigerated medications to room temperature before infusing are just two of several strategies that hospitals can use to reduce the number of infusion pump alarms, according to an industry expert. With infusion pumps increasingly connected to wireless networks, it’s now possible to collect and analyze the types of alarms seen in hospital units, said Tim Vanderveen, PharmD, vice president of CareFusion’s Center for Safety and Clinical Excellence, in San Diego, and a member of the Association for the Advancement of Medical Instrumentation’s (AAMI) board of directors. He spoke March 12 at a kick-off meeting for the National Coalition for Infusion Therapy Safety, an initiative by the AAMI Foundation and industry partners to develop and promote solutions that improve infusion therapy–related patient outcomes. Evaluating data collected by the company’s Alaris pumps, Dr. Vanderveen said one of the most frequent alarms is known as a below-the-pump, or downstream, occlusion. “Catheters are frequently placed in the patient’s elbow or wrist, and when they eat, comb their hair, brush their teeth or just move their arm, if they kink that catheter, there can be a very quick alarm that says this medication is not going in because the pump senses it has an occlusion,” he explained. These alarms most frequently occur in adults in medical-surgical

units or ICUs, he noted. Nurses know about these alarms, Dr. Vanderveen added, but often an emergency medical technician or emergency department staffer places the catheter in a patient’s elbow “because it’s easy,” and many hospitals have a policy that if a patient is admitted, the IV site does not need to be changed for the first 24 hours. Adding to the problem, boards to keep arms straight are used infrequently. In addition, drugs such as albumin and amiodarone, if not handled properly, can cause the pumps to alarm for air, he said. “Typically, these are drugs that have certain ingredients that make them foam or frothy,” he said, and like a cold soda that warms and forms bubbles, the medication can do so in the IV tubing, tripping the pump’s air detector to sound an alarm.

reduction in air alarms. Overall, alarms decreased from 1.26 to 0.34 per infusion. The study results, which are still being analyzed, will be presented at AAMI’s annual conference in June. “Nurses were saying they didn’t think

Nurses’ Attitudes Key CareFusion sponsored a study at Palomar Health in Escondido, Calif., to study nurses’ attitudes about alarms and reduce the number of alarms. The work, directed by LaQuoia Johnson, PharmD, a health system pharmacy administrative resident, and Diana Schultz, MHSA, manager of medication safety, found that most alarms occurred within the first five minutes of setting up the pumps. Investigators surveyed nurses about the most frequent cause of alarms and how many alarms sounded per shift, while CareFusion staff pulled alert data from the pumps, observed nurses in action and looked at drug storage in the hospital pharmacy.

Staff Retraining Smart pumps were first introduced at Cleveland’s 244-bed Rainbow Babies and Children’s Hospital in 2009, but only the neonatal and pediatric ICUs had active drug libraries, so the remaining units used the pumps mostly for basic infusion, said Jacquelyn McClary, PharmD, BCPS, a clinical pharmacist specialist at the hospital. “There was no logic behind it,” she said. “Most nurses used them just as they did the old pumps.” By October 2011, a more extensive pediatrics library was built, but it still was used infrequently. Compliance rates hovered around 15% when a new pharmacy director arrived in early 2012 and made a push for better drug library compliance. The pharmacy team and others employed several tactics to change the work culture. “We had to teach staff that basic infusion was not acceptable, and if they used basic infusion, they needed to tell us why, like if a drug was not in the library,” Dr. McClary said.

A nursing consultant worked with some hospital nurses to revise the pump training, and re-educated staff nurses about proper setup and features of the pumps. Staff changed the pump settings to be less sensitive to arm movement,

Working with nurse educators, they retrained the staff on using the pumps (Alaris System, CareFusion), and instituted pharmacist-led compliance rounds to see what drugs were being used through the library versus basic infusion. This way, Dr. McClary said, they could have real-time discussion and feedback from the nurses. A few months later, they started pulling compliance reports from the smart pump vendor, which could identify which units were less compliant, and shared those data monthly with nursing leaders. This became a friendly competition, she said. In addition, they learned from nurses where gaps were in the libraries, and highlighted good catches to staff.

‘Nurses were saying they didn’t think they needed more education [on infusion pump alarms], but once they got it, they were believers.’ —Diana Schultz, MHSA and added an anti-siphon valve for medications such as lipids, total parenteral nutrition, immune globulins, amiodarone, albumin and etoposide to reduce air in the lines, resulting in a 300%

they needed more education, but once they got it, they were believers,” Ms. Schultz said. “Some nurses said it would be nice to turn down the alarm volume

These steps slowly turned things around. By June 2012, compliance had climbed to 61.5%, and by the end of 2013, to 80%. In January 2015, the hospital reached 91% overall compliance. Dr. McClary acknowledged that there are still some general pediatric units where certain nurses like using basic infusion; thus, quality improvement (QI) efforts are ongoing. But overall, she said she is pleased: “A lot of good catches have been made with continuous infusions in the ICUs. It makes it safer for patients. “Compliance rounds are completely necessary,” she added. “Getting out there and doing them, that’s the first step.”

he led to summarize recommendations, attendees discussed paying attention to drug library adherence over time. “It’s not a fire-and-forget-it thing, where you set it up once and don’t look at it again,” Mr. Schneider said. The original drug library may not be perfect, and the ways hospitals use libraries can change over time. Thus, a periodic improvement process should be built into ongoing smart pump maintenance and QI efforts. Some smart pump vendors can produce reports for hospitals and offer monitoring services. Furthermore, Mr. Schneider said, think of the extent to which you are getting compliance. If pumps aren’t networked to your electronic records, he said, “it’s really hard to see how well your libraries are performing.”

Don’t Underestimate Workload Dennis Schneider, chief marketing officer of OnPoint Marketing, in Nashua, N.H., told Pharmacy Practice News that “it’s pretty common for people to massively underestimate how much work is involved” in maintaining drug library compliance. In a breakout group

see SMARTER ALARMS, page 41

—Karen Blum Dr. Pappas received an honorarium from Baxter Healthcare for her presentation. None of the other sources reported any relevant ﬁnancial conﬂicts of interest.

38 Spotlight on Technology

Pharmacy Practice News • June 2015

Hi-Tech Solutions for Thwarting Drug Diversion D

rug diversion in the nation’s hospitals remains a frustratingly stubborn operational challenge. Part of the problem is the frequency of drug abuse. In the general population, such abuse runs around 5%. But experts suggest the figure is likely higher for health care workers, simply due to convenient access to the drugs. And once diversion starts to take hold, the fallout can be severe: hospital staffers diverting patient pain medications for their own use have been linked to six infectious disease outbreaks over the past decade ((Mayo Clin Proc 2014;89[7]:878-887). Although not a “magic bullet,” automated dispensing cabinets are a good starting point for deterring drug diversion, said Allison Cannon, MS, PharmD, a manager of controlled drugs and surgical services with the Cleveland Clinic pharmacy in Ohio. The following discusses offerings by a selection of technology vendors that help hospitals halt or limit drug diversion.

Parata Systems, Durham, N.C. (888-989-7822) The Parata Max and Parata Mini highspeed automated dispensers have five different authorized access levels. With Parata’s optional patented locking cells, users can load only one cell at a time, and all drug cells remain in the dispensers during the loading process. These cells open for replenishment only when an authorized user’s barcode matches a stock bottle’s national drug code to a cell; they lock automatically when closed, and stay locked if ever removed from the Parata Max or Mini units. Because the locking cells restrict access and track user transactions as they occur, the dispensers can record employee ID, plus the date, time and activity details in an easily auditable format. Parata launched its Controlled Medication Kit after the DEA recently reclassified all hydrocodone combination products (HCPs) as Schedule II. Pharmacies using the kit with Parata Max and Mini dispensers can fulfill HCPs as an automated process, while using its software and locking cells to tighten security and limit diversion. A pharmacy manager can decide who can replenish controlled substances and assign access accordingly. Marcus Kennedy, Parata’s senior director of product development, said because hospitals face stricter regulations and increasing exposure and accountability for diversion-related incidents, the company will soon release a package that prevents cells from ever being physically removed from the units. Strip packaging could be another deterrent and used instead of blister packs or medication cups to administer doses,

Mr. Kennedy added. The Parata PASS 208 and PASS 500 Packagers automate preparation of unit- and multidose strip packages, to organize prescription and over-the-counter oral solids by day and time of dose in clear, plastic pouches that can be customized to include barcodes. Nurses scan these codes at the patient bedside to link medication administration activity to the patient’s electronic medical record. Also, the packaging itself quickly reveals whether a scheduled dose is missing or tampering occurred.

Omnicell’s Controlled Substance Management System provides closedloop accountability of narcotic move-

Omnicell Inc., Mountain View, Calif. (800-850-6664) Omnicell’s Pandora analytics software extracts key data from a hospital’s medication and supply dispensing systems, which pharmacy managers see on interactive dashboards. Dashboards identify suspicious activity by tracking override activities, discrepancies, and null or cancelled transactions. An anomalous usage widget lets managers quickly drill down to individual staff members. “At-a-glance views of key metrics and trends [make it] faster for managers to detect diversion than automated dispensing cabinet [ADC] reports,” said Kristin Russel, Omnicell’s senior director of product marketing and development. “Managers can review data beyond the nursing units—in operating rooms [ORs] and procedural areas, for example—all places where diversion can occur.” The optional OmniDispenser singledose dispensing module stores medications in a separate, secured location within the ADC and dispenses each dose individually, similar to a vending machine. Because nurses can access only the specified quantities, controlled substances and high-value medications are more secure, diversion is impeded, and hospitals can better comply with Joint Commission and other regulatory standards. A locking lid drawer within the ADC restricts access to one preselected medication at a time. Tamper-proof steel lids help to prevent “shopping around” by clinicians, she added. Security features enable pharmacy personnel to monitor clinician behaviors during the login/access process. The system emits audible alarms, on-screen messages and e-messages to the pharmacy department if someone attempts incorrect bin access. These alerts also conform to Joint Commission and other regulatory standards.

ment from medical distributors to pharmacy and patient care areas, and back to pharmacy. It manages perpetual inventory and chain of custody in real time, automates audit trails, reports anomalies in medication distribution and helps to resolve discrepancies quickly. The system also provides documentation for federal and state compliance. The automated anesthesia workstation securely stores all medications and supplies needed for a full day of cases in an OR in one place. It secures controlled substances 24/7, requires biometric access and automates reconciliation of controlled substances. It also tracks inventory usage and expiration dates, and reports in multiple formats for regulatory inspections.

CareFusion Corp., San Diego, Calif. (888-876-4287) The CareFusion CUBIE and Minidrawer pocket types for Pyxis cabinets restrict nurse access to one type or one dose of medication to enhance security of high-risk, high-alert drugs. Moreover, central pharmacies use the Pyxis CII Safe System to manage perpetual inventory of controlled drugs, explained David Swenson, RPh, the vice president of clinical strategy, medical systems for CareFusion Corp. Using the pharmacy’s existing network, it polls the individual MedStations in patient

care areas to determine refill quantities. An authorized technician then scans each package for accuracy and pulls the items from the CII Safe cabinet in the pharmacy for delivery to each MedStation cabinet, at which point the medications are scanned into inventory. The CII Safe is used in the same manner to refill Pyxis Anesthesia ES System cabinets in ORs and procedural areas. The cabinets hold most of the drugs that anesthesiologists require during surgery—and give pharmacists the visibility to control inventory and monitor for diversion. Since Pyxis integrates with information technology, users can manage user access via biometric sign-on privileges. The Anesthesia ES System has a special protected drawer for bulkier high-risk medications, and software that alerts to medication removal and e-documents waste and returns during workflow. The CareFusion diversion surveillance software lodges a “discrepancy” when the physical count of a controlled drug is found to differ from the software’s count. The software guides users through the process of reconciling this “discrepancy” between the user who found it and the most recent prior user to access that same pocket. Medacist RxAuditor software evaluates key metrics such as average numbers of controlled substance dispenses and discrepancies, medication overrides, waste and cancelled transactions, stock-outs, refills and inventory shrinkage. It identifies authorized users who dispense drugs beyond the parameters of all other users within a network.

Swisslog Healthcare Solutions, Denver, Colo. (800-764-0300) Swisslog integrates several technologies to track chain of custody and to help prevent diversion, according to Joni Kripal, the vice president of solutions management, Swisslog Healthcare Solutions. Among them: The Swisslog BoxPicker Automated Pharmacy Storage System is a robot that replaces static shelving, vertical carousels, refrigerated drug storage and narcotic vaults. It is a single dispensing and loading point—with password-protected access to a single box at a time, and secure, tamper-proof storing, dispensing and tracking of narcotics. It records all transactions, and when paired with an ADC interface, secures a closed loop to see SOLUTIONS, page 40

►

40 Spotlight on Technology

SOLUTIONS continued from page 38

track medications. It also supports an e-audit trail for medication administration at the bedside. The MedRover Mobile Dispensing Cabinet uniquely stores and tracks—from pharmacy to the patient bedside—narcotics, patient-specific medications and supplies in a single, compact mobile cart. Biometrics and locked drawers restrict access. MedRover e-audits the patient, nurse and administered medications

Pharmacy Practice News • June 2015

to support reconciliation. The cabinet releases narcotics only to a specific caregiver at the bedside, matched to the patient’s prescription, to prevent diversion during unsecured transport.

ScriptPro Mission, Kansas (800-606-7628) ScriptPro’s Robotic Prescription Dispensing Systems include several security features for ensuring that only approved staffers can access stored medications, according to Brian Glaves, the com-

pany’s sales director. As a standard hardware feature, Mr. Glaves noted, all ScriptPro systems have keyed, lockable cabinets. “The chief pharmacist can determine who has a key and thus control access,” he said. For an extra level of security, hospitals can opt to add electronic door locks, he noted. To access cabinets that are fitted with this feature, users can enter a unique four-digit PIN code or scan a bar code on their badge, which immediately unlocks the cabinet doors. After a configurable length of time, the doors auto-

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matically relock once they are closed. For drugs that require an added level of control, hospitals can add a locking cell column that restricts access to up to 25 medications. “This feature acts as a subcolumn positioned in front of those 25 items to prevent removal by a technician or clerk who does not have the proper authorization,” Mr. Glaves explained. “Any security feature can be retrofitted to any of our SP line of robots, from our first one in 1997 to the ones we are building today at our facilities,” he added. Regardless of hardware options, all systems include robust tracking services as a standard feature, Mr. Glaves stressed. “Everything that goes into the system is scanned in, scanned out and can be tracked to the person who accesses the drug cabinet,” he said. “That way, if a pharmacist catches a user error—a cabinet cell that was refilled incorrectly, for example—a supervisor can go back and pinpoint who made the error, and when— in some cases down to the second.” Such pinpoint tracking, he noted, “gives you the ability to go to that person and provide corrective action and document the incident.” Moreover, “you can go back to patients who are at risk for being adversely affected by the stocking error and take appropriate action.” Certain ScriptPro robots offer additional security features. The company’s SP 50 Robotic Dispensing System, for example, has a relatively small footprint and thus is suitable for use in narcotics vaults. Like other ScriptPro systems, to control access to drug stocks, operators must enter an electronic PIN or scan a unique ID badge, which helps facilitate prescription verification, drug cell replenishment and other tasks. Managers can generate detailed reports on staff utilization as a further security tool. —Al Heller

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Spotlight on Technology 41

Pharmacy Practice News • June 2015

medical-surgical units than in the ICU, where patients can be on 16 pumps,” Dr. Blake said. The relationship between pump manufacturers and clinicians should be a “true partnership,” she added. “Our goal is to have fewer alerts that require a clinician to be in the room.”

SMARTER ALARMS continued from page 37

at night, not realizing that already was a feature in our pumps.” “There really are some things that hospitals can do that are very low-tech that could have some very quick, positive impacts on the experience that both nurses and patients/family members have,” said Dr. Vanderveen, who offered several tips to help reduce alarms: • Prime IV tubing slowly to prevent air from getting in. Closing the roller damp before priming and filling the drip chamber two-thirds full keeps air from entering the IV tubing. • Do not “burp” the air from IV bags, as this can lead to significant air in the tubing arising from air in the drip chamber. • Pause infusions before changing IV containers; turning the IV spike upside down allows air to enter the set. • Certain refrigerated infusions will release gas as they warm up; warm fluids to room temperature when possible. • Consider arm boards, catheter placement or limited motion dressings to reduce catheter kinking and occlusion alarms. • If transport attendants or physical therapists bring patients back to their rooms, have them plug in the pumps to avoid low battery alarms. • Turn down alarm volume at night. • Evaluate the need for certain alerts, such as those that occur near the end of infusion. Physicians and patients frequently ask why alarms must ring at the bedside, Dr. Vanderveen said. That feature is currently required by the FDA for device approval. “They’re not going to stop alarming at the bedside, but they could pre-alarm and tell the nurse that an infusion is going to finish in 10 minutes, or other information to better prioritize their work,” he noted. “Distributing pump alarms directly to the patient’s nurse is a goal, but it requires associating the pump to the patient and the nurse, and this is rarely accomplished today.”

—Karen Blum Dr. Vanderveen is an employee of CareFusion. None of the other sources reported any relevant ﬁnancial conﬂicts of interest.

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Pharmacy Practice News • June 2015

Software Helps Guide a Hospital in Reducing Readmissions

t Kishwaukee Hospital, part of the KishHealth System in DeKalb, Ill., the use of real-time clinical surveillance and data analysis software has helped cut the 30-day readmission rate by 50% in patients with congestive heart failure (CHF), pneumonia and acute myocardial infarction (AMI) over an 18-month period. To achieve these gains, care teams followed a streamlined process. The

continuity-of-care discharge planners received notification from the software to alert them to inpatients at risk for future readmissions. The clinical surveillance software runs twice a day and issues email and phone text alerts to the Continuity and Quality Departments about these patients—so they can collaboratively plan joint interventions/teaching sessions for the next morning’s rounds.

The most likely candidates for the surveillance program have Centers for Medicare & Medicaid Services (CMS) core measure ailments (such as pneumonia, CHF, AMI, or knee or hip replacement); have already been readmitted at least once; have abnormal laboratory results; or are postsurgery (to avoid infections and manage use of opioids). Interventions guided by software profiles occur on once-a-day, morning

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rounds with pharmacists, clinical lead nurses and the hospitalists who oversee patient care. The software’s automated alerts lead caregivers to richer interventions and timely care adjustments at the bedside. Each quality team nurse saves 30 minutes per day in labor because they are freed up to attend patient rounds during this process. They separately interview readmitted patients against the backdrop of their “previous diagnosis and discharge, psychosocial and financial implications, who the physicians were, and which readmits may have been prevented,” Diane Rapp, MBA, RHIA, CPHQ, CPPS, a quality data analyst for KishHealth System, told Pharmacy Practice News. Ms. Rapp’s data analysis from the care process, coupled with information gleaned during patient interviews and completed questionnaires, help determine best practices for patient care that can improve key outcomes. Among numerous process improvements are sharing more medication information at discharge, preventing medication errors and spotting adverse drug events. Those improvements also have the potential for yielding financial benefits as well, Ms. Rapp said, including savings that result from a lower risk for incurring CMS value-based purchasing penalties.

360-Degree Surveillance The Micromedex 360 Care Insights does the clinical surveillance and the CareDiscovery module analyzes the care process data. Using these systems, the 98-bed Kishwaukee Hospital slashed preventable readmissions by 50% and saved an estimated $24 per discharge or $127 per bed, according to information from Truven Health Analytics, the software provider. The study period lasted from the start of the third quarter 2012 through the end of the fourth quarter 2013. Kishwaukee data provided by Ms. Rapp in an interview showed the hospital’s overall readmission rate (for all patients, not just Medicare or Medicaid patients) rose from an initial 31% to 32%, then fell steadily to 25%, 21%, 18% and 15% in successive quarters as the staff’s sophistication and trust of the tool increased. Her review of more recent data demonstrated that readmissions for cardiac patients dropped in raw numbers from 38 in 2012 to 30 in 2014, and readmissions for patients with chronic obstructive pulmonary disease decreased from 40 in 2012 to 27 in 2014. The Truven software used by the hospital includes a separate core measure module that submits data automatically to CMS. All are compatible with

Spotlight on Technology 43

Pharmacy Practice News • June 2015

Kishwaukee’s Meditech mainframe and Meditech pharmacy management system. “Meditech tells us which patients to look at. We bring them up in Truven to see which profiles they come under to inform rounds participants about specific topics and intervention opportunities for each patient,” said Kristi Stice, PharmD, BCPS, the pharmacy clinical development coordinator at Kishwaukee Hospital. The KishHealth System also launched a CHF project in 2015, using the same clinical surveillance tool to identify patients with CHF in-house, so Kishwaukee and some of its other care sites could start qualifying them for outpatient cardiac rehabilitation. “Truven’s software solutions have incredible opportunity,” Dr. Stice said.

“The clinical data from CareDiscovery and Care Insights are powerful. Who can argue with data from your own system? We can look at everything from outcomes and costs to real-time clinical data to make sure we’re improving patients’ health through cost-effective therapies.”

Real-Time Clinical Data Deemed Crucial It is essential for the health care team to use real-time clinical data to identify inpatients at high risk for readmission, according to Cyndy Kowalski, RN,

Based on the findings, “mHealth continues to evolve as a tool to drive healthcare efficiencies,” said David Collins, the senior director of HIMSS mHealth Community. Like any new technology, cost can be a barrier to mHealth implementation. But according to the HIMSS survey, although 51% of respondents cited budget constraints as a roadblock, 54% indicated they had achieved cost savings as a result of overcoming those challenges and deploying the technology. Mobile technology–assisted interventions that yielded cost savings included preventative support care (24%), telehealth (23%) and resource utilization (21%). To download the complete HIMSS report, visit: http://www.himss.org/ 2015-mobile-survey. y —PPN Staff

patients with a propensity to be readmitted—and that giving pharmacists real-time information on the number and type of medications taken and allergies, creates openings to “educate patients and caregivers while they are still in the hospital.” —Al Heller Dr. Stice spoke once at a Truven conference, where the company covered hotel costs and waived the conference admission fee. None of the other sources reported any relevant ﬁnancial conﬂicts of interest.

IMPORTANT CORRECTION OF DRUG INFORMATION ABOUT EXPAREL® (BUPIVACAINE LIPOSOME INJECTABLE SUSPENSION)

Mobile Tech Gains Traction: HIMSS HIMSS released the results of its 2015 Mobile Technology Survey at the group’s Annual Conference and Exhibition in Chicago. This year’s study, of more than 200 health care provider employees, found that nearly 90% of respondents use mobile devices within their organizations to engage patients. Respondents reported using a variety of mobile “mHealth” tools, including app-enabled patient portals (73%), telehealth services (62%) and text communications (57%).

MPA, the manager of coding, accreditation and clinical services at Besler Consulting, in Princeton, N.J. “To collect and analyze data on comorbidities, sociodemographics and medication reconciliation provides a valuable opportunity to begin the discharge process at admission,” she said. “Prepared patients and caregivers have a lesser chance of readmission.” Ms. Kowalski, who authored the 2015 e-book, “Readmission Reduction” (http://goo.gl/sXmcxR), noted that polypharmacy is an indicator of

Pacira Pharmaceuticals, Inc., received a warning letter from the US Food and Drug Administration (FDA) Office of Prescription Drug Promotion (OPDP) on September 22, 2014 concerning an advertisement for EXPAREL, which you may have seen published in several professional journals. This publication provides important corrective information about the false and misleading claim. The FDA stated that the advertisement was false or misleading because it overstates the efficacy of EXPAREL. The FDA objected to the claims that EXPAREL provides pain control that lasts for up to 72 hours because the claims suggest that EXPAREL has been shown to provide pain control beyond 24 hours. According to the Prescribing Information, “The primary outcome measure was the AUC [area under the curve] of the NRS [numeric rating scale] pain score (cumulative pain scores) collected over the first 72 hour period.…In this clinical study, EXPAREL demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. The difference in mean pain intensity between treatment groups occurred only during the first 24 hours following study drug administration. Between 24 and 72 hours after study drug administration, there was minimal to no difference between EXPAREL and placebo treatments on mean pain intensity.” Excerpts from the applicable sections of the FDAapproved package insert for EXPAREL follow. The FDA has reviewed and approved this communication. Indication for EXPAREL EXPAREL is a liposome injection of bupivacaine, an amide-type local anesthetic, indicated for administration into the surgical site to produce postsurgical analgesia. EXPAREL has not been studied for use in patients younger than 18 years of age. Clinical Studies Hemorrhoidectomy The primary outcome measure was the AUC of the NRS pain intensity scores (cumulative pain scores) collected over the first 72 hour period. There was a significant treatment effect for EXPAREL compared to placebo. ©2015 Pacira Pharmaceuticals, Inc. Parsippany, NJ 07054 PP-EX-US-0623

2/15

In this clinical study, EXPAREL demonstrated a significant reduction in pain intensity compared to placebo for up to 24 hours. The difference in mean pain intensity between treatment groups occurred only during the first 24 hours following study drug administration. Between 24 and 72 hours after study drug administration, there was minimal to no difference between EXPAREL and placebo treatments on mean pain intensity; however, there was an attendant decrease in opioid consumption, the clinical benefit of which was not demonstrated. Important Safety Information EXPAREL is contraindicated in obstetrical paracervical block anesthesia. EXPAREL has not been studied for use in patients younger than 18 years of age. Non-bupivacaine-based local anesthetics, including lidocaine, may cause an immediate release of bupivacaine from EXPAREL if administered together locally. The administration of EXPAREL may follow the administration of lidocaine after a delay of 20 minutes or more. Other formulations of bupivacaine should not be administered within 96 hours following administration of EXPAREL. Monitoring of cardiovascular and neurological status, as well as vital signs should be performed during and after injection of EXPAREL as with other local anesthetic products. Because amide-type local anesthetics, such as bupivacaine, are metabolized by the liver, EXPAREL should be used cautiously in patients with hepatic disease. Patients with severe hepatic disease, because of their inability to metabolize local anesthetics normally, are at greater risk of developing toxic plasma concentrations. In clinical trials, the most common adverse reactions (incidence ≥10%) following EXPAREL administration were nausea, constipation, and vomiting. Reporting Adverse Events Heath care providers and patients are encouraged to report adverse events in patients taking EXPAREL to Pacira at 1-855-793-9727. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. Please see accompanying brief summary of Prescribing Information.

44 Spotlight on Technology

Pharmacy Practice News • June 2015

Surveillance Tool Helps Boost HCAHPS Scores

t Arkansas Methodist Medical Center (AMMC), in Paragould, rounding pharmacists use the clinical surveillance tool Micromedex Pharmacy Intervention (MPI) on iPads to help educate inpatients about their medications. The mobile app has improved the rural facility’s scores on the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. The tool replaced the hospital’s man-

ual process begun in the first quarter of 2013 to identify, target and educate inpatients on anticoagulants about their medications—without adding to the full-time equivalent payroll, according to Stan Carmack, PharmD, the director of pharmacy services at AMMC. Even today, AMMC is only partly on an electronic health record system. So without the tool, sifting through paper records for patient histories, laboratory values,

progress notes, prescribed medications and more while rounding would be too laborious and make it unfeasible to scale consultations to more patients, Dr. Carmack noted. AMMC has an average daily census of 70, and dispenses 38,000 inpatient scripts per quarter. MPI is part of the Micromedex 360 Care Insights suite. “We had looked at clinical surveillance tools when we saw MPI had a mobile application and the Micromedex Drug

Reference,” he said. “We went from ‘we can’t see these patients’ to setting a goal to see 50% of all inpatients per quarter who stayed longer than 24 hours.” AMMC surpassed its goal. Before the use of the MPI tool, 69.2% of inpatients said the hospital staff explained the reason for a new medication; by the end of a six-month review in the third quarter of 2013, that figure rose to 85.7%. Also, before MPI use, 53.8% of inpatients said possible side effects were explained to them; after six months, that figure increased to 67.3%. During 2014, “the only times our hospital scored 85% or above on the HCAHPS question, ‘When given a new medication, were you told what it was for,’ was when we were seeing 70% or more of our inpatients,” Dr. Carmack said. He set a goal to educate 90% of inpatients by May 2015. As of March 2015, “we’re five pharmacists here; we all participate on patient rounds; and we’re already hitting that mark,” he said. The pharmacy team set parameters “to target patients needing more attention—such as those on anticoagulants, who have atrial fibrillation, or take five or more medications a day,” he explained. MPI automates the process of identifying at-risk patients. It also alerts pharmacists to patients prescribed new medications; gives rounding pharmacists real-time, patient-specific data that inform consults; and has a form for pharmacists to enter consult notes on the spot. “MPI has reduced our patient-rounding preparation time by 75% to 80%. It also speeds our clinical work in IV-to-PO [oral] conversions and renal dosing, helps in antibiotic stewardship, and [aids] in creating patient profiles for our certified diabetes educators,” Dr. Carmack said. “We can also build unlimited monitoring profiles—such as for TPN [total parenteral nutrition] and electrolytes—without increasing pharmacist time, because it won’t show unless a result occurs. MPI has nearly doubled our clinical services, and paid for itself within the first year.”

A Help to Clinical Pharmacy Michele Higgins, PharmD, MBA, the pharmacy informatics coordinator at Nebraska Methodist Health System, in Omaha, concurred that “clinical surveillance tools can help streamline pharmacy workflows. Real-time alerts to changes in a patient’s labs … [lead to] timelier interventions, such as faster IVto-PO conversions or [earlier spotting of ] potential adverse drug reactions.” —Al Heller The sources reported no relevant ﬁnancial conﬂicts of interest. EXP-AP-0020-201301

Spotlight on Technology 45

Pharmacy Practice News • June 2015

Cyber Attacks Cost Health Care Industry $6 Billion

ata breaches in the health care industry could be costing $6 billion, according to a new report by the Ponemon Institute, which conducts independent research on privacy data protection and information security policy. More than 90% of health care organizations have experienced multiple security incidents and nearly all have faced a data breach, according to the 2015 annual report (http://goo.gl/nPQT0W). W Forty percent have had more than five data breaches in the past two years. These data breaches cost health care organizations an average of $2.1 million. Not only are hospitals and insurers at risk, the report said, but business associates—those that perform services for a health care organization—are also at risk, increasing the chances that an individual’s personal health information will be stolen. Breaches in health care have become the No. 1 target for criminals, where they can obtain not only personal health records, but also Social Security numbers and credit or banking information.

“Criminal attacks on health care organizations are up 125% compared with five years ago,” the report stated. “In fact, 45% of health care organizations said the root cause of the data breach was a criminal attack and 12% said it was due to a malicious insider. Business associates surveyed said that 39% are due to a criminal attack and 10% to a malicious insider. “Online technology has forever changed the world we live in. We’re online, in one form or another, all day long. Our phones and computers have become reflections of our personalities, our interests and our identities. With this online presence comes the need to protect our privacy and the security of our data,” Amy Hess, executive assistant director of Science and Technology Branch of the FBI said in testimony before the House Oversight and Government Reform Committee, Subcommittee on Information Technology on April 29. The FBI expects computer crimes aimed at stealing health information to continue to rise due to the federal man-

date that all records be transitioned from paper to electronic health records, lax security standards and a lucrative black market for medical records, according to an FBI notification released in 2014.

One Costly Break-In Just one attack—a 2014 data breach at the Community Health Systems, which operates 206 hospitals in 29 states— affected 4.5 million patients. The stolen data included patient names, addresses, birthdates, telephone numbers and Social Security numbers, although no credit card, medical or clinical information was taken. Because of the breach, patients filed several lawsuits against

the health system this year, claiming that the health system should have prevented the breach, and therefore should provide monetary compensation to its patient victims. The Department of Health and Human Services (HHS) tracks breaches of unsecured protected health information that affect 500 or more individuals. From Jan. 1, 2010 to Dec. 18, 2014, HHS reported 88 hacking-related breaches of health information. In that time, there were just more than 1,000 breaches overall, 741 of which occurred through a digital medium. “The reality is that cyber adversaries will exploit any vulnerability they find,” Ms. Hess testified. “But security risks are better addressed by developing solutions during the design phase of a specific product or service, rather than resorting to a patchwork solution when law enforcement presents the company with a court order after the product or service has been deployed.” —Marie Rosenthal

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46 Spotlight on Technology

Pharmacy Practice News • June 2015

Oncology Pharmacy Service Transforms Itself Anaheim, Calif.—When pharmacists at the University of Cincinnati Medical Center in Ohio found program-wide deficiencies in their oncology service in 2011, they promptly began an overhaul of their chemotherapy management processes. They beefed up their staff size, updated and integrated their electronic medical record (EMR) system and developed a series of EMR-based processes to improve the safety of chemotherapy drug use. As evidenced by an American Society of Health-System Pharmacists Best Practices Award the project received at the 2014 ASHP Midyear Clinical Meeting, the changes have transformed the oncology pharmacy into an exemplary service. “This team has demonstrated that an integrated pharmacy team using an integrated EMR can standardize care and minimize or eliminate communication breakdowns that can occur during handoffs [among] practitioners when oncology patients move through the health system,” said Christina Michalek, PharmD, a medication safety specialist at the Institute for Safe Medication Practices (ISMP), who was not involved in the EMR project. Katherine Hanger, PharmD, clinical coordinator, Hematology/Oncology Services at the University of Cincinnati Medical Center, said a 2011 decision by the university to augment the size of its cancer care program spurred the oncology pharmacy to scrutinize chemotherapy administration processes. The review, Dr. Hanger said, high-

Chemotherapy Checklist Items

✔ Confirm that orders are

consistent with the oncologist’s documented plan.

✔ Make sure agents and dosing

match the supplied reference.

✔ Ensure the time interval since last treatment is appropriate.

✔ Ensure treatment parameters are met.

✔ Confirm that consent is completed.

✔ Ensure orders are signed by an attending physician.

✔ Confirm doses according to

height, weight and body surface area.

Table. Errors for Inpatient Chemotherapy Orders Before and After EMR System With Oncology Module Inpatient Chemotherapy Order Errors Clarified by Pharmacist

Type of Error

Pre-Oncology EMR Systema Mean ± SD # of Errors/100 Orders

Post-Oncology EMR Systemb Mean ± SD # of Errors/100 Orders

P Value

Missing or incorrect diagnosis

5.7±23

<0.001

Missing allergy profile or medication ordered with documented allergy

38.2±46

3.5±18

<0.001

Missing or incorrect measurements (height, weight, body surface area)

16.6±37

1.5±12

<0.001

Missing or incorrect cycle number, day of treatment, or planned treatment date

29.3±47

Missing or incorrect monitoring parametersc

47.1±45

4.7±21

<0.001

70.7±52

3.8±19

<0.001

61.2±83

0.7±7.6

<0.001

Incorrect chemotherapy drug name, dosing, or frequencyc

22.9±50

2.0±14

<0.001

Missing or incorrect diluent, final volume, or durationc

377.7±298

6.1±24

<0.001

37.6±63

1.2±11

<0.001

Missing or incorrect treatment parameters

Missing or inappropriate antiemetic orders

Missing or incorrect supportive care agents ND, not determined a

Data from 157 paper chemotherapy orders between July 2011 and July 2012.

Data collected from 344 electronic chemotherapy orders between October 2012 and July 2014.

Error may occur more than once per chemotherapy order.

lighted “program-wide deficiencies in the provision of care and opportunities for improvement of patient safety and quality management. “Although these problems were not necessarily specific to pharmacy, we recognized an opportunity to expand pharmacy’s role in improving processes and outcomes,” she said. The two-year undertaking that followed left no stone unturned. The team expanded its oncology pharmacy staff from one pharmacist to five clinical pharmacists, created a dedicated EMR pharmacist position and appointed a pharmacist to coordinate oncology pharmacy activities. A critical element of the transition was switching to a new EPIC EMR system, which includes an oncology-specific Beacon module, and simultaneously integrating the inpatient and outpatient EMR systems, Dr. Hanger explained. “The EMR system we previously had was suboptimal for taking care of oncology patients because information entered by physicians in the outpatient EMR system in their respective clinics was not accessible in the infusion suite, where patients were being treated,” she said. The previous system also lacked uniformity and standardization, which meant providers made occasional dosing errors, used unapproved abbreviations and sometimes neglected to include supportive

agents in the patient’s treatment plans. Dr. Hanger said her team chose not to use the built-in Beacon treatment plan templates, and instead created treatment plans using the available published literature. Between 2011 and receipt of their ASHP award, the team collaborated with other hospital providers to generate 612 evidence-based treatment plans for dozens of disease states. The team also linked additional protocols to the oncology treatment plans. For example, the team developed standardized supportive treatment plans, such as antiemetic order protocols that were tailored to the emesis risk associated with specific chemotherapy treatments or regimens; standardized premedication order sets in anticipation of possible emergency hypersensitivity reactions; included automatic dosing adjustments based on renal and hepatic parameters; and implemented automatic laboratory orders specific to the treatment regimens. To help providers adhere to the standardized processes, the team developed a “Chemo Checklist,” which includes items related to ordering, verification, dispensing and administration of cytotoxic drugs (box). “The checklist is in the EMR system and is used each time a chemotherapeutic agent is administered,” Dr. Hanger said. Spearheaded by the EMR pharmacist,

the team also devised other EMR-based tools to improve drug administration efficiency, documentation and pharmacy workflow. For example, after finding occasional delays in the administration of antibiotics in patients with febrile neutropenia, the team created presigned orders for culture testing and antibiotics that were then linked with high-risk infusion plans. That protocol has significantly shortened the time between ordering and administration of antibiotics in these patients, Dr. Hanger said. “Our EMR pharmacist continuously reviews adverse events and incident reports and devises ways to reduce risk by developing new and creative EMRbased solutions,” she said. The new measures also have led to significant reductions in a variety of medication error types (Table), and the oncology pharmacy is now fully compliant with 85% of the standards (149 of the 175) in the 2012 ISMP International Medication Safety Self-Assessment for Oncology, Dr. Hanger noted. “Our team has blossomed into an exemplary, comprehensive and integrated service line that serves as a best practices leader and facilitator across disciplines,” she said. —David Wild None of the sources reported any relevant ﬁnancial conﬂicts of interest.

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