Inside Pharmacy October 2014 by Value-Based Cancer Care

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October 2014 VOL. 2 • NO. 5

CARDIOMETABOLIC

8 Pharmacy Role

in Controlled Substance TakeBack Programs

19 Retail Health

Provides Access for General Primary Care Needs

Health Prediabetes: Practical Information for Retail Clinicians, Patient Education, and Type 2 Diabetes Prevention PAGE 10

29 Identifying

Accurate and Useful Information on Drug–Grapefruit Juice Interactions

40 Europay/

MasterCard/Visa Migration Status

CPE AVAILABLE PAGE 24

? Transforming Retail Pharmacies into

Pharmacists • Chain Headquarters • Independents •

Call for submissions

Pediatric Theme Issue

Deadline: November 15, 2014

Inside Pharmacy will be publishing a theme issue on Pediatric Care in 2015.

Pharmacists, PA/NPs, retail executives, and other primary care clinicians are invited to submit articles for publication in this theme issue on topics relevant to the clinical, business, and policy aspects of pediatric care.

Topics of high interest include:

Special considerations in the pediatric or adolescent population • How to communicate with pediatric patients and their caregivers • Patient education tools • Pediatric dosing algorithms • Updates on pediatric recommendations • Counseling women who are pregnant and/or breast feeding • Allergic reactions in the pediatric population • Patient guidance on when to come to the pharmacy/clinic or primary care provider/emergency department • Immunization controversies in pediatric patients • Patient/caregiver education on proper use of inhalers and other devices • Selecting OTC products for pediatric patients •

Send us your ideas!

Submit a 1200- to 1500-word article, previously unpublished, to Inside Pharmacy to share practical information addressing challenges, opportunities, patient counseling, clinical advances, regulatory changes, and business impacts on retail pharmacy.

Submit to: Frederique H. Evans, MBS, Editorial Director | fevans@the-lynx-group.com

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MISSION STATEMENT Inside Pharmacy is an independent journal founded on the principle of value-based, patient-centered, evidence-based healthcare. As retail pharmacies transform into healthcare delivery companies, Inside Pharmacy offers a forum for pharmacists, chain headquarters, independent pharmacies, physician assistants, and nurse practitioners to navigate the healthcare system and achieve professional success. Each issue of the journal includes resources to support the entire healthcare team inside the pharmacy, including how to attract, retain, and engage customers; answer patient questions on prevention and wellness, acute treatment, and monitoring and management of chronic conditions; and empower retail clinicians in a value-based healthcare system. Contact information: For subscription information and editorial queries, please contact: fevans@the-lynx-group.com; tel: 732-9921895; fax: 732-992-1881.

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INSIDE PHARMACY ❚ October 2014

Transforming Retail Pharmacies into Healthcare Delivery Companies

October 2014 Volume 2 Number 5

Pharmacists • Chain Headquarters • Independents • Physician Assistants • Nurse Practitioners

INSIDE

CARDIOMETABOLIC

Health

Cardiometabolic 14 ANDROGEN DEFICIENCY AND THE EMERGING ROLE OF COMMUNITY PHARMACISTS

PAGE

THE FIRST WORD

Donald J. Dietz, RPh, MS

With the uncertainty of testosterone therapy, pharmacists need to understand various dosage forms, indications, and potential adverse events.

Pharmacy Role in Controlled Substance Take-Back Programs

Patient Care

2 CALL FOR SUBMISSIONS

18 FIVE TIPS TO PREVENT OBESITY

6 EDITORIAL BOARD

These tips are general guidelines to improve patients’ health and prevent obesity.

7 LETTER FROM THE EDITOR

The Pharmacy

30 IDENTIFYING ACCURATE AND USEFUL INFORMATION ON DRUG–GRAPEFRUIT JUICE INTERACTIONS

STARTS

ON PAGE

An analysis of prescribing and written patient drug information from the United States and Canada.

COVER STORY I CARDIOMETABOLIC HEALTH

36 IMPACT OF LONG-ACTING INJECTABLE ANTIPSYCHOTICS ON SCHIZOPHRENIA

Prediabetes: Practical Information for Retail Clinicians, Patient Education, and Type 2 Diabetes Prevention

Money

❚

Pharmacists and retail clinicians can counsel patients about the use of long-acting injectables and improve their attitude toward medication and increase adherence.

42 HOW TO MAKE THE BEST OF YOUR 401(K) PLAN

If your 401(k) is your main or only investment vehicle for retirement, it is possible for you to work around its limitations.

COLUMNS

19 PHARMACY RETAIL CLINIC NEWS® 24 CONTINUING EDUCATION 40 CHAIN HEADQUARTERS NEWS® 43 INSIDE PHARMACY ONLINE 46 DRUG UPDATE

W hat patients need to know to decrease their risk for type 2 diabetes

❚

Understanding the risk factors and prediabetes diagnosis

❚

How to increase patient awareness

Inside Pharmacy, ISSN (requested), is published 6 times a year by Novellus Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Novellus Healthcare Communications, LLC. All rights reserved. Inside Pharmacy is a trademark of The Lynx Group, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

INSIDE PHARMACY ❚ October 2014

InsidePharmacyOnline.com

DISPENSE Albuterol Sulfate HFA as PROAIR HFA Inhalation Aerosol

NO GENERIC ALBUTEROL INHALER CURRENTLY EXISTS

the Editorial Board

The board members and consultants contribute expertise and analysis that help shape the content of Inside Pharmacy

“ PAGE 8

Editor-in-Chief Donald J. Dietz, RPh, MS Vice President Pharmacy Healthcare Solutions, Inc Pittsburgh, PA

The DEA rule implements a 2010 law seeking to reduce abuse, misuse, diversion, and accidental ingestion of controlled substances from medicine cabinets.” —Donald J. Dietz, RPh, MS

James S. Beaumariage, RPh Chief Operating Officer NuScript Rx Nashville, TN

John O. Beckner, RPh Senior Director Strategic Initiatives National Community Pharmacists Association Alexandria, VA

Mitch Betses, RPh Senior Vice President Retail Pharmacy Services CVS Caremark Corporation Woonsocket, RI

Ami Bhatt Senior Director Operations Health & Wellness Wal-Mart Bentonville, AR

Thomas R. Bizzaro, RPh Vice President, Health Policy and Industry Relations, First Databank Indianapolis, IN

Rebecca Wheeler Chater, RPh, MPH, FAPhA Executive Healthcare Strategist Ateb, Inc Raleigh, NC

Scott R. Drab Professor, Department of Pharmacy & Therapeutics School of Pharmacy University of Pittsburgh Pittsburgh, PA

Albert Garcia Executive Vice President Navarro Health Services Medley, FL

Mark J. Gregory, RPh Senior Vice President of Store Operations Kerr Drug, Inc Raleigh, NC

Kevin James, RPh, MBA Vice President Payer Strategy US Bioservices Phoenix, AZ

Alexandra Jung Principal, Advisory Services, Ernst & Young, LLP; former Senior Vice President, Corporate Strategy, Walgreens

Jack Kelly, RPh Chief Business Development Officer, Pharmacist Partners, CKO

Scot L. Kemme Vice President/General Manager Chain Segment McKesson Pharmacy Systems & Automation Livonia, MI

Kevin Letz, DNP, MBA Chairman/Founder Advanced Practice Provider Executives

Tripp Logan, PharmD Vice President Logan & Seiler, Inc Charleston, MO

Stephen C. Mullenix, RPh Senior Vice President Public Policy & Industry Relations, NCPDP Scottsdale, AZ

Richard J. Ptachcinski, PharmD, FCCP President American Pharmacotherapy Pittsburgh, PA

Ernie Richardsen, RPh, MBA Group Vice President Pharmaceutical Purchasing and Clinical Services Rite Aid Corporation Camp Hill, PA

Debbie Sheppard Vice President Sales and Marketing Ateb, Inc Raleigh, NC

Elliott M. Sogol, PhD, RPh, FAPhA Vice President Professional Relations Pharmacy Quality Solutions, Inc Springfield, VA

INSIDE PHARMACY ❚ October 2014

ask us Have a question for our board members? E-mail your question to fevans@the-lynx-group.com

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Letter from the Editor Retail Pharmacy Is the New Primary Care of Today by FREDERIQUE H. EVANS, MBS, Editorial Director, Inside Pharmacy

October is American Pharmacy Month. Its purpose, according to the American Pharmacists Association, is to draw attention to the work of pharmacists and celebrate the profession. }} }} RETAIL PHARMACIES, and the team inside the pharmacy, are quickly becoming an extension of primary care. As such, it is important for pharmacists and retail clinicians to raise awareness of their invaluable contributions in the community. In this issue, which focuses on cardiometabolic health, we feature an article by Keri Medlin, PharmD, on prediabetes and provide useful information that pharmacists and retail clinicians alike can use to encourage patients to take small steps toward a healthier lifestyle and prevent type 2 diabetes (see “Prediabetes: Practical Information for Retail Clinicians, Patient Education, and Type 2 Diabetes Prevention,” on page 10). Timothy Winschel, PharmDc, from the University of Pittsburgh, provides an update on androgen therapy, controversies surrounding its use, and the emerging role of community pharmacists (see “Androgen Deficiency and the Emerging Role of Community Pharmacists,” on page 14). In addition to these featured articles, we have also included a tip on obesity prevention to share with your patients (see “5 Tips to

InsidePharmacyOnline.com

Prevent Obesity,” on page 18). This resource can also be downloaded from InsidePharmacyOnline.com. Inside Pharmacy Retail Clinic News®, Nancy J. Gagliano, Chief Medical Officer of MinuteClinic and Senior Vice President of CVS Health, shares with us trends in retail healthcare delivery and the impact of retail clinics on patient access to

Inside Pharmacy is the new journal for the new primary care. care (see “Retail Health Provides Access for General Primary Care Needs,” on page 19). “Retail clinics will become more of an extension of the healthcare system right into the community,” she said during our interview. “Where a physician can say, ‘It’s 5 o’clock,’ to a patient, ‘go to MinuteClinic, I’ll get the note in my electronic medical record tomorrow. If they see any problem, they’ll let me know.’” Inside The Retail Pharmacy, Linh

B. Van, PharmD, BCPS, and Donna D. Huynh, PharmD, BCPS, report an analysis of prescribing and written patient drug information from the United States and Canada (see “Identifying Accurate and Useful Information on Drug–Grapefruit Juice Interactions,” on page 30), and is followed by an article on the role of pharmacists in counseling patients on the use of long-acting injectable antipsychotics in patients with schizophrenia (see “Impact of LongActing Injectable Antipsychotics on Schizophrenia,” on page 36). Inside Business Chain Headquarters News®, Timothy A. Wimsett, BSBA, discusses Europay/MasterCard/Visa migration status in the United States and the ways to be prepared for the transition by the October 2015 deadline (see “EMV Migration Status,” on page 40). We hope you enjoy this issue of Inside Pharmacy—the new journal for the new primary care. As retail pharmacies transform into healthcare delivery companies, look to Inside Pharmacy to provide you with practical information to achieve professional success. ❚

INSIDE PHARMACY ❚ October 2014

The First Word Pharmacy Role in Controlled Substance Take-Back Programs by DONALD J. DIETZ, RPH, MS, Editor-in-Chief, Inside Pharmacy

“

Pharmacies are now one of the entities that can become authorized collectors of unwanted controlled substances.”

n September 8, Attorney General Eric Holder announced a new Drug Enforcement Administra tion (DEA) regulation that would allow pharmacies, hospitals, clinics, and other authorized collectors to serve as take-back points for controlled substances.1 The DEA rule implements a 2010 law seeking to reduce abuse, misuse, diversion, and accidental ingestion of controlled substances from medicine cabinets.

Growing Confidence in Pharmacies Effective October 9, 2014, pharmacies are now one of the entities that can become authorized collectors of unwanted controlled substances by registering with the DEA as a reverse distributor. Pharmacies have been able to accept unwanted noncontrolled substances for years, but this new rule expands their ability to accept controlled substances. This can take the form of takeback events, a mail-back program, or collection receptacles.2 As a pharmacist, this new rule makes me proud that the government and the gen-

INSIDE PHARMACY ❚ October 2014

5 factors to consider: ❚ New training procedures ❚ New internal audit processes ❚ Security concerns ❚ Compensation for services rendered ❚ Added costs

eral public have confidence in their pharmacy to play an important role in removing unwanted controlled substances from public access. This is especially important for teens: “Nearly 4 in 10 teens who have misused or abused a prescription drug have obtained it from their parents’ medicine cabinet,” according to Attorney General Holder.1 How will this new rule impact pharmacies interested in taking back controlled substances from the community? Initially, there will be administrative paperwork to modify the pharmacy’s DEA registration to meet the new legal and security man-

dates for mail-back and collection receptacles. To accept controlled substances with the intent of destruction, pharmacies will need to register as reverse distributors.

Factors to Take into Account Pharmacies will also need to develop and implement new training procedures for all pharmacy personnel focusing on the additional requirements to accept, store, do inventory, and return controlled substances. New internal audit processes will also be implemented to ensure ongoing training and compliance with this new role as reverse distributor. New security concerns for the pharmacy will also need to be considered. If a limited number of pharmacy locations accept returned controlled substances, will those pharmacies be at greater risk for robbery or burglary from addicts seeking large supplies of controlled substances? The new administrative paperwork, storage, training, shipping or destruction, auditing, and security do not occur without an additional expense to the pharmacy. Who is going to pay for these added costs? With more than 90% of all prescrip-

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The First Word tions paid by a third-party insurer, it is unlikely that pharmacies will be able to pass along this cost in the prescription pricing. It is also doubtful that many customers will willingly pay an out-of-pocket fee to the pharmacy to return their controlled substance medications. Continued pressure on retail pharmacy margins will make it difficult for retail pharmacies to simply absorb the added expense of accepting controlled substances at all pharmacy locations. Compensation to pharmacies for this new value-added service remains an unanswered challenge.

Acknowledgment of the New Rule Most state boards of pharmacy have not addressed controlled substance medication take-back programs for disposal, though a few states have. For example, in Pennsylvania, any medication take-back falls under the state’s Department of Environmental Protection and is restricted because it is considered hazardous waste.3 According

to the Notification for Registration of Onsite Pharmaceutical Drug Collection Program, “controlled substances shall not be accepted.”4 Be sure to look into your state’s laws and regulations on the subject; states may decide to modify their existing laws and regulations based on this new regulation from the DEA. There have been limited public comments from leaders of pharmacy organizations and leading pharmacy chains on this new DEA rule. Retail pharmacy organizations, from large chains to individual owners, will be examining the effort and cost needed to successfully implement, comply, and ensure the security of both personnel and product in their pharmacies before accepting controlled substances. Some pharmacy owners may decline to become a reverse distributor. The DEA has stated that they have “no plans to sponsor more nationwide Drug Take-Back Days in order to give authorized collectors the opportunity to provide this valuable service to their communities.”5 The

last scheduled Drug Take-Back Day was set for September 27, 2014. ❚

References

1. Department of Justice. Attorney General Holder Announces New Drug Take-back Effort to Help Tackle Rising Threat of Prescription Drug Addiction and Opioid Abuse. www.justice.gov/opa/pr/attorney-generalholder-announces-new-drug-take-back-effort-help-tack le-rising-threat. Published September 8, 2014. Accessed September 19, 2014. 2. Drug Enforcement Administration, Department of Justice. Disposal of controlled substances [Docket No. DEA-316]. https://s3.amazonaws.com/public-inspection. federalregister.gov/2014-20926.pdf. Accessed September 15, 2014. 3. Pennsylvania Pharmacists Association. DEA Issues Final Rule on Controlled Substances Return Programs. PPA Weekly Bulletin. September 17, 2014. 4. Pennsylvania Department of Environmental Protection. Notification for Registration of Onsite Pharmaceutical Drug Collection Program. www.elibrary. dep.state.pa.us/dsweb/Get/Document-82549/ 2520-FM-BWM0010%20Instructions.pdf. Published November 2010. Accessed September 18, 2014. 5. Drug Enforcement Administration, Department of Justice. DEA Releases New Rules That Create Convenient But Safe and Secure Prescription Drug Disposal Options. www.justice.gov/dea/divisions/ hq/2014/hq090814.shtml. Published September 8, 2014. Accessed September 18, 2014.

Mr Dietz is Editor-in-Chief of the journal, and Vice President of Pharmacy Healthcare Solutions, Inc, Pittsburgh, PA.

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INSIDE PHARMACY ❚ October 2014

INSIDE

ANDROGEN THERAPY

Androgen deficiency and the role of retail clinicians [14]

Cardiometabolic Health

Cover Story

Prediabetes: Practical Information for Retail Clinicians, Patient Education, and Type 2 Diabetes Prevention by KERI MEDLIN, PHARMD, FASCP

Prediabetes. You hear the term often, but what does it really mean to patients, pharmacists, and other retail clinicians? }} KEY POINTS ❚ Prediabetes can increase the risk for type 2 diabetes and cardiovascular disease ❚ Several tests are available to diagnose patients with diabetes, including A1C, fasting blood glucose, and oral glucose tolerance ❚ Lifestyle modifications may decrease the risk for diabetes by more than half

}} WHAT DO PEOPLE need to do now to help decrease their risk for type 2 diabetes in the future? Prediabetes can increase the risk for type 2 diabetes and cardiovascular disease.1 In 2012, 86 million Americans 20 years of age and older had prediabetes compared with 79 million in 2010.2 It has been projected that 470 million people worldwide will have prediabetes by 2030.3 The American Diabetes Association (ADA) defines prediabetes as “blood glucose levels that are higher than normal but not yet high enough to be diagnosed as diabetes.”4 Prediabetes can also be known as impaired glucose tol-

INSIDE PHARMACY ❚ October 2014

erance or impaired fasting glucose; both are considered risk factors for type 2 diabetes. Patients can have prediabetes for years before developing type 2 diabetes. They are also more likely to develop diabetes within 10 years after a prediabetes diagnosis.5

Who Is at Risk for Prediabetes? Physicians may recommend that patients who are 45 years of age and older, and overweight, be tested for prediabetes.6 Patients are also at risk for prediabetes if they are younger than 45 years of age, overweight, and have addi-

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Intended as a guide. Lower acquisition costs alone do not necessarily reflect a cost advantage in the outcome of the condition treated because there are other variables that affect relative costs. Formulary status is current as of March 2014 and is subject to change. By texting FLEX to 51212, you consent to receive a one-time text message containing a link to the requested information from Novo Nordisk. Your consent is voluntary and you are not required to consent to receive information or other benefits from Novo Nordisk. Standard text messaging rates will apply.

Needles are sold separately and may require a prescription in some states. Reference: 1. Fingertip Formulary ®, March 2014.

Inside Cardiometabolic Health RISK FACTORS FOR PREDIABETES In patients who are overweight or obese, or ≥45 years of age: ❚ Sedentary lifestyle

❚ Gestational diabetes

❚ Immediate family member with diabetes (parents or siblings)

❚ Polycystic ovary syndrome ❚ Acanthosis nigricans on neck and under armpits

❚ High blood pressure

❚ African American, American Indian, Asian American, Hispanic/Latino, or Pacific Islander

❚ Abnormal cholesterol levels (low-density lipoprotein, high-density lipoprotein, or triglycerides)

tional risk factors, including sedentary lifestyle, an immediate family member with diabetes, or high blood pressure (See “Risk Factors for Prediabetes,” on page 12).

There are no clear symptoms associated with prediabetes. How Is Prediabetes Diagnosed? There are several ways for healthcare providers to screen for prediabetes, including A1C, determining fasting blood glucose, and oral glucose tolerance test.4,6 The A1C test measures average blood glucose in the past 3 months.4 The A1C range for prediabetes is between 5.7% and 6.4%. The fasting plasma glucose test ideally is performed early in the morning, and patients should be instructed not to eat for 8 hours prior to the test. A fasting plasma glucose level ranging from 100 to 125 mg/dL is indicative of prediabetes. Another method is the oral glucose tolerance test, which measures blood

INSIDE PHARMACY ❚ October 2014

glucose before and 2 hours after drinking Glucola.4 Patients are diagnosed with prediabetes if their blood glucose 2 hours after drinking Glucola is between 140 and 199 mg/dL.

Patient Awareness Needed There are no clear symptoms associated with prediabetes,4 and many patients with the condition may be unaware of it. Patients should be monitored annually and be screened for cardiovascular disease modifiable risk factors, including obesity, hypertension, and dyslipidemia.5 Prediabetes can put the patient at risk for diseases such as retinopathy, neuropathy, and chronic kidney disease, and increase the risk of macrovascular disease. Working Toward Prevention, Management The onset of diabetes can be delayed or prevented in patients with prediabetes. Lifestyle modifications have shown to decrease the risk for diabetes by 58%.4 What can patients with prediabetes do now to help decrease their risk for type 2 diabetes in the future? Lose weight. Losing 7% of body weight can help decrease the risk for diabetes.4 Eating a diet that is low in fat with more fruits and vegetables as well as reducing portion size can help with weight loss. In addition, patients should aim to be more physically active. Moderate exercise for 30 minutes a day, 5 days a week can be beneficial. Physical activity can help the body’s muscles use insulin more efficiently. The ADA has also suggested that some patients with prediabetes may be considered for metformin therapy. Patients with impaired glucose tolerance, impaired fasting glucose, or an elevated A1C (5.7%-6.4%) should be considered for metformin therapy, specifically if they have a body mass index greater than 35 kg/m2, are 60 years of age or younger, and are women who

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Inside Cardiometabolic Health have a history of gestational diabetes.5 Metformin, like exercise, can help the body’s muscles use insulin more efficiently. Metformin, along with lifestyle modifications, may be beneficial for diabetes prevention for high-risk patients.

ier lifestyle could potentially reverse prediabetes. ❚

References

1. Centers for Disease Control and Prevention. Diabetes Public Health Resource: Prevent Diabetes. www.cdc.gov/ diabetes/consumer/prevent.htm. Accessed September 19, 2014. 2. American Diabetes Association. Statistics about diabetes. www.diabetes.org/diabetes-basics/statistics. Published September 10, 2014. Accessed September 15, 2014. 3. Tabak AG, Herder C, Rathman W, et al. Pre-diabetes: a high-risk state for diabetes development. Lancet. 2012;379:2279-2290. 4. American Diabetes Association. Diagnosing diabetes and learning about pre-diabetes. www.diabetes.org/diabe tes-basics/diagnosis. Published March 27, 2014. Accessed August 24, 2014. 5. American Diabetes Association. Standards of medical care in diabetes 2014. Diabetes Care. 2014;37:S16-S17. 6. National Diabetes Information Clearinghouse (NDIC). Diabetes prevention program. http://diabetes.niddk.nih. gov/dm/pubs/preventionprogram. Published September 9, 2013. Accessed September 15, 2014.

Conclusion As pharmacists and retail clinicians, it is our role to educate and encourage our patients. Being diagnosed with prediabetes can be scary, but it is manageable. The ADA and the National Diabetes Education Program have wonderful resources that can be shared with your patients. Explain to your patients that even small steps toward a health-

Transforming Retail Pharm

Pharmacists • Chain

acies into Healthcare

Dr Medlin is a clinical/ consultant pharmacist with Kerr Health in Raleigh, NC.

Delivery Companies

nts • Nurse Practitioners

dents • Physician Assista

Headquarters • Indepen

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InsidePharmac

October 2014 VOL. 2 • NO. 5

CARDIOMETABOLIC

8 Pharmacy Role

in Controlled Substance TakeBack Programs

19 Retail Health

Provides Access for General Primary Care Needs

Health Information for Prediabetes: Practical nt Education, and Retail Clinicians, Patiention Type 2 Diabetes Preve PAGE 10

29 Identifying

Accurate and Useful Information on Drug–Grapefruit Juice Interactions

40 Europay/

MasterCard/Visa Migration Status

CPE AVAILABLE PAGE 24

Inside Pharmacy is an independent journal founded on the principle of value-based, patient-centered, evidence-based healthcare. Each issue of the journal includes resources to support the entire healthcare team inside the pharmacy, including how to attract, retain, and engage customers; answer patient questions on prevention and wellness, acute treatment, and monitoring and management of chronic conditions; and empower retail clinicians in a value-based healthcare system.

InsidePharmacyOnline.com

INSIDE PHARMACY ❚ October 2014

Inside Cardiometabolic Health

Androgen Deficiency and the Emerging Role of Community Pharmacists

“

Pharmacists need to continually adapt to the ever-changing world of medicine and work to understand clinical research.”

by TIMOTHY WINSCHEL, PHARMDc, BSBA

Testosterone therapy has recently skyrocketed as more men are being introduced to the idea of “low T” through an ever-increasing advertising push. }} KEY POINTS ❚ Manufacturers have drastically increased their advertising spending for testosterone therapy ❚ Pharmacists need to understand the clinical pearls of each dosage form to provide optimal care to their patients

}} MANUFACTURERS have drastically increased their advertising spending from $14.3 million in 2011 to $107.3 million in 2012.1 The US Food and Drug Administration (FDA) estimates that almost 2.3 million patients were on testosterone therapy in 2013, a 77% increase from 2010.2 This increase begs the question whether testosterone therapy has the data to support its use. One study estimated that the crude prevalence of hypogonadism was 38.7% in men aged 45 years and older, and suggested that 13.8 million men in that age group visiting primary care physicians in the United States may have low testosterone.3 Although opinions vary and studies differ, the number of patients on testosterone therapy continues to grow and it is imperative for pharmacists to grasp this complex treatment.

INSIDE PHARMACY ❚ October 2014

Dosage Forms Available The recent population spike in the testosterone market has enticed numerous manufacturers to enter the market with an array of testosterone dosage forms, ranging from oral tablets to surgically implanted pellets. Pharmacists need to understand the clinical pearls of each dosage form to provide optimal care to their patients. The oral dosage form has been associated with hepatic adverse events, including cholestatic jaundice syndrome, neoplasm of the liver, and peliosis hepatis.4 For this reason, physicians often do not recommend the use of current oral testosterone dosage forms. Intramuscular testosterone injections are used more routinely. The advantages of an intramuscular injection are the potential for improved adherence in relation to their infrequent administra-

InsidePharmacyOnline.com

Inside Cardiometabolic Health tion and reduced cost. Depending on the specific testosterone product, intramuscular injections can be dosed once every 2 weeks, even as little as once every 10 weeks. There are some downsides as many patients may fear the idea of a slow, deep intramuscular injection into the gluteal muscle. One product even carries a black box warning due to the increased risk for pulmonary oil microembolism; and anaphylaxis is required for office or hospital administration.4 Transdermal and topical testosterone dosage forms provide a convenient, nonintrusive delivery method. The ease of application that these products offer the patient is apparent. Patches are applied every 24 hours (at night) to the back, abdomen, upper arms, or thighs; patients need to remove the old patch before applying a new one. Application sites should be rotated daily, and the same site should not be used for at least 7 days. In addition, patients should wait at least 3 hours before showering or bathing. Application site reactions can occur frequently with patches,5 underlying the important role of pharmacists to highlight adverse events. Topical gels come in tubes, packets, and metered-dose pumps. Testosterone gel is applied every 24 hours (in the morning) to the shoulders, upper arms, or abdomen. Patients must wash their hands thoroughly with soap and water immediately after application, and wait at least 5 hours before showering or bathing. The gel should be allowed to dry completely before any covering is applied. Metered-dose pumps differ from the packet and tube form in that they require 3 priming pumps before the first use. The potential for skin transfer has led to testosterone gels carrying a black box warning. If an unknowing person comes into contact with the application site or an unwashed article of clothing, unintended testosterone exposure can occur. Pharmacists have an excellent opportunity to prevent secondary exposure with proper patient counseling.6 Topical testosterone solutions are

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almost identical to the gel, except that the solution is applied to each axilla every 24 hours (in the morning). The testosterone solution is dispensed through a metered-dose pump and should be primed using 3 pumps prior to first use. Apply deodorant or antiperspirant at least 2 minutes before using the testosterone solution in an effort to avoid cross-contamination. Allow the solution to dry before dressing to

Pharmacists have an excellent opportunity to prevent secondary exposure with proper patient counseling. promote proper absorption, and do not shower or bathe for at least 2 hours after application. Analogous to the gel, pharmacists play a significant role in preventing secondary exposure through proper patient education.7 Unlike the topical dosage forms, the subcutaneous testosterone implant is an invasive alternative method of testosterone administration. Testosterone pellets are implanted into the buttocks, lower abdominal wall, or thigh and slowly dissolve while releasing the hormone. The procedure, which occurs in a physicianâ&#x20AC;&#x2122;s office and lasts approximately 15 minutes, will have to be repeated every 3 to 6 months. Once implanted, adherence is a nonissue. That being said, testosterone implants are often not recommended because of their invasiveness, as well as risks for spontaneous pellet extrusion and infection.4,8 Direct absorption of testosterone through the oral mucosa, which avoids first-pass metabolism improving bioavailability, is available in the form of a buccal tablet. One buccal testosterone tablet is applied to the upper gum above the incisor tooth twice daily in the morning and evening, rotating the application site. The tablet is held in

INSIDE PHARMACY â?&#x161; October 2014

Inside Cardiometabolic Health place for 30 seconds by pushing down on the outside of the upper lip. Buccal tablets should not be chewed or swallowed. Gum irritation can be a frequent occurrence with the use of buccal testosterone, providing pharmacists with an opportunity to intervene in a meaningful manner to limit this adverse event.9 Recently, the FDA approved a nasal testosterone dosage form supplied as a metered-dose pump known as Natesto. Natesto is not yet available and will be the first nasal dosage form on the market. Application is easy, but patients with adherence issues may struggle because it requires frequent administration (ie, 1 pump in each nostril 3 times daily). Nasal adverse events have been shown in clinical trials, which may further complicate potential adherence issues.4

Pharmacists have the opportunity to intervene in a meaningful manner to limit adverse events. Pharmacists’ Intervention As testosterone use soars, it becomes essential for the most accessible healthcare provider, the pharmacist, to not only understand the dosage forms, but also the risks associated with therapy to optimize patient care. Contraindications for testosterone therapy include breast or prostate cancer, and serious adverse events such as sleep apnea, erythrocytosis, benign prostatic hyperplasia, and venous thromboembolism.4 Of late, the FDA has required manufacturers to include a general warning for venous thromboembolism on testosterone medication labeling.10 Recently, evidence relating testosterone therapy to an increased risk for cardiovascular events has been thrust into the limelight. The FDA and the Endocrine Society have acknowledged the issue, alerted clinicians, and begun an investigation into the potential association.11

INSIDE PHARMACY ❚ October 2014

Two main observational studies, one of which was published in JAMA, brought about this newfound unease.12,13 The first study suggested that testosterone therapy increased the risk for stroke, myocardial infarction, and death by 30%.12 The second study found that men aged 65 years and older on testosterone therapy had a 2-fold increased risk for myocardial infarction, and men aged less than 65 years with a preexisting heart condition had almost a 3-fold increased risk of myocardial infarction.13 That being said, the FDA has made it clear that they have not concluded that testosterone therapy increases the risk of suffering a cardiometabolic event; it is only being investigated. As both studies had retrospective designs and a multitude of the study participants had prior cardiovascular disease, further large-scale, randomized controlled trials are needed to establish a true relationship between the exposure and outcome. In addition, the JAMA study has been the target of scrutiny over its credibility because of large data errors and misreporting of data.14 Twenty-nine medical societies and 160 of the leading testosterone researchers have called for the retraction of the study. Pharmacists need to continually adapt to the ever-changing world of medicine and work to understand clinical research. New concerns are often raised, and it is the responsibility of pharmacists to stay current with these warnings. An FDA panel recently voted 20-1 for a labeling change highlighting the lack of benefit associated with testosterone on the effects of aging. They also reiterated that evidence linking testosterone therapy to cardiometabolic events was “inconclusive,” but voted that manufacturers conduct long-term studies to further evaluate the existence of a relationship.15 Testosterone therapy has become a topic of heated discussion around its indications and risks. With all the uncertainty surrounding testosterone therapy, and its use being at an all-time high,

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Inside Cardiometabolic Health pharmacists not only need to understand the various modes of administration, but they must be able to use their clinical knowledge when assessing indications and potentially life-threatening adverse events. ❚

References

1. Consumer Reports. Do you need to be treated for low testosterone? Drugmakers spent more than $100 million advertising the drugs last year, but our experts aren’t buying it. www.consumerreports.org/cro/magazine/2013/07/ do-you-need-to-be-treated-for-low-testosterone/index.htm. Published July 2013. Accessed September 16, 2014. 2. Perrone M. Associated Press. FDA: little evidence to support testosterone drugs. http://bigstory.ap.org/article/ fda-little-evidence-support-testosterone-drugs. Published September 3, 2014. Accessed September 16, 2014. 3. Mulligan T, Frick MF, Zuraw QC, et al. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract. 2006;60:762-769. 4. Snyder PJ. Testosterone treatment of male hypogonadism. In: UpToDate, Post AM (Ed), UpToDate, Waltham, MA. 5. Androderm [package insert]. Parsippany, NJ: Watson Pharmaceuticals Inc; 2013. 6. AndroGel [package insert]. Chicago, IL: AbbVie Inc; 2014. 7. Axiron [package insert]. Indianapolis, IN: Eli Lilly and Company; 2014.

8. Testopel [package insert]. Rye, NY: Bartor Pharmaceuticals; 2013. 9. Striant [package insert]. Chesterbrook, PA: Actient Pharmaceuticals LLC; 2014. 10. US Department of Health & Human Services. US Food and Drug Administration. FDA adding general warning to testosterone products about potential for venous blood clots. www.fda.gov/Drugs/DrugSafety/ucm401746.htm. Accessed September 17, 2014. 11. US Department of Health & Human Services. US Food and Drug Administration. FDA evaluating risk of stroke, heart attack and death with FDA-approved testosterone products. www.fda.gov/Drugs/DrugSafety/ucm383904.htm. Accessed September 17, 2014. 12. Vigen R, O’Donnell CI, Barón AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310:1829-1836. 13. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS ONE. 2014;9:e85805. 14. The Androgen Study Group. Complaint to the journal oversight committee at JAMA. www.androgenstudygroup. org/initiatives/complaint-to-journal-oversight-committee-at-jama. Accessed September 17, 2014. 15. Perrone M. Associated Press. Experts want restrictions on testosterone drug use. http://bigstory.ap.org/arti cle/91599e0bd98f4cc98b55ce51f2fcc87b/experts-skepti cal-testosterone-drug-benefits. Published September 17, 2014. Accessed September 18, 2014.

Mr Winschel is a Pharmacy Student, University of Pittsburgh, PA.

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Patient Care 5 TIPS TO PREVENT OBESITY Obesity is a significant health concern today in both adults and children in the United States. The following tips are general guidelines to improve patients’ health and prevent obesity: 1 Know Your BMI

2 Eat Fruits and Vegetables

3 Be Physically Active

Using a body mass index (BMI) calculator, you can find out whether you are underweight, have a healthy body weight, are overweight, or obese, and determine if you need to gain, maintain, or lose weight. A BMI calculator is available on the Centers for Disease Control and Prevention website at http://goo.gl/Oiy9Ed. Increasing the consumption of fruits and vegetables is a good way to maintain a healthy and balanced diet, reduce the risk for chronic diseases, and manage your weight. Adults should aim for 150 minutes of a moderate-intensity aerobic activity such as walking briskly on a weekly basis, or 75 minutes of a vigorous aerobic activity like jogging, in addition to muscle-strengthening at least 2 days a week.

4 Don’t Get Discouraged!

5 Maintain a Healthy Body Weight

Leading a healthy lifestyle takes time. Don’t get discouraged if a healthy diet and exercise does not give instantaneous results. The key is being consistent and developing long-lasting habits.

An important component of weight management is to maintain and monitor your body weight after your weight goals have been met, and make adjustments as needed.

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Source: Centers for Disease Control and Prevention. Overweight and Obesity: Recommendations. www.cdc.gov/obesity/resources/recommendations.html. Accessed September 17, 2014.

INSIDE PHARMACY ❚ October 2014

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Pharmacy Retail Clinic News Retail Health Provides Access for General Primary Care Needs In a recent interview with Inside Pharmacy, Nancy J. Gagliano, MD, Chief Medical Officer, MinuteClinic, and Senior Vice President, CVS Health, discussed trends in healthcare delivery and the impact of retail clinics on patient access to care.

How are retail pharmacies evolving to accommodate changes in healthcare delivery? NJG: The world is changing and I think only for the better. We look at healthcare as a broader responsibility where, traditionally, healthcare was thought of as a predominantly physician-owned space. But, as a society, we are coming to the realization that the solution to improving the health of American citizens really lies within each and every one of us, and that retail pharmacy is an important component to improving the healthcare delivery system. There are a couple of areas in particular to highlight. For example, it is terrific if a physician writes the correct pre-

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scription for the patientâ&#x20AC;&#x2122;s condition. But if the patient does not understand how to take it, does not fill the prescription, does not take it for the right period or duration, or stops taking it, the adherence can have a dramatic impact, not only on that individual patient but on the order of magnitude of billions of dollars of healthcare expense across the nation. We have estimated that nonadherence to medication in a patient who has high blood pressure, for example, is associated with over $2000 in additional costs to the healthcare system compared with a patient who is adherent. Pharmacies obviously are a great place to help with adherence, under-

standing, and education. At CVS Health, we have a program that we call First Fill. If a patient is on a brand new medication, the pharmacist will provide education to make sure that the patient understands the impact and the reasons they are taking the medicine, and lets the physician know if the patient does not come in for their First Fill prescription. Also, once a patient starts a medication, if he or she does not come in for refills, we will reach out to the patient, let them know that they are due, and encourage them to stay adherent. We have also realized that a patient with a chronic condition actually comes into their retail pharmacy more often in a month than they would

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to see their physician. A typical patient with diabetes may only see their provider once every 3 months or so, whereas patients with diabetes who use CVS will often be in 6 to 8 times a month, obtaining refills and other needs. There is a terrific opportunity for patients with a chronic condition to develop a nice, strong relationship with their pharmacist as another person in their healthcare delivery team. There is an opportunity for retail pharmacies to become an important player in the healthcare delivery system. What is the role of retail clinics in this capacity? NJG: A retail clinic has a number of opportunities to support the healthcare delivery system. We are facing a dramatic shortage of primary care across the country, with an estimated 40,000 primary care physician (PCP) shortage expected in the next decade. Retail health can provide access for general primary care needs for conditions such as sore throats and earaches, as well as vaccinations. When we start thinking about how we fit into the role of a retail clinic

INSIDE PHARMACY â?&#x161; October 2014

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Pharmacy Retail Clinic News in a retail pharmacy, then you can think about a broader system where you could imagine a patient with high blood pressure being seen at the pharmacy by the pharmacist, getting educated about their medication, and then, using a MinuteClinic a couple of weeks later to check their blood pressure to make sure they have responded appropriately. MinuteClinic would then send the results to the patient’s PCP. If everything is great, no follow-up is necessary. If his or her blood pressure continues to be elevated, or the patient has side effects, then MinuteClinic would send the patient back to the PCP. It is truly an extension of primary care, right into the community in a convenient location. How are the changes in retail pharmacy impacting the consumer? NJG: People would agree that the goal is to impact the consumer in a very positive way. The concept that CVS Health has made the important decision to eliminate cigarettes and tobacco products from its retail locations demonstrates a commitment to healthcare, and sends a very clear message to the consumer that their healthcare is

ENGAGING PHARMACISTS IN EDUCATION AND ADHERENCE ACTIVITIES HELPS THE CONSUMER. very important to them. Retail pharmacies are really looking at opportunities to make it easier for patients to take care of themselves; simple things such as a drive-in pharmacy pickup. That type of concept makes it easy for the patient to get their medication and then stay adherent. Engaging pharmacists in education and adherence activities helps the consumer. It makes it easier for them to have access to information, guidance, and reinforcement to take their medications, as well as access to additional expertise. We are all very much aware that although the physician is the center of the patient’s care, having other access points to support the patient’s care can only help the consumer. Anything that we can do to make it easier for the patient to access knowledge, their prescriptions, and other healthcare delivery mech anisms is only going to

INSIDE PHARMACY ❚ October 2014

have a positive impact on the consumer. What patient group have you seen take the most advantage of retail clinics? NJG: There are a couple of different groups we have seen take advantage of retail clinics. Fifty percent of the patients who come to retail clinics do not have a PCP. Clearly, it is people who may be insured, because 85% of our patients use their insurance. They may be insured, but they are somewhat disenfranchised. They either do not have a PCP or they just moved into a community, and are on a wait list for a PCP. In addition, 50% of the patients who visit us, come evenings and weekends. Folks are using us as an alternative to an emergency room when their PCP’s office is closed. Along that line, we are often seeing people who are extremely busy, and taking time off from work or getting to see their PCP is very challenging to them. Folks who have more of a consumer focus on access and convenience are often the users of our retail clinics. About a quarter of the patients who come to us are pediatric patients. The core population is adults. We tend to see more folks here in

the employed age. We do see older patients, but it is a smaller percentage. What additional services do you see available at retail clinics in the future? NJG: I think you will be seeing more in the spectrum of wellness services and chronic care support. For example, with the Affordable Care Act and accountable care organizations moving more toward a population health focus rather than acute illness and fee-for-service– type of financial models, the focus is geared more toward early intervention. We would, obviously, rather have somebody lose 10 lb before they became hypertensive or had diabetes. Focusing on the early stages and the risk factors, MinuteClinic, for example, launched a program for smoking cessation, which combines coaching and prescription medication, as well as medication advice, because nicotine replacement is recommended and does not require a prescription. We also launched a weight-loss program that is based on the DASH diet, a dietary approach to stop hypertension, a very healthcare-based diet. In addition to that, we have added services to

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Pharmacy Retail Clinic News screen, monitor, and support chronic disease. How is the healthcare team inside and outside the pharmacy coordinat ing patient care? NJG: Adherence is one example. If you think of the healthcare team as being the provider and the office nurse—or the patient care medical home initiating a patient on medication—and the pharmacy as the place where electronically prescribed prescriptions arrive, there is tremendous opportunity for the pharmacist to close the loop with the care team and inform them that the patient has not picked up their script and/or to reinforce the importance of adherence. We are also launching a new project called bedside delivery, which we are piloting with a couple of healthcare systems, where either a pharmacist or a pharmacy technician goes to the hospital before the patient is discharged and ensures that the patient has their discharged medications, and understands them before they leave. Obviously, if a patient is hospitalized and sent home, it is vitally impor tant that they take the new medications that have been prescribed as part of the hospitaliza-

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tion. If a patient goes home and does not stop by the pharmacy or does not have their new medications with them, obviously, that puts the patient at risk for having a relapse or not improving. We believe that approximately two-thirds of hospital readmissions are related to not taking medication appropriately and not having good access to appropriate care in the short period of time after hospitalization. A program that has a pharmacist or pharmacy system supporting the patient, getting their prescriptions before they go home, helps to support the healthcare team, ensuring patient care. How would provider’s status of pharmacist impact their role in retail pharmacies? NJG: This is an area that we want to get some additional input, but, in general, there are certain things that if a pharmacist could, he or she can create additional opportunities for care to be delivered. Right now, for example, vaccinations are often administered in pharmacy settings. Sometimes they are given under the orders of a physician. If we are looking at population health, we know we want to get as many people vaccinated as possible for in-

WE WANT TO MAKE IT EASY FOR PEOPLE TO GET THE CARE THAT WILL HELP THEM AND SOCIETY. fluenza, for example. When more people in a society get vaccinated, it creates herd immunity, which decreases the likelihood in society of an epidemic. We want to make it easy for people to get the care that will help them and society. There have been some studies that have shown that a pharmacist involved in providing education about diabetes, or being able to do a hemoglobin A1C and provide education to the patient about their level, improves the overall quality of the patients or management of the patient’s diabetes. Allowing pharmacists to have a more active role in healthcare provides additional healthcare resources and can definitely improve healthcare across the country. How do pharmacists interact with clinical staff in the MinuteClinic? NJG: It is a complicated

issue because there are privacy rules related to how the pharmacist and MinuteClinic staff can interact. We have to make sure that the patient’s information is kept private and we have to abide by regulations. That being said, there are opportunities to enhance care by having a MinuteClinic within a pharmacy. Obviously, if a MinuteClinic practitioner is seeing a patient and has questions related to the medication, there is a pharmacist available that can answer the questions. Patients can choose to have their prescription filled at that pharmacy or wherever they prefer. If the patient chooses to have their prescription filled at that same CVS, he or she can easily get their medication, and therefore, have a higher likelihood of taking the medication prescribed. In addition, sometimes the patient will ask the pharmacist a medical question that is outside their scope and the patient may not have a PCP, for example. The pharmacist would always refer the patient back to their PCP, but if a patient does not have access to one, the Min uteClinic, being at that location or nearby, can allow the pharmacist to easily refer the patient for the care that they may

INSIDE PHARMACY ❚ October 2014

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Pharmacy Retail Clinic News need. There are a number of ways where they both can work together. Do retail clinics contribute to disruptive healthcare innovation and how so? NJG: I definitely view retail clinics as a disruptive healthcare innovation in a number of ways. (1) Traditional healthcare is based on the model where the patient goes to the healthcare system. (2) The patient sets an appointment, and then goes when there is availability to accommodate the patient, not necessarily at the patient’s convenience. (3) Healthcare systems are designed to provide a high level of overhead that makes the healthcare system traditionally very costly. There are secretaries who answer the phones, scheduling systems, referral coordinators, billing coordinators—an assortment of infrastructure to support traditional healthcare. The MinuteClinic model is designed to do a few things. It is a walk-in model and that model is therefore designed on patient choice and patient convenience. A patient comes when it meets his or her needs. It is open evenings and weekends, which is also quite innovative and disruptive, and the model is based on guideline-driven healthcare.

THIS LEVEL OF HEALTHCARE STANDARDIZATION ALLOWS FOR HIGH QUALITY, SAFETY, AND EFFICIENCY. The services are developed and the list of services that are available to the patients are services that can be given and provided in a very safe, high-quality manner that is based on research and standards, and those are embedded into the electronic medical record so that if a patient comes from a MinuteClinic in New Jersey with a sore throat, they will get the exact same care as a patient who was seen in California. This level of healthcare standardization allows for high quality, safety, and efficiency. It is disruptive in that it creates access, it is low cost, and it is very high quality. How do you think this model will evolve or change in the next 5 or 10 years? NJG: I think as healthcare evolves and certain different aspects of it can be a little bit more standardized, those services can then be added to the

INSIDE PHARMACY ❚ October 2014

MinuteClinic model. One of the things we do is point-of-care testing right in the clinic: We can do rapid strep tests; we can do a cholesterol test. There is also a significant collaboration and affiliation with healthcare systems. As payment models change and population health grows, we are getting high-quality, cost-effective care, which is really the underlying focus, and the relationships between retail systems, retail clinics, and the healthcare system will naturally grow. Retail clinics will become more of an extension of the healthcare system right into the community where a physician can say, “It’s 5 o’clock,” to a patient, “go to MinuteClinic. I’ll get the note in my electronic medical record tomorrow. If they see any problem, they’ll let me know.” There will be much more of a collaborative partnership between retail clinics and the health system. Then, finally, a very exciting area will be the growth of telehealth and different ways we can see patients in retail through telehealth opportunities.

nities with the Affordable Care Act and more patients becoming insured, in addition to the fact that we have a primary care shortage and an epidemic of obesity, diabetes, and other chronic illnesses, the need for healthcare is definitely paramount. I think that on top of consumerism where patients have higher expectations of access, there is a dramatic opportunity for retail health to grow and expand to meet these needs. MinuteClinic is growing at a rate of about 160 new clinics annually with the expectation that by the end of 2017, 60% of Americans will have access to a MinuteClinic. When you think about that, the opportunity then really becomes that MinuteClinic can have a national impact on healthcare. ❚

What key opportunities and challenges lie ahead for retail clinics? NJG: I think the opportu-

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Empowering Community Pharmacists as Health Consultants: Ten Hot Topics to Foster Delivery of Quality Patient Care A 10-PART SERIES

Oct obe r 201 4 VOL . 2 • NO. 5

CARDIOMET

8 Pharmacy Ro

le in Controlled Substance Tak eBack Programs

19 Retail He alth

Provides Acces s for General Pri mary Care Needs

InsidePh

armacyO

nline.com

ABOLIC

Health

Prediabete s: Retail Clin Practical Informatio ici Type 2 Diab ans, Patient Educat n for ion, and etes Preven PAG E 10 tion

29 Identifying

Accurate and Use Information on ful Drug–Grapefrui t Juice Interacti ons

40 Europay/

The publishers of Inside Pharmacy are proud to present Empowering Community Pharmacists as Health Consultants: Ten Hot Topics to Foster Delivery of Quality Patient Care series.

MasterCard/Vis a Migration Sta tus

CPE AVAILA PAGE 24

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Topics include: • • • • • • • • • •

Diabetes Detection and Control of Hypertension: Role of the Community Pharmacist Improving Women’s Health with Pharmacist-Led Osteoporosis Screening and Medication Closing the Loop: Pharmacist-Assisted Management of Asthma Pharmacist’s Perspective on the Management of Irritable Bowel Syndrome Pharmacist Involvement in the Management of Chemotherapy-Induced Nausea and Vomiting Community Pharmacist Intervention in Noncancer Pain Management Common Dermatologic Conditions: Pharmacists’ Perspectives Spectrum of Rheumatologic Diseases: Pharmacists’ Perspectives Community Pharmacists’ Role in Medical Management: Case-Based Illustration of Polypharmacy in the Geriatric Population Empowering Community_IP A-SIZE_100114

View the complete series online at:

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Continuing Education Release date: October 1, 2014 Expiration date: October 31, 2015 Estimated time to complete activity: 0.7 hour Jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC.

This activity is supported by an independent educational grant from AstraZeneca. TARGET AUDIENCE This activity has been designed to meet the educational needs of community clinical and retail pharmacists. EDUCATIONAL OBJECTIVES After completing this activity, the participant should be better able to: • Explain the role of community pharmacists in ensuring safe and effective medication use • Review factors that can impact clinical outcomes, including patient, disease, and medication • Utilize strategies to improve patient care, including patient education and medication adherence counseling • Describe the ways that community pharmacists can help their patients achieve optimal health and value through the knowledge and application of traditional and nontraditional care • Provide accurate and appropriate counsel as part of the treatment team FACULTY Karen Whalen, PharmD, BCPS, CDE Director, MS Pharmacy, MTM Degree Program Clinical Professor, College of Pharmacy University of Florida Gainesville, FL Pharmacist Continuing Education Accreditation Statement Postgraduate Institute for Medicine is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation Postgraduate Institute for Medicine designates this continuing education activity for 0.7 contact hour(s) (0.07 CEUs) of the Accreditation Council for Pharmacy Education. (Universal Activity Number - 08099999-14-208-H01-P)

Empowering Community Pharmacists as Healthcare Consultants: Diabetes by KAREN WHALEN, PHARMD, BCPS, CDE

iabetes is a chronic metabolic disorder characterized by hyperglycemia that results from insulin resistance, diminished or absent insulin secretion, or both. The disease is estimated to affect 29.1 million Americans, or more than 9% of the total US population.1 With an increase in overweight and obese Americans, the prevalence of diabetes is expected to rise in the foreseeable future. The most common form of diabetes, which accounts for Disclosure of Conflicts of Interest Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high-quality CME/ CE activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/ life partner have with commercial interests related to the content of this CE activity:

Type of Activity: Knowledge

INSIDE PHARMACY ❚ October 2014

Name of Faculty or Presenter Karen Whalen, PharmD, BCPS, CDE

Reported Financial Relationship Ownership interest: Merck

approximately 95% of all cases, is type 2 diabetes—that is, diabetes associated with insulin resistance.2 Given the complex nature of diabetes, and its common complications and comorbidities, the disease is best managed by a team of healthcare professionals.3 Since community pharmacists are in frequent contact with patients with diabetes who require medications, devices, or monitoring supplies, they are well positioned to play an important role in the diabetes care team. The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CE activity: The following PIM planners and managers—Laura Excell, ND, NP, MS, MA, LPC, NCC; Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CCMEP; and Jan Schultz, MSN, RN, CCMEP—hereby state that they or their spouse/ life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Center of Excellence Media, LLC: Susan Berry hereby states that she or her spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Instructions for Credit There is no fee for this activity. To receive credit after read-

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Continuing Education Screening in High-Risk Patients Early detection of diabetes allows for timely treatment, and adequate control of glucose early in the disease course may decrease the severity of complications. Although widespread screening of the general population for diabetes is not recommended, screening high-risk individuals can be both cost-effective and life-saving. High-risk patients are adults who are overweight or obese (body mass index ≥25 kg/m2) and who have at least one additional risk factor for diabetes, including high-risk race/ ethnicity (African American, Latino, Native American, Asian American, or Pacific Islander); family history of diabetes; physical inactivity; or a history of dyslipidemia (low high-density lipoprotein cholesterol level or high triglyceride level), hypertension (blood pressure ≥140/90 mm Hg or receiving treatment for hypertension), or cardiovascular disease (CVD).3 Pharmacists should also be vigilant for the use of certain medications, such as atypical antipsychotics and corticosteroids, which may contribute to a person’s risk for type 2 diabetes. The pharmacy waiting area is a ing this CME/CE activity in its entirety, participants must complete the posttest and evaluation. The posttest and evaluation can be completed online at http://ce.lynxcme. com/COE176-1. Upon completion of the evaluation and scoring 75% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 75% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. If you have any questions regarding the CE certification for this activity, please contact Postgraduate Institute for Medicine at: information@pimed.com or 303-799-1930. Pharmacists: Upon successfully completing the posttest with a score of 75% or better and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks. Media: Printed report Disclosure of Unlabeled Use This educational activity may contain discussion of pub-

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prime location to educate patients who may be at risk for diabetes. Strategic placement of posters or other educational materials that outline risk factors for diabetes, use of paper or electronic quizzes to assess risk, and short educational videos are all excellent ways

Although widespread screening of the general population for diabetes is not recommended, screening high-risk individuals can be both cost-effective and life-saving. for patients to pass the time and learn more about the disease. Many of these educational resources are available on the American Diabetes Association (ADA) website.4 Pharmacies that do not have dedicated waiting areas can use bag stuffers to deliver information or can post a sign at the counter that reads as follows: “Are you at risk lished and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

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Continuing Education for diabetes? For more information, ask your pharmacist.” Each of these strategies can serve as conversation starters for the pharmacist to engage the patient in a discussion about the importance of screening for diabetes. For patients who are hesitant about screening, pharmacists may use motivational interviewing (MI) techniques. MI is a beneficial tool for empowering patients to change their behaviors,5 and training in MI should be considered by all community pharmacists who want to serve in a healthcare consultant role.

Pharmacists who conduct screenings should use appropriate, well-maintained glucose monitors and suitable personal protective equipment. Community pharmacists who intend to conduct diabetes screenings should be knowledgeable of criteria for the diagnosis of the disease (fasting plasma glucose ≥126 mg/dL or hemoglobin A1c [HbA1c] ≥6.5%).3 In most cases, a finding suggestive of diabetes should be confirmed with a repeat test. Pharmacists should refrain from providing a patient with a diagnosis, however, and, more appropriately, should suggest that he or she consult with a healthcare provider for follow-up testing. Pharmacists who conduct screenings should use appropriate, well-maintained glucose monitors and suitable personal protective equipment. In addition, the pharmacy site must obtain a Clinical Laboratory Improvement Amendments waiver prior to performing any type of testing for the presence of disease.6

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Patient Education Nonpharmacologic interventions, medications, self-monitoring, goals of treatment, and potential complications are important educational points for patients with diabetes. Nonpharmacologic interventions include such lifestyle modifications as medical nutrition therapy (MNT) and exercise, and such surgical options as bariatric surgery.7,8 Pharmacists may become familiar with these interventions by reviewing position statements and guidelines from the ADA.3 In general, MNT for patients with diabetes should involve a registered dietitian,3 and pharmacists should consider networking with local dietitians so that they may recommend one when appropriate. Exercise regimens should not be recommended without approval or clearance from the patient’s healthcare provider. Appropriate medication counseling is essential to maximize the effectiveness of regimens for diabetes and minimize the risk for adverse events. For instance, pharmacists should communicate that certain medications (eg, exenatide, repaglinide) are more effective when taken preceding a meal and that the risk for adverse events associated with the use of other medications (eg, metformin) is lower when these drugs are taken with food. Spending a few minutes with a patient to make certain that he or she understands how to administer a new pen device (eg, exenatide regular or extended-release, liraglutide, and insulin pens) can have a major impact on efficacy and adherence rates. If the pharmacist is unfamiliar with the device, a quick refresher can be obtained by accessing most product websites, which usually provide detailed instructions and/or video demonstrations. Pharmacists can also familiarize themselves with the treatment options available for patients with diabetes by reviewing recommended treatment

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Continuing Education algorithms from the ADA9 and the American Association of Clinical Endocrinologists.10 Both of these organizations provide summary charts of medications, including the advantages and disadvantages associated with the use of each agent. Self-monitoring of blood glucose levels should be encouraged among all individuals with diabetes. The frequency of monitoring will vary based on the severity of the disease. For example, patients on intensive insulin therapy should monitor their levels at least 3 to 4 times daily, whereas those with fairly well-controlled type 2 diabetes can monitor a few times weekly, alternating between fasting and postprandial (1-2 hours after the start of a meal) glucose checks.3 For most patients, suggested blood glucose targets are 70 to 130 mg/dL for fasting blood glucose, <180 mg/dL for postprandial glucose, and HbA1c <7.0%.3 Glucose goals and target HbA1c may be adjusted depending on the age, frailty, life expectancy, and comorbidities of the patient. When counseling patients on self-monitoring, the pharmacist should consult with their provider to confirm the desired glucose goals and frequency of monitoring. Diabetes affects ethnically diverse populations,11 and many patients with the disease have low levels of health literacy. Pharmacists should be prepared to deliver education in a culturally sensitive manner and at a literacy level appropriate for each individual patient.

Acute and Chronic Complications Hypoglycemia and severe hyperglycemia (diabetic ketoacidosis [type 1] or hyperosmolar hyperglycemic nonketotic syndrome [type 2]) are both considered acute complications of diabetes. The risk for hypoglycemia is minimized by appropriate dosing of medications based on patient age, activity level, severity of dis-

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ease, and renal function (eg, avoidance of glyburide in patients with diminished kidney function); monitoring of blood glucose levels; and patient education. Patients and caregivers should be educated on the signs, symptoms, and management of hypoglycemia.12 Hyperglycemia

Substantial evidence demonstrates that controlling blood glucose levels prevents the development and progression of microvascular complications. is best avoided by appropriate titration of medication, adherence to medication, and appropriate sick day management. Community pharmacists can play a role in educating patients on the signs and symptoms of hypoglycemia/hyperglycemia and suggesting an action plan to manage these complications. In addition, pharmacists can be instrumental in identifying adherence issues that contribute to uncontrolled hyperglycemia. Chronic complications of diabetes include microvascular complications, such as nephropathy, neuropathy, and retinopathy. Substantial evidence demonstrates that controlling blood glucose levels prevents the development and progression of microvascular complications.13,14 Furthermore, adequate control of blood pressure reduces the risk for both nephropathy and retinopathy.3 In general, patients should be screened annually for diabetic kidney disease, and those with persistent albuminuria may benefit from treatment with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) to reduce the risk or slow the progression of nephrop-

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Continuing Education athy. Painful symptoms of neuropathy can be managed with such medications as pregabalin, duloxetine, venlafaxine, or valproate. The risk for CVD is significant in persons with diabetes, with heart disease or stroke claiming the lives of 2 of 3 patients.15 Controlling other risk factors, such as hypertension and dyslipidemia, is paramount in reducing the

Controlling other risk factors, such as hypertension and dyslipidemia, is paramount in reducing the occurrence of CVD in patients with diabetes. occurrence of CVD in patients with diabetes. Although some differences of opinion exist in recent guidelines, most concur that the risk for CVD is reduced when a target blood pressure of <140/80 mm Hg or <140/90 mm Hg is achieved.2,16 Traditionally, blood pressure regimens for patients with diabetes have contained an ACE inhibitor or an ARB. Recent evidence suggests, however, that a calcium channel blocker or a thiazide-type diuretic may be an appropriate first-line option in black patients with diabetes.16,17 With respect to dyslipidemia, the ADA supports a target low-density lipoprotein (LDL) cholesterol level of <100 mg/dL for most individuals (LDL <70 mg/dL for those with CVD), and recommends statin therapy for patients with clinical CVD or those >40 years of age with other risk factors for CVD.3 In contrast, the American College of Cardiology/American Heart Association cholesterol guidelines do not advocate for specific LDL cholesterol goals, but instead recommend moder-

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ate- or high-intensity statin therapy for most patients with diabetes.18 In addition to blood pressure and lipid control, aspirin therapy (75-162 mg/day) should be considered for patients with CVD, and for male patients >50 years of age and female patients >60 years of age with diabetes and other CVD risk factors.3 Pharmacists can provide key interventions by screening for patients with diabetes who may benefit from ACE inhibitor, statin, or aspirin therapy, and by monitoring for adherence issues with these valuable treatments.

Recent Advances in Pharmacologic Treatment Along with new dipeptidyl peptidase-4 (DPP-4) inhibitors (eg, alogliptin, linagliptin)19,20 and glucagon-like peptide-1 (GLP-1) receptor agonists (eg, extended-release exenatide, albiglutide),21,22 the sodium-glucose cotransporter 2 (SGLT2) inhibitors represent a recent addition to the treatment armamentarium for patients with type 2 diabetes. SGLT2 inhibitors (eg, canagliflozin, dapagliflozin, and empagliflozin) improve glycemic control by increasing urinary glucose excretion in the urine.23-25 Since these agents work in the kidneys, they should be avoided in patients with renal dysfunction. Elderly patients and those taking diuretics may be susceptible to hypotension if treated with an SGLT2 inhibitor. Other common adverse effects associated with the use of SGLT2 inhibitors include female genital mycotic infections and urinary tract infections.23-25 With an increasing number of medications available for the treatment of diabetes, the use of dual and triple combination therapies is on the rise. Pharmacists should be on the alert for drug interactions and inappropriate combinations of antihyperglycemic

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Continuing Education agents. For instance, the risk for hypoglycemia increases when a sulfonylurea (eg, glipizide) is combined with a DPP-4 inhibitor (eg, saxagliptin, sitagliptin) or a GLP-1 receptor agonist (eg, exenatide, liraglutide). Overall, most combinations of drugs for type 2 diabetes are acceptable. Combination therapy with sulfonylureas and meglitinides (eg, repaglinide, nateglinide) or with DPP-4 inhibitors and GLP-1 receptor agonists should be avoided, however, because of overlapping mechanisms of action and/ or increased risk for toxicity.10

Conclusion Community pharmacists are well positioned to play a vital role in the diabetes healthcare team. Significant contributions to the care of patients with diabetes can be achieved through patient education and counseling; management of pharmacologic therapies; identification of those individuals who may benefit from added treatments, such as statins, ACE inhibitors, and aspirin; and monitoring for potentially deleterious drug interactions. ❚ References

1. American Diabetes Association. Statistics about diabetes. www.diabetes.org/diabetes-basics/statistics/?loc=db slabnav. Accessed September 1, 2014. 2. Centers for Disease Control and Prevention (CDC). National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States, 2011. Atlanta, GA: US Department of Health & Human Services, Centers for Disease Control and Prevention, 2011. www.cdc.gov/diabetes/pubs/factsheet11. htm. Accessed September 9, 2014. 3. American Diabetes Association. Standards of medical care in diabetes—2014. Diabetes Care. 2014;37(suppl 1):S14-S80. 4. American Diabetes Association. Are you at risk? www. diabetes.org/are-you-at-risk/. Accessed September 2, 2014. 5. Bundy C. Changing behaviour: using motivational interviewing techniques. J R Soc Med. 2004;97(suppl 44):43-47. 6. Centers for Disease Control and Prevention (CDC). Clinical Laboratory Improvement Amendments (CLIA). www.cdc.gov/clia/. Accessed September 2, 2014.

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7. American Diabetes Association. Food and fitness. www. diabetes.org/food-and-fitness/?loc=ff-slabnav. Accessed September 2, 2014. 8. American Diabetes Association. BMI guidelines for bariatric surgery in diabetes: how low can we go? Diabetes Care. 2012;35:1399-1400. 9. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55:1577-1596. 10. Garber AJ, Abrahamson MJ, Barzilay JI, et al. American Association of Clinical Endocrinologists’ comprehensive diabetes management algorithm 2013 consensus statement. Endocr Pract. 2013;19(suppl 2):1-48. 11. American Association of Diabetes Educators. AADE position statement. Cultural sensitivity and diabetes education. Diabetes Educ. 2012;38:137-141. 12. Seaquist ER, Anderson J, Childs B, et al. Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care. 2013;36:1384-1395. 13. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986. 14. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589. 15. American Diabetes Association. Heart disease. www.dia betes.org/living-with-diabetes/complications/heart-disease/. Accessed September 2, 2014. 16. James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507-520. 17. Weber MA, Schiffrin EL, White WB, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich). 2014;16:14-26. 18. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;129(25 suppl 2):S1-S45. 19. Nesina [package insert]. Deerfield, IL: Takeda Pharma ceuticals America, Inc.; 2013. Revised: June 2013. 20. Tradjenta [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2014. 21. Bydureon (exenatide extended-release for injectable suspension) [package insert]. Wilmington, DE. AstraZeneca; 2014. 22. Tanzeum for injection, for subcutaneous use [package insert]. Wilmington, DE: GlaxoSmithKline LLC; 2014. 23. Invokana [package insert]. Titusville, NJ: Janssen Pharma ceuticals, Inc; 2013. 24. Farxiga [package insert]. Princeton, NJ: Bristol-Myers Squib Company; 2014. 25. Jardiance [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2014.

Dr Whalen is Director, MS Pharmacy, MTM Degree Program, Clinical Professor, College of Pharmacy, University of Florida, Gainesville, FL.

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INSIDE

SCHIZOPHRENIA Impact of long-acting injectable antipsychotics [36]

The Retail Pharmacy Identifying Accurate and Useful Information on Drug–Grapefruit Juice Interactions An analysis of prescribing and written patient drug information from the United States and Canada by LINH B. VAN, PHARMD, BCPS, and DONNA D. HUYNH, PHARMD, BCPS

KEY POINTS ❚ Oral drugs with low oral bioavailability that are metabolized by the cytochrome P450 3A4 isozyme have the most potential to interact with grapefruit juice ❚ Pharmacists should refer to both the PI and WPDI for drug–grapefruit juice interactions because of inconsistencies between these documents ❚ Pharmacists should be aware that the WPDI may not present drug–grapefruit juice interactions in a clear or actionable manner

Grapefruit juice may interact with many medications because it contains furanocoumarins, which inhibit the cytochrome P450 3A4 (CYP3A4) enzymes }} }} FOUND IN THE PARENCHYMAL cells of the liver and within the epithelial cells lining the small intestines and colon.1 Oral drugs with low oral bioavailability that are metabolized by the CYP3A4 isozyme have the most potential to interact with grapefruit juice.1 Commonly prescribed and dispensed oral medications,2 such as carbamazepine, lovastatin, lurasidone, simvastatin, tacrolimus, and vardenafil, may interact with grapefruit juice. Community pharmacists will often counsel patients on these medications and need to know where to find reliable and accurate

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information about the drug–grapefruit juice interaction.

Using Medication’s PI Pharmacists, especially those working in the community, often use a medication’s prescribing information (PI) to determine whether an interaction exists between the particular medication and any foods. The US Food and Drug Administration (FDA) recommends that manufacturers report potential interactions with grapefruit juice and include that information in the patient counseling section of the PI.3

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Inside the Retail Pharmacy However, the documentation of drug– food interactions in the PI can be inconsistent and varies between countries.4,5 Furthermore, the PI may not include adequate information concerning drug interactions,6 resulting in a lack of guidance to avoid or reduce incidences of common drug interactions.7 In addition to reporting potential interactions with grapefruit juice within the PI, manufacturers author prescription drug information that patients may use to identify drugs that interact with grapefruit juice. In the United States, written patient drug information (WPDI) approved by the FDA, which includes medication guides and patient information leaflets (PILs), is distributed to patients to convey serious risks associated with certain medications.8 PILs, also available in Canada, are reviewed and approved by Health Canada. The FDA advises that it is acceptable to drink grapefruit juice if the WPDI does not mention the interaction.9 Oftentimes, community pharmacists will also direct patients to read the WPDI; therefore, it is important that the WPDI contains accurate information.

Evaluating the PI and WPDI from the United States and Canada Because pharmacists and patients may use the PI or WPDI to determine whether grapefruit juice can be safely consumed with a particular medication, these documents should be reliable, comprehensive, and clear. To compare the clinical management recommended for the grapefruit juice interaction by the product’s PI in the United States and Canada, we determined the availability of pharmacokinetic data regarding the interaction in the PI. In addition, we evaluated whether grapefruit juice information between the WPDI and PI were consistent. The language used to convey the information about grapefruit juice interaction in the WPDI was also evaluated based on whether it requires patients to take any action.

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Drug products were identified from the literature, including those with published pharmacokinetic data10 and those with documented or predicted increases in oral bioavailability1,11 with grapefruit juice. Drug products that interact with grapefruit juice from First Databank’s patient education monograph and drug– food interaction modules were also included.12

Interactions, Availability of Pharmacokinetic Data For products approved in the United States and Canada, a current PI was obtained from the FDA website13 and Health Canada Drug Product Database website,14 respectively. The National Library of Medicine’s DailyMed website was also used if the PI could not be located on the FDA website.15 When available, the innovator PI or PI for the brand name product was selected for comparison. If multiple generic PI were available, the PI with a revision date of 2009 or later was selected. Each website was accessed from May 2013 to July 2013. Two investigators (LBV, DDH) independently reviewed each PI for qualitative and quantitative information. Data were collected regarding the description of the grapefruit juice interaction, recommendation for its clinical management, and availability of pharmacokinetic data. Clinical management was coded as one of the following: avoid; use with caution; no clinically significant interaction; or interaction was not mentioned. For interactions that might lead to fatal adverse events, the clinical management was also coded as “avoid.” PI with recommendations to either avoid grapefruit juice or use grapefruit juice with caution were grouped together because these required an action from the clinician, such as informing the patient about the interaction. Conversely, PI that did not mention the interaction or stated that there was no clinically significant interaction with grapefruit juice were grouped together because no action would be required by the clinician.

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Inside the Retail Pharmacy Figure. Drug products evaluated from the United States and Canada

202 drug products identified from review references and FDB database

Excluded Drug Products (N = 106) 22 no active products in the United States 3 PIs (erroneous information) 81 PIs without MGs/PILs

96 US Drug Products Evaluated 38 MGs/PILs mentioned grapefruit juice 58 MGs/PILs did not mention grapefruit juice

Excluded Drug Products (N = 71) 58 no active products in Canada 4 PIs not located 9 PIs without MGs/PIL

131 Canadian Drug Products Evaluated 61 MGs/PILs mentioned grapefruit juice 70 MGs/PILs did not mention grapefruit juice

FDB indicates First Databank; MG, medication guide; PI, prescribing information; PIL, patient information leaflet.

Consistency, Quality of Information If the PI also contained a PIL and/ or a medication guide, the WPDI was reviewed to determine the presence and quality of the grapefruit juice interaction information. The FDA Useful Written Consumer Medication Information states the information given to patients should be “sufficiently specific and comprehensive” and “presented in an understandable and legible format that is readily comprehensible to consumers.”16 If the WPDI noted a specific action to take with regard to consumption of grapefruit juice, the message in the WPDI was counted as actionable. In addition, the PI and WPDI for a specific drug product from the same manufacturer were compared to determine whether the grapefruit juice interaction information was consistent between the 2 documents. Any discordance regarding the coding of the data was resolved through discussion by the investigators. Statistical Analysis Descriptive statistics were used to describe the percentage of actionable WPDI and the percentage of PI with pharmacokinetic data on grapefruit juice interaction. Kappa (κ) statistics17 were used to calculate the agreement between US and Canadian PI on actionable clinician management and to determine agreement between a product’s PI and WPDI on clinical management of the grapefruit juice interaction. A statistic of

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0.81-0.99 was ranked as almost perfect, 0.61-0.80 substantial, 0.41-0.60 moderate, 0.21-0.40 fair, 0.01-0.20 slight, and <0 less-than-chance agreement.17 The statistics were calculated manually.

Substantial Agreement Observed We identified 202 drug products that could potentially interact with grapefruit juice. Of the 202 drug products, 25 were excluded from the US products due to lack of product availability or inability to locate PI, leaving 177 drug products evaluated. Sixty-two drug products were excluded from the Canadian products due to lack of product availability, no PI available, or product discontinuation; 140 drug products were evaluated. Overall, we identified 3 errors among the US PI based on the proposed mechanism of the interaction (Table 1).13-15 That is, grapefruit juice can increase orally administered drug levels by bypassing first-pass metabolism, preventing the drug from being metabolized twice before reaching the systemic circulation.1 Drugs given intravenously, such as ixabepilone18 and temsirolimus,19 and those given rectally, such as ergotamine/ caffeine,20 mechanistically should not interact with grapefruit juice since they would not undergo first-pass metabolism. Table 2 shows the clinical management recommended for the grapefruit juice interaction for the 135 drug products found in both the United States

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Inside the Retail Pharmacy Table 1. Errors in reporting grapefruit juice interaction in prescribing information for specific drug products Drug & Route

Comment

US Prescribing Information

Ixabepilone Intravenous injection

Intravenous route bypasses first-pass metabolism; bioavailability 100%

Avoid concomitant grapefruit juice administration13

Ergotamine/caffeine Rectal

Rectal route bypasses firstpass metabolism

Potent CYP3A4 inhibitors should not be given concomitantly with ergotamine. While these reactions have not been reported with less potent CYP3A4 inhibitors, there is a potential risk for serious toxicity, including vasospasm, when these drugs are used with ergotamine. Examples of less potent CYP3A4 inhibitors include grapefruit juice14

Temsirolimus Intravenous injection

Intravenous route bypasses first-pass metabolism; bioavailability 100%

Grapefruit juice may also increase plasma concentrations of sirolimus, a major metabolite of temsirolimus, and should be avoided15

CYP3A4 indicates cytochrome P450 3A4.

and Canada. Ninety-one products (67%) had consistent clinical management recommendations for the grapefruit juice interaction between the US and Canadian PI. The US PI for 7 products (5%) recommended avoiding grapefruit juice, but the Canadian PIs did not. For 18 products (13%), the Canadian PI provided some grapefruit juice information, but the US PI did not mention the interaction. Overall, agreement between the US and Canadian PI regarding whether an action was required by a clinician to manage the grapefruit juice interaction was substantial (κ = 0.61). Of the 177 US and 140 Canadian PI, pharmacokinetic data about grapefruit juice interaction were provided in 38 US PI (21%) and 25 Canadian PI (18%). Forty percent and 31% of US and Canadian PI, respectively, provided pharmacokinetic data to support their recommendation to avoid grapefruit juice (Table 3). The manufacturer-specific WPDI and PI were also compared within each country (Figure). Of the 96 US and 131 Canadian products with a WPDI, 78 US (81%) and 114 Canadian (87%) products had consistent information regarding grapefruit juice in their WPDI and PI. The agreement between WPDI and

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Table 2. Clinical management of grapefruit juice interaction recommended by US and CA prescribing information Clinical Management Avoid Use with caution

US Products, n (%) (N = 135)

CA Products, n (%) (N = 135)

40 (30)

43 (32)

7 (5)

13 (10)

No clinical significance

21 (15)

17 (12)

Did not mention

67 (50)

62 (46)

CA indicates Canadian.

PI were substantial in both the United States (κ = 0.67) and Canada (κ = 0.78). The 18 US products with WPDI that were not consistent in their PI included high-risk medications, such as fentanyl lozenges. For example, the PI for fenta nyl lozenges states that grapefruit juice should be avoided because it increases fentanyl concentrations21; however, the corresponding medication guide makes no mention of the interaction.22 Of the 96 US products with a WPDI, 58 did not mention an interaction with grapefruit juice, and of the 131 Canadian products with a WPDI, 70 did not mention the interaction. WPDIs for all 38 US products (100%) that mentioned the interaction contained actionable information, whereas only 44 Canadian products (63%) contained actionable information.

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Inside the Retail Pharmacy Table 3. Availability of PK data in US and CA prescribing information on grapefruit juice interaction based on clinical management recommendation US Products (N = 177)

CA Products (N = 140)

PK Data Provided, Yes (%)

PK Data Provided, No (%)

PK Data Provided, Yes (%)

PK Data Provided, No (%)

21 (40)

32 (60)

14 (31)

31 (69)

Use with caution

2 (15)

11 (85)

1 (7)

14 (93)

No clinical significance

15 (50)

10 (59)

7 (41)

0 (0)

81 (100)

0 (0)

63 (100)

Clinical Management Avoid

Did not mention

CA indicates Canadian; PK, pharmacokinetic.

Discussion Inconsistencies in the PI from various countries on other drug–drug interactions and their clinical management have been noted. Hirata-Koizumi and colleagues noted that the interaction between valproic acid and meropenem varies from being a contraindication in Japan to only a precaution in the United States.4 In our study, although there was substantial agreement between the US and Canadian PI regarding whether an action was required by a clinician to manage the grapefruit juice interaction, the inconsistent cases included drugs with a potential for serious adverse events if administered with grapefruit juice. If they rely solely on the information provided in the PI, clinicians may inadvertently tell patients it is okay to drink grapefruit juice, without realizing the actual risks. There is also a paucity of pharmacokinetic data within the PI to help clinicians evaluate the significance of the grapefruit juice interaction. Saito and colleagues demonstrated that the US PI provided more quantitative data regarding grapefruit juice interaction with calcium channel blockers than did the United Kingdom or Japan23; of the 7 calcium channel blockers in their study, US PI provided quantitative data for 4 of these interactions, UK PI provided quantitative data for 1 interaction, and Japan PI provided no quantitative infor-

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mation.23 Our study demonstrates that the percentage of PI with quantitative data on grapefruit juice is much lower, regardless of drug class. Surprisingly, more pharmacokinetic data are provided in the PI when the manufacturers deemed the interaction to be of no clinical significance. Pharmacists should continue to rely on the primary literature for pharmacokinetic data on grapefruit juice interactions. Our study found 3 errors in the US PI that should not have included the grapefruit juice interaction, based on the mechanism of this interaction. When interpreting data found in PI regarding the grapefruit juice interaction, pharmacists should remember the characteristics that make a drug particularly vulnerable to grapefruit juice effects. Although our study showed the agreement between WPDI and PI to be substantial for each country, the inconsistent cases included high-risk medications (eg, fentanyl) and other medications (eg, atorvastatin, varden afil) with potential for serious adverse events if taken with grapefruit juice. In all 3 cases, the PI recommended avoidance of grapefruit juice, but the WPDI did not mention the interaction. Underreporting of the grapefruit juice interaction in the WPDI could be potentially dangerous. In general, WPDI should accurately reflect what is stated

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Inside the Retail Pharmacy in the PI. By not giving a consistent message, manufacturers are potentially causing confusion and patient harm. The inconsistent cases from our study illustrate the need for health regulatory agencies to ensure that a manufacturer provides a consistent message regarding drug–food interactions when approving the PI and WPDI for a drug product. When counseling patients, pharmacists should refer to both the PI and WPDI for drug–grapefruit juice interactions because of the inconsistencies between these documents. Finally, we found that some WPDI used language that might not be clear to patients. WPDI related to grapefruit juice interactions should be conveyed in a clear, useful, and actionable manner to avoid any ambiguity regarding administration. Actionable information about drug–grapefruit juice interactions is essential to avoid adverse events. Our study has several potential limitations. The study sample does not represent the entire population of PI and WPDIs available, because only 1 current PI per drug product was selected. Although we tried to use the brand/ innovator PI or current PI, there is a potential for selection bias. In addition, we did not look at every relevant dosage form available for every drug. Our analysis demonstrates that, in general, US and Canadian manufacturers are consistent in their recommendations for managing the grapefruit juice interaction; however, more pharmacokinetic data should be provided in the PI to support their recommendations. Errors in PI, lack of actionable language in WPDI, and inconsistencies between a drug product’s WPDI and PI warrant caution of sole use of either by pharmacists, especially those working in the community. ❚ Acknowledgment A portion of the study results (WPDI) was presented during the poster session at the 2014 National Patient Safety Foundation Annual Congress.

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References

1. Bailey DG, Dresser G, Arnold JMO. Grapefruitmedication interactions: forbidden fruit or avoidable consequences? CMAJ. 2013;185:309-316. 2. IMS Health Drug Audit. www.imshealth.com/portal/site/ imshealth/menuitem.051a1939316f851e170417041ad8c22 a/?vgnextoid=7311e590cb4dc310VgnVCM100000a48d 2ca2RCRD&vgnextfmt=default. Accessed June 20, 2014. 3. US Food and Drug Administration. Guidance for industry drug interaction studies—study design, data analysis, implications for dosing, and labeling recommendations. www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/UCM292362.pdf. Accessed May 27, 2014. 4. Hirata-Koizumi M, Saito M, Miyake S. Adverse events caused by drug interactions involving glucuronoconjugates of zidovudine, valproic acid and lamotrigine, and analysis of how such potential events are discussed in package inserts of Japan, UK, and USA. J Clin Pharm Ther. 2007;32:177-185. 5. Gharibyar H, Sharif Y, Ghandour SE. Measuring compliance of package inserts in the Emirate of Abu Dhabi—UAE. Health. 2013;5:834-837. 6. Boyce RD, Handler SM, Karp JF. Age-related changes in antidepressant pharmacokinetics and potential drug-drug interactions: a comparison of evidence-based literature and package insert information. Am J Geriatr Pharmacother. 2012;10:139-150. 7. Saidul Islam M, Farah S. Availability and characteristics of information on drug-drug interactions in the drug package inserts: an experience from Bangladesh. Internet Journal of Health. 2007;6(1):8. 8. Wolf MS, King J, Wilson EA, et al. Usability of FDAapproved medication guides. J Gen Intern Med. 2012;27: 1714-1720. 9. US Food and Drug Administration. GFJ and medicine may not mix. www.fda.gov/forconsumers/consumerupdates/ ucm292276.htm. Accessed December 1, 2013. 10. Pharmacist Letter. Potential drug interactions with grapefruit. http://pharmacistsletter.therapeuticresearch. com/pl/articledd.aspx?pt=2&segment=5165&dd=290101. Accessed May 1, 2013. 11. Hanley MJ, Cancalon P, Widmer WW. The effect of GFJ on drug disposition. Expert Opin Drug Metab Toxicol. 2011;7:267-286. 12. First Databank. Patient Education Module™. www.fdbhealth.com/fdb-medknowledge-clinical-modules/patient-ed ucation/. Accessed June 6, 2014. 13. US Food and Drug Administration. Drugs @ FDA: FDA approved drug products. www.accessdata.fda.gov/scripts/ cder/drugsatfda/. Accessed June 4, 2014. 14. Health Canada. Drugs and health products. Updated November 16, 2012. www.hc-sc.gc.ca/dhp-mps/prodpharma/ index-eng.php. Accessed June 4, 2014. 15. DailyMed. About DailyMed. http://dailymed.nlm.nih. gov/dailymed/about.cfm. Accessed June 4, 2014. 16. US Food and Drug Administration. Guidance: useful written consumer medication information. www.fda.gov/ downloads/drugs/guidancecomplianceregulatoryinforma tion/guidances/ucm080602.pdf. Accessed July 1, 2013. 17. Viera AJ, Garrett JM. Understanding interobserver agreement: the kappa statistic. Fam Med. 2005;37:360-363. 18. Ixempra (ixabepilone) kit for injection, intravenous infusion [prescribing information]. Princeton, NJ: BristolMyers Squibb; October 2011. 19. Torisel (temsirolimus) injection, for intravenous infusion [prescribing information]. Philadeliphia, PA: Wyeth Pharmaceuticals, Inc; May 2012. 20. Migergot (ergotamine tartrate and caffeine) suppository [prescribing information]. South Plainfield, NJ: G&W Laboratories, Inc; September 2011. 21. ACTIQ (fentanyl citrate) oral transmucosal lozenge [pre scribing information]. Frazer, PA: Cephalon, Inc; December 2011. 22. ACTIQ (fentanyl citrate) oral transmucosal lozenge [medication guide]. Frazer, PA: Cephalon, Inc; December 2011. 23. Saito M, Hirata-Koizumi M, Miyake S. Comparison of information on the pharmacokinetic interactions of Ca antagonists in the package inserts from three countries (Japan, USA and UK). Eur J Clin Pharmacol. 2005;61:531-536.

Linh B. Van

Dr Van is Clinical Pharmacist, and Dr Huynh is Clinical Pharmacist, First Databank Inc, South San Francisco, CA.

INSIDE PHARMACY ❚ October 2014

Inside the Retail Pharmacy

Impact of Long-Acting Injectable Antipsychotics on Schizophrenia

“

Pharmacists can counsel patients about the use of LAIs and their benefits to reduce the stigma of injections, improve attitudes toward medication, and increase adherence.” by NICOLE L. EAST, PHARMD; MEGAN MARONEY, PHARMD, BCPP; and MEI T. LIU, PHARMD, BCPP

KEY POINTS ❚ Antipsychotics are the mainstay of treatment for patients with schizophrenia ❚ The 2 most common causes of relapse in these patients are medication discontinuation and nonadherence ❚ Strategies to reduce relapse rates include support programs, assertive community treatment, psychoeducation, and long-acting injectables

chizophrenia affects approximately 1% of the adult population in the United States and accounts for a total of $63 billion a year in direct treatment, societal, and family costs.1 Schizophrenia is a debilitating psychotic disease that is associated with a disruption in a patient’s perception, cognition, and emotion.1 Antipsychotic medications are a key component for positive outcomes in people with many serious psychiatric diagnoses, including schizophrenia, bipolar disorder, and major depressive disorder. Unfortunately, research shows that even with treatment, the majority of patients with schizophrenia relapse within 5 years, with poor adherence to oral antipsychotics being one of the most common causes in more than half of these patients.2 Long-acting injectable (LAI) antipsychotic medications have been pro-

INSIDE PHARMACY ❚ October 2014

moted as a way to improve medication adherence in this patient population, potentially leading to lower relapse rates, decreased hospitalizations, and a lower economic burden on the healthcare system. There are currently 6 LAI antipsychotics that are commercially available. This article will focus on the impact of LAIs on medication adherence, the advantages and disadvantages of LAIs, and the potential role that community pharmacists and other retail clinicians can play in mental health treatment.

Impact of Medication Adherence Literature suggests that the 2 most common causes of relapse in patients with schizophrenia are medication discontinuation and nonadherence. In the Clinical Antipsychotic Trial for Intervention Effectiveness (CATIE) study, results showed that medication discontinuation rates in these patients were as high as 74%.2,3 Moreover, patients who discontinue

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Inside the Retail Pharmacy Table. Risk Factors for Antipsychotic Nonadherence in Schizophrenia4-6 Patient factors4,6

Medication factors5

Family factors5

• • • • • • •

• Complex dosing regimen • Delayed onset • Intolerability of side effects

• Demanding family members • Overly emotional family members

Substance abuse Ongoing depression No treatment response Poor insight into illness Frequent hospitalizations Poor quality of life Negative attitudes toward medication

and restart medications of their own accord are more likely to discontinue again. Patients who are adherent at 6 months are more likely to remain adherent, whereas nonadherence in the first year of treatment with an antipsychotic medication is a predictor of poor outcomes.2 Not only is medication nonadherence associated with high relapse rates, but it also poses an economic burden in the treatment of schizophrenia. Patients who are nonadherent have increased rates of hospital admissions, rehospitalizations, and persistent psychotic symptoms. As a result of nonadherence, treatment resistance, increased risk of suicide, and longer psychiatric hospital stays can occur.2 Strategies currently used to reduce nonadherence include support programs, assertive community treatment, psychoeducation, and LAIs.4,5 Risk factors that can lead to nonadherence are classified into 3 different categories: patient, medication, and family factors (Table).4-6

Available LAIs The 6 available LAI antipsychotics (2 first-generation and 4 second-generation), products, and information are outlined in a Supplementary Online Table. Mechanism of action and side effects will be discussed within each class, although local injection site pain and redness are possible adverse events with all LAIs.7-12 First-generation.7,8 The first-generation antipsychotics (FGAs) are primar-

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ily dopamine-2 (D2) antagonists. These medications are associated with an increased risk of extrapyramidal symptoms (EPS) and hyperprolactinemia. Both haloperidol and fluphenazine require a Z-track administration, which consists of pulling the subcutaneous lay-

Risk factors that can lead to nonadherence are classified into 3 different categories. ers of the skin out of alignment with the muscles to break the junction of each layer. This allows the medication to be trapped in the muscle postinjection. It is also recommended not to massage the area after injection. It is important to note that both formulations are in a sesame seed oil base, and this information should be considered when checking a patient’s allergy history. Second-generation.9-12 The secondgeneration antipsychotics (SGAs) are different from the first because of their serotonin type 2A (5HT2A) antagonism effect and D2-antagonism. Although some SGAs still lead to EPS and hyperprolactinemia, the main concern with these medications is the risk of metabolic side effects. EPS is more common with risperidone and paliperidone; increased weight gain and appetite are more common with olanzapine.9-11 It is important to be aware that olanzapine has a black box warning of postinjection delirium/

INSIDE PHARMACY ❚ October 2014

Inside the Retail Pharmacy sedation syndrome (PDSS); therefore, a patient must be directly observed by a healthcare professional for 3 hours postinjection for fatigue and dizziness. This is why the prescriber, patient, facility, and pharmacy must be trained and enrolled in a national registry if dispensing olanzapine via the Risk

Psychiatrist and patient attitudes toward injections are considered barriers to the use of LAIs. Evaluation and Mitigation Strategy protocol.11 Most second-generation LAIs must be reconstituted and are dispensed in a kit that gives all the products necessary for the injection process.9-12 Risperidone and aripiprazole LAIs also require overlap treatment with oral medication for the first 2 to 3 weeks after starting the injection.9,12

Nicole L. East

Dr East is a PGY2 Psychiatric Pharmacy Resident at Rutgers, The State University of New Jersey; Dr Maroney is Psychiatry Clinical Pharmacist, Monmouth Medical Center, and Clinical Assistant Professor at the Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey; and Dr Liu is Psychiatry Clinical Pharmacist, Princeton House Behavioral Health, and Clinical Assistant Professor, Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey.

Advantages of LAIs A study by Peuskens and colleagues13 demonstrated that LAIs are associated with a decrease in hospitalizations and relapse, as well as improved cost-effectiveness and adherence in patients with schizophrenia compared with oral antipsychotics. This also leads to a decrease in overall healthcare costs.2,13 Not only can LAIs decrease relapse rates through earlier detection of nonadherence, but they can also allow for more predictable and stable serum drug concentrations. This reduces the risk of accidental or deliberate overdose.14 Studies also have shown that patients started and maintained on an LAI prefer it to oral medications, and are twice as likely to remain on an LAI.2 Based on the results of a study by Bartzokis and colleagues,15 it has also been suggested that in patients initiating treatment early, LAIs may be neuroprotective due to an increase in intracortical myelination volume.15

INSIDE PHARMACY â?&#x161; October 2014

Barriers to LAIs Injections in the psychiatric population have long been associated with a way of restraint and may pose a stigma for a patient when offered LAIs. This may be why physicians have decreased their use within the past 5 years by about 50%, despite the recognition of better adherence with LAIs.2 Patients also may have concerns with the fear of pain, loss of autonomy, and inconvenience of more frequent clinic visits for the injection.2,4 Psychiatrists may also be deterred by insurance coverage and the possibility of the patient not having access to the medication. Psychiatrist and patient attitudes toward injections are considered barriers to the use of LAIs.2 Community Pharmacists and Retail Clinicians There are many roles that can be identified for community pharmacists and other retail clinicians, especially related to the barriers to using LAIs. Pharmacists can counsel patients about the use of LAIs and their benefits to reduce the stigma of injections, improve attitudes toward medication, and increase adherence. Also, many insurance providers recognize that LAIs can prevent hospitalizations, and, therefore, cover the cost of medications for these patients. Community pharmacists and other retail clinicians can bridge the communication gap between the patient and psychiatrist as to whether the patient prefers an LAI, as well as between the psychiatrist and the insurance provider to advocate for the coverage of LAIs in their patients. Also, by following these patients, pharmacists may be able to recognize inadequate adherence by late refills with oral antipsychotics and can follow up with the physician. It is suggested that outpatient LAI use may be underutilized because of the limited availability of experienced personnel to administer intramuscular formulations at psychiatric office practices and community mental health centers.2 Pharmacists have the ability to admin-

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Inside the Retail Pharmacy ister immunizations in all 50 states, Washington, DC, and Puerto Rico; and 21 states allow pharmacists to administer nonvaccine injections. Currently, pharmacists in Texas, Washington, Maryland, and Washington, DC, are able to administer LAIs. The programs in Washington and Texas are specifically in community pharmacies.16 Community pharmacists can play a major role if they assist in LAI administration and can become a vital part of reducing the relapse rates within this population. ❚

References

1. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161:1-56. 2. Kaplan G, Casoy J, Zummo J. Impact of long-acting injectable antipsychotics on medication adherence and clinical, functional, and economic outcomes of schizophrenia. Patient Prefer Adherence. 2013;7:1171-1180. 3. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223. 4. Ciudad A, San L, Bernardo M, et al. Relapse and therapeutic interventions in a 1-year observational cohort study of nonadherent outpatients with schizophrenia. Prog

Neuropsychopharmacol Biol Psych. 2012;36:245-250. 5. Leucht S, Heres S. Epidemiology, clinical consequences, and psychosocial treatment of nonadherence in schizophrenia. J Clin Psychiatry. 2006;67:S3-S8. 6. Patel MX, de Zoysa N, Bernadt M, David AS. A cross-sectional study of patients’ perspectives on adherence to antipsychotic medication: depot versus oral. J Clin Psychiatry. 2008;69:1548-1556. 7. Fluphenazine Decanoate [package insert]. Schaumburg, IL: APP Pharmaceuticals, LLC; 2010. 8. Haloperidol Decanoate [package insert]. Schaumburg, IL: APP Pharmaceuticals, LLC; 2011. 9. Risperdal Consta [package insert]. Titusville, NJ: Janssen Pharmaceuticals Ltd; 2014. www.janssencns.com/risperdal/ risperdal-prescribing-information. 10. Invega Sustenna [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2014. www.invegasustenna. com/pdf/invegasustenna-prescribing-info.pdf. 11. Zyprexa Relprevv [package insert]. Indianapolis, IN: Eli Lilly and Company; 2011. http://pi.lilly.com/us/zyprexa_relprevv.pdf. 12. Abilify Maintena (aripiprazole) [package insert]. Rockville, MD: Otsuka America Pharmaceutical Inc; 2013. 13. Peuskens J, Olivares JM, Pecenak J, et al. Treatment retention with risperidone long-acting injection: 24-month results from the Electronic Schizophrenia Treatment Adherence Registry (e-STAR) in six countries. Curr Med Res Opin. 2010;26:501-509. 14. Patel MX, Taylor M, David AS. Antipsychotic long-acting injections: mind the gap. Br J Psychiatry. 2009;52:S1-S4. 15. Bartzokis G, Lu PH, Raven EP, et al. Impact on intracortical myelination trajectory of long acting injection versus oral risperidone in first-episode schizophrenia. Schizophr Res. 2012;140:122-128. 16. Oji V, McKoy-Beach Y, Pagan T, et al. Injectable administration privileges among pharmacists in the United States. Am J Health-Syst Pharm. 2012;69:2002-2005.

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8 Pharmacy Role

in Controlled Substance TakeBack Programs

19 Retail Health Provides Access for General Primary Care Needs

Health Information for Prediabetes: Practical nt Education, and Retail Clinicians, Patiention Type 2 Diabetes Preve PAGE 10

29 Identifying

Accurate and Useful Information on Drug–Grapefruit Juice Interactions

40 Europay/

MasterCard/Visa Migration Status

CPE AVAILABLE PAGE 24

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INSIDE PHARMACY ❚ October 2014

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Chain Headquarters News

Europay/MasterCard/Visa Migration Status by THOMAS WIMSETT, BSBA

ON AUGUST 9, 2011, Visa announced plans to accelerate the migration to contact chip and contactless Europay/MasterCard/Visa (EMV) chip technology in the United States. They believed that the adoption of dualinterface chip technology would provide stronger authentication and transaction security, and help prepare the US payment infrastructure for the arrival of Near Field Communication–based mobile payments by building the necessary infrastructure to accept and process chip transactions. Visa set an effective date of April 1, 2013, for acquirer processors and subprocessor service providers to support merchant acceptance of EMV chip transactions.1 In January 2012, Master Card announced their US road map to enable the next generation of electronic payments with EMV as the foundational technology.

Migration Process The United States is one of the last countries to migrate to EMV chip technology (see “EMV by the Numbers,” on page 41).2 On October 1, 2012, Visa was the first of the major card brands to announce changes to their operating rules that would shift liability for various types of card fraud to the entity involved in the transaction process that provides the least secure environment. Since Visa’s announcement, Master Card, American Express (AMEX), and Discover have all followed suit with rule changes that are essentially the same. EMV deadlines for rollout in the United States as mandated by card networks are: Visa (October 2015). The party that is the cause of a contact chip transaction not occurring will be financially liable for any counterfeit fraud losses. Does not include automated fuel dispensers. MasterCard (October

INSIDE PHARMACY ❚ October 2014

IT IS MORE IMPORTANT THAN EVER TO MOVE TO A TECHNOLOGY WITH A HIGHER LEVEL OF SECURITY. 2015). If at least 95% of MasterCard transactions originate from EMV compliant point-of-sale (POS) terminals, the merchant is relieved of 100% of account data compromise penalties (excluding fuel). AMEX (October 2015). AMEX has instituted a Fraud Liability Shift (FLS) policy that transfers liability for certain types of fraudulent transactions away from the party that has the most secure form of EMV technology. Discover (October 2015). Discover has instituted an FLS in the United States, Canada,

and Mexico. The policy is a risk-based payments hierarchy that benefits the entity that leverages the highest level of available payments security.

Higher Level of Security Needed With the pending liability shift and the increasing number of data breaches occurring in the United States today, it is more important than ever to move to a technology with a higher level of security. EMV secures the payment transaction with enhanced functionality in 3 areas: card authentication, protecting against counterfeit cards; cardholder verification, authenticating the cardholder, and protecting against lost and stolen cards; and transaction authorization, using issuerdefined rules to authorize transactions. An EMV card stores payment information in a secure chip rather than

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Chain Headquarters News on a magnetic stripe. Unlike a magnetic stripe card, it is virtually impossible to create a counterfeit EMV card that can be used to conduct an EMV payment transaction successfully. Although large data breaches will unfortunately continue to occur, the perpetrators of these crimes will find it increasingly difficult to use these data to successfully conduct payment card fraud. Several factors are now driving a dramatic increase in the issuance of EMV-enabled cards in the United States. In fact, the Aite Group recently predicted that by December 2015, 70% of credit and debit cards in the United States will contain a computer chip that conforms to the EMV protocol.3

What Should Merchants Be Doing? 1/ Assign in-house EMV expert/owner 2/ Ensure POS system supports all EMV payment types (contact, contactless/Near Field Communication, mag-stripe) 3/ Ensure POS provider and acquirer can assist by deadline 4/ Develop training program for employees affected 5/ Seek independent advice if you feel like

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EMV by the Numbers

Chip-Enabled Terminals

99.9 % 84.7% 86.3% 71.7%

The number of countries in various stages of EMV chip migration, including Canada and countries in Europe, Latin America, and Asia

2.37 billion

The number of chip payment cards in use globally your acquirer or POS provider is trying to take advantage of this change

What Not To Do 1/ Do not sign a lease for any standalone POS devices. Month-tomonth rental programs for EMV-enabled terminals are available for less than $10 2/ Avoid long-term commitments, particularly if the provider can modify processing rates 3/ Don’t ignore the importance of migrating your POS to an EMVenabled environment Conclusion US-based merchants not yet prepared for EMV functionality, need to be preparing now. With fraudsters target-

In Europe

In Canada, Latin America, and the Caribbean In Africa and the Middle East In Asia Pacific

ing US-based merchants more and more—partly because of our continued reliance on mag-stripe technologies versus the rest of the world’s migration to EMV—US-based merchants do not want to be the “weak link” where card fraud liability will reside. ❚

References

1. Visa Sets US. Acquirer processor mandate for chip transaction processing. Visa Bulletin. http://usa.visa. com/download/merchants/bulletin-usacquirer-mandate-080911.pdf. Accessed August 9, 2014. 2. Smart Card Alliance. EMV chip payment technology: frequently asked questions. www.emv-connection.com/ emv-faq. Accessed August 9, 2014. 3. Morrison D. EMV adoption prediction: 70% in 18 months. Credit Union Times. www.cutimes.com/2014/ 06/10/emv-adoption-prediction-70-in18-months?eNL=53976cbc150ba0d 70ae07952&utm_source=Daily&utm_ medium=eNL&utm_campaign= CUT_eNLs&_LID=170047018. Accessed June 10, 2014.

Mr Wimsett is Chairman and Managing Partner, Wimsett & Company, Louisville, KY; Director, Jack Henry & Associates, Monet, MO; and Board Chairman of Town & Country Bank & Trust Company, Bardstown, KY. Address correspondence to: Thomas A. Wimsett at twimsett@bardstown.com

INSIDE PHARMACY ❚ October 2014

INSIDE

Money How to Make the Best of Your 401(k) Plan by W. BEN UTLEY, CFP, and LAWRENCE B. KELLER, CFP, CLU, CHFC, RHU, LUTCF

We see a number of changes you might make to improve your financial security, but one item is usually beyond your control: your 401(k) plan. }}

KEY POINTS ❚ To improve your odds of reaching your retirement goal, you can save outside your 401(k) plan ❚ Think about your 401(k) plan, your traditional IRAs, and your taxable accounts as if they were all 1 retirement portfolio

}} UNLESS YOU ARE SELF-EMPLOYED, there is practically nothing you can do if your 401(k) has limited investment options, low contribution limits, or tax consequences. If your 401(k) is your main (or maybe your only) investment vehicle for retirement, we have good news for you: It is possible to work around your 401(k) plan’s limitations so you can get on track toward retirement.

1/ Low Limits

You may be operating under the mistaken belief that, if you max out your 401(k) plan contributions, you will be all set for retirement. Pharmacists, nurse practitioners, and physician assistants should strive to save 20% of their gross income toward retirement—starting the day they begin working. For example, a pharmacist earning $100,000 should strive to save $20,000 annually. But did you know that the maximum amount

INSIDE PHARMACY ❚ October 2014

of money you can elect to defer into your 401(k) this year is only $17,500 ($23,000 if you will be aged 50 years or older by December 31)? Although it is true that if you start early, you can save less, saving 20% provides flexibility for years where you may not be able to save as much, to allow for poor investment returns, or for a personal or financial catastrophe such as divorce or disability. If all goes well and none of these scenarios materialize, then you will be left with a wonderful choice: retire earlier or retire wealthier. Using the Rule of 72, it is easy to calculate approximately how long it is going to take for your money to double. You just take the number 72 and divide it by the interest rate you hope to earn on your investment. Therefore, assuming a 6% rate of return on your investment, your money will double in 12 years. Another rule of thumb often used by

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Inside Money financial planners is that you can safely withdraw about 4% of your nest egg each year of retirement. This rule says, in essence, that you must save about 25 times your annual expenses, or that you can withdraw approximately 4% of your portfolio in the first year of retirement and then adjust that amount for inflation each year, with little chance of running out over a 30-year retirement.

Look at your retirement investments holistically. To improve your odds of reaching your retirement goal, you can save outside your 401(k) plan. Even if you cannot deduct the contributions you make to a traditional IRA, you can still contribute $5500 this year ($6500 if you will be aged 50 years or older by December 31), and if you max out your own IRA, your spouse can also contribute up to $5500 to his or her IRA ($6500 if he or she will be aged 50 years or older by December 31) even if he or she is not earning an income. Depending upon your tax situation, it might also make sense to convert these contributions to a Roth IRA, doing what is known as a “backdoor” Roth IRA contribution. Once the money is in a Roth IRA, it can grow tax-free for the rest of your life. Of course, this still might not be enough to allow you to retire comfortably, so you should consider investments outside of your 401(k) plan and IRAs.

2/ Limited Options

You probably haven’t read the fine print behind your 401(k) plan, but you are betting that your employer or human resources department has carefully vetted both your 401(k) plan provider and the investments offered inside your plan. Don’t rely on it! If your plan charges more than 50 basis points (0.50%) on top of mutual

INSIDE PHARMACY ❚ October 2014

fund operating expenses, your plan’s costs are draining an unfair share of your retirement savings. To get this under control, you need to review your plan carefully. It’s more common to see an investment lineup consisting mostly, if not entirely, of actively managed mutual funds. At a time when most prudent investors recognize that passively managed index funds have been shown to have delivered better results at a lower cost than the average actively managed fund, there’s no good reason that your plan should continue to limit you to subpar investment options. To work around these issues, look at your retirement investments holistically. Think about your 401(k) plan, your traditional IRAs, and your after-tax accounts (mutual funds and brokerage accounts), as if they were all 1 “retirement portfolio.” Then use the best investment options available in your 401(k) and pair them with the best options available within other accounts that make up the balance of your portfolio.

3/ Tax Time Bomb

You already know that you pay more than your fair share of taxes. But did you know that you are probably setting yourself up to pay more taxes on your 401(k) than you really should? That’s right. There’s a perverse little wrinkle in the tax code that can turn your 401(k) plan into a tax time bomb. To understand this trap, you need to know a little bit about how investments are taxed. Withdrawals from your 401(k) plan will be taxed at your marginal income tax rate, which may be as high as 39.6% for federal income tax. At the same time, capital gains and qualified dividends from mutual funds held in taxable accounts outside your 401(k) plan are taxed at a maximum federal rate of 23.8% (which is 20% plus the new 3.8% Medicare surtax). This means that your 401(k) nearly doubles the tax rate you pay on capital gains and qualified income

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Inside Money by effectively converting these taxfavored returns into tax-trapped ordinary income. Consider holding equity mutual funds in a taxable account, or better yet, own them in your Roth IRA or the Roth subaccount of your 401(k), if you have one. If your 401(k) is a lousy place to stash your stock funds, what should you hold there instead? Consider lowgrowth, income-producing investments, including bond funds and stable value funds. If you have an appetite for more aggressive fare, consider high-yield (“junk”) bond funds or emerging market bond funds. Outside your 401(k) plan, these investments may be taxed at your highest marginal rate, so it’s a good idea to protect their income by keeping it inside the tax shelter of your 401(k) plan. Again, the best workaround for this

tax trap is to view your entire retirement portfolio—including your 401(k) plan, your IRAs, and your other accounts that are earmarked for retirement—as 1 portfolio. Choose to own the best investments in the accounts that make the most sense from the standpoint of expense, risk, return, and taxation.

Summary Even if your 401(k) plan has limitations, you can still make the best of the situation. All you have to do is take a look at the big picture, think outside the box, and make smart moves to put yourself on track for a solid retirement. Since there are many variables that need to be taken into consideration, you may even want to consult with a Certified Public Accountant and/or financial advisor to help you make decisions based on your specific situation. ❚

Lawrence B. Keller Mr Utley, CFP®, is the lead advisor with Physician Family Financial Advisors. Mr Keller, CFP®, CLU®, ChFC®, RHU®, LUTCF, is the founder of Physician Financial Services.

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Inside

Drug Update Zontivity (Vorapaxar), First-in-Class PAR-1 Antagonist, Receives FDA Approval to Reduce the Risk for Heart Attack, Stroke, and Cardiovascular Death by LORETTA FALA, Medical Writer

Heart disease and stroke impose an inordinate burden on patients and on society as a whole. }} }} IN THE UNITED STATES, heart disease is the number one cause of death, claiming the lives of approximately 600,000 people annually—a staggering 1 in every 4 deaths.1,2 Coronary heart disease (CHD) alone accounts for nearly 380,000 deaths yearly.2 Myocardial infarction (MI) is a common type of CHD affecting 720,000 Americans every year. Of these total MIs, 515,000 are first MIs, and 205,000 are recurrent MIs.2 Stroke is the fourth leading cause of mortality in the United States, accounting for 1 of every 19

deaths annually.1,3 In fact, every 4 minutes someone dies of a stroke. Overall, stroke affects an estimated 795,000 Americans annually; of this total, 610,000 are first strokes, and 185,000 are recurrent strokes. In addition, stroke is a leading cause of disability, particularly in individuals aged ≥65 years.3 Peripheral arterial disease (PAD), a condition characterized by plaque buildup in the legs, increases the risk for MI and stroke.4 It is estimated that 1 in every 20 Americans aged >50 years has PAD.4 CHD accounts for

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$108.9 billion total costs annually in the United States.2 Stroke alone accounts for $38.6 billion annually in healthcare costs and lost productivity.3 Adequate control of hypertension and high low-density lipoprotein cholesterol (LDL-C) has been shown to reduce the risk for stroke and CHD.5-7 Other factors that may reduce the risk for cardiovascular (CV) disease include exercising, refraining from smoking, and maintaining a healthy diet and weight.1 Pharmacologic approaches for patients at risk for CV disease include therapies that control hypertension and reduce high LDL-C and/or antithrombotic therapies.8

Patients at high risk for thrombotic events may be managed with an antithrombotic drug—either an anticoagulant or an antiplatelet.8 Many patients who have an MI undergo thrombolysis, a procedure with a clot-dissolving agent, to restore coronary artery blood flow.9 Other patients may need an urgent coronary revascularization procedure, including a coronary artery bypass graft surgery or a percutaneous intervention to improve blood flow.9 For patients with acute coronary syndromes, the use of platelet inhibitors was shown to reduce the rate of thrombotic events; however, these agents are

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Drug Update associated with a risk of bleeding.10 Recently, research has focused on the efficacy and safety of intensifying antiplatelet therapy in patients with established atherosclerosis by adding an agent with a different pharmacologic pathway.11 One of these pathways targets thrombin, a serine protease that facilitates thrombosis through the selective inhibition of protease-activated receptor (PAR)-1, the main thrombin receptor on human platelets.11

Vorapaxar: A Novel Antiplatelet Treatment Option On May 8, 2014, the US Food and Drug Administration (FDA) approved vorapaxar (Zontivity; Merck)—the firstin-class PAR-1 antagonist––for the reduction of thrombotic CV events in patients with a history of MI or with PAD.12 Vorapaxar has been shown to reduce the rate of a combined end point of CV death, MI, stroke, and urgent coronary revascularization.11 The FDA approval of vorapaxar was based on the TRA 2P-TIMI 50 (Thrombin Receptor Antagonist in the Secondary Prevention of Atherothrombotic Ischemic Events-Thombolysis in Myocardial Infarction) clinical trial, a dou-

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Table 1. Vorapaxar versus Placebo: Event Rates for Primary and Secondary End Points in the TRA 2P-TIMI 50 Study 3-yr Kaplan-Meier event rate Placebo, % (N = 13,224)

Vorapaxar, % (N = 13,225)

Hazard ratioa

Primary: composite of CV death, MI, stroke, and UCR

12.4

11.2

0.88 (95% CI, 0.82-0.95)

.001

Secondary: composite of CV death, MI, and stroke

10.5

9.3

0.87 (95% CI, 0.80-0.94)

<.001

End points

P value

Vorapaxar group versus placebo group. CI indicates confidence interval; CV, cardiovascular; MI, myocardial infarction; UCR, urgent coronary revascularization. Source: Zontivity (vorapaxar) tablets prescribing information; May 2014. a

ble-blind, placebo-controlled, phase 3 study that included more than 26,000 patients.11,13 The FDA’s labeling requires vorapaxar to be dispensed with a patient medication guide that includes instructions for its use and important safety information. This guide directs healthcare professionals to inform patients about the increased risk for bleeding and bruising associated with this medication and to instruct patients to report any unanticipated, prolonged, or excessive bleeding or blood in the stool or urine.12 According to Ellis Unger, MD, Director of the Office of Drug Evaluation in the FDA’s Center for Drug Evaluation and Research, “In patients who have had a heart attack or who have peripheral arterial disease, this drug will lower the risk of heart attack, stroke, and

cardiovascular death. In the study that supported the drug’s approval, Zontivity lowered this risk from 9.5 percent to 7.9 percent over a 3-year period—about 0.5 percent per year.”12

Dosing and Administration Vorapaxar is available as a 2.08-mg tablet (equivalent to 2.5 mg of vorapaxar sulfate) and is administered orally once daily, with or without food. The use of vorapaxar with aspirin and/or clopidogrel should follow the indications or standards of care for these medications. There is limited clinical experience with other antiplatelet drugs or with vorapaxar as the only administered antiplatelet agent.13 Mechanism of Action Vorapaxar reduces the risk for MI and stroke by decreasing the tendency

of platelets to form blood clots.9 Vorapaxar is a reversible antagonist of PAR-1 expressed on platelets, but its long halflife makes it effectively irreversible. In in vitro studies, vorapaxar has been shown to inhibit thrombin-induced and thrombin receptor agonist peptide-induced platelet aggregation.13

The Pivotal TRA 2P-TIMI 50 Clinical Trial The efficacy of vorapaxar is supported by clinical evidence from the pivotal TRA 2P-TIMI 50 clinical trial, a randomized, double-blind, placebo-controlled phase 3 clinical trial in patients with evidence or a history of atherosclerosis involving the coronary system (ie, spontaneous MI ≥2 weeks but ≤12 months before the study), the cerebral system (ie, ischemic stroke), or the peripheral

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Drug Update Table 2. Vorapaxar versus Placebo: Time to First Event in Patients with Post-MI or PAD and No History of Stroke or TIA in the TRA 2P-TIMI 50 Study Placebo (N = 10,090)

Efficacy end points Primary: composite of CV death, MI, stroke, UCRa Secondary: composite of CV death, MI, strokea

Vorapaxar (N = 10,080)

Patients with events,a N (%)

KaplanMeier,b %

Patients with events,a N (%)

KaplanMeier,b %

1073 (10.6)

11.8

896 (8.9)

10.1

0.83 (95% CI, 0.76-0.90)

<.001

851 (8.4)

9.5

688 (6.8)

7.9

0.80 (95% CI, 0.73-0.89)

<.001

Hazard ratioc

P value

Other secondary efficacy end points (first specified event at any time)d CV death

239 (2.4)

2.8

205 (2.0)

2.4

0.86 (95% CI, 0.71-1.03)

569 (5.6)

6.4

470 (4.7)

5.4

0.82 (95% CI, 0.73-0.93)

Stroke

145 (1.4)

1.6

98 (1.0)

1.2

0.67 (95% CI, 0.52-0.87)

UCR

283 (2.8)

3.0

249 (2.5)

2.8

0.88 (95% CI, 0.74-1.04)

Each patient was counted only once in the component of the primary efficacy end point. Kaplan-Meier estimate at 1080 days. c Vorapaxar group versus placebo group. d Including patients who could have had other nonfatal events or subsequently died. CI indicates confidence interval; CV, cardiovascular; MI, myocardial infarction; NR, not reported; PAD, peripheral arterial disease; TIA, transient ischemic attack; UCR, urgent coronary revascularization. Source: Zontivity (vorapaxar) tablets prescribing information; May 2014. a

vascular system (ie, documented PAD).11,13 The patients were randomized to receive daily treatment with vorapaxar (N = 13,225) or placebo (N = 13,224) in addition to the standard of care. The primary end point was a composite of CV death, MI, stroke, or recurrent ischemia leading to urgent coronary revascularization. The secondary end point was a composite of CV death, MI, or stroke. The median follow-up time was 2.5 years (up to 4 years).11,13 Table

1 describes the findings for the primary and secondary efficacy end points. Table 2 shows the findings in patients with post-MI or PAD and without a history of stroke or transient ischemic attack (TIA). The effect of long-term treatment with vorapaxar on the primary and key secondary end points was maintained for the duration of the trial (median follow-up of 2.5 years, up to 4 years).11,13 Among patients with post-MI or PAD who survived an on-study event,

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the incidence of subsequent events was lower with vorapaxar. The time from the previous MI to randomization had no relationship to the treatment benefit for the primary study outcome.11,13

Adverse Events The safety of vorapaxar was evaluated in the TRA 2P-TIMI 50 study, and included 13,186 patients––2187 of whom received treatment with this medication for more than 3 years. The patients randomized to vorapaxar

received treatment for a median of 2.3 years. The most common adverse reactions reported in patients receiving vorapaxar were bleeding, including life-threatening and fatal bleeding.11,13 The results for the bleeding end points in patients with post-MI or PAD and without a history of stroke or TIA are shown in Table 3. Vorapaxar was associated with a 55% increase in moderate or severe bleeding as measured by GUSTO (Global Utilization of

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Drug Update Table 3. Non–CABG-Related Bleeding Events in Patients with Post-MI or PAD and No History of Stroke or TIA (First Dose to Last Dose + 30 days) in the TRA 2P-TIMI 50 Study

Bleeding events

Placebo (N = 10,049)

Vorapaxar (N = 10,059)

Patients with events, N (%)

KaplanMeier,a %

Patients with events, N (%)

KaplanMeier,a %

82 (0.8)

1.0

100 (1.0)

1.3

Hazard ratiob,c

GUSTO bleeding categories Severe Moderate or severe Any GUSTO bleeding (severe, moderate, mild)

1.24 (95% CI, 0.92-1.66)

199 (2.0)

2.4

303 (3.0)

3.7

1.55 (95% CI, 1.30-1.86)

1769 (17.6)

19.8

2518 (25.0)

27.7

1.52 (95% CI, 1.43-1.61)

Fatal bleeding

14 (0.1)

0.2

16 (0.2)

0.2

1.15 (95% CI, 0.56-2.36)

Intracranial hemorrhage

31 (0.3)

0.4

45 (0.4)

0.6

1.46 (95% CI, 0.92-2.31)

Clinically significant bleedingb

950 (9.5)

10.9

1349 (13.4)

15.5

1.47 (95% CI, 1.35-1.60)

Gastrointestinal bleeding

297 (3.0)

3.5

400 (4.0)

4.7

1.37 (95% CI, 1.18-1.59)

Kaplan-Meier estimate at 1080 days. b Clinically significant bleeding includes any bleeding requiring medical attention, including intracranial hemorrhage, or clinically significant overt signs of hemorrhage associated with a drop in hemoglobin (Hb) of ≥3 g/dL (or, when Hb is not available, an absolute drop in hematocrit of ≥15% or a fall in hematocrit of 9 to <15%). c Vorapaxar group versus placebo group. CABG indicates coronary artery bypass graft surgery; CI, confidence interval; GUSTO, global utilization of streptokinase and tissue plasminogen activator for occluded arteries; MI, myocardial infarction; PAD, peripheral arterial disease; TIA, transient ischemic attack. Source: Zontivity (vorapaxar) tablets prescribing information; May 2014. a

Streptokinase and Tissue Plasminogen Activator for Occluded Arteries).11,13 GUSTO severe bleeding was defined as fatal, intracranial, or bleeding with hemodynamic compromise requiring intervention. GUSTO moderate bleeding was defined as bleeding requiring transfusion of whole blood or packed red blood cells without hemodynamic compromise. Although this study was not designed to evaluate the relative benefits and risks of vorapaxar in individual patient subgroups, patients with a

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history of stroke, TIA, or intracranial hemorrhage (ICH) showed an increased risk for ICH events.11,13

Warnings and Precautions Boxed warning. The prescribing information for vorapaxar includes a boxed warning about the risk for bleeding. Vorapaxar should not be used in patients with a history of stroke, TIA, ICH, or active pathologic bleeding. Furthermore, antiplatelet agents, including vorapaxar, increase the risk for bleeding, in-

cluding ICH and fatal bleeding.13 Contraindications. The use of vorapaxar is contraindicated in patients with a history of stroke, TIA, or ICH, because of an increased risk for ICH in this patient population. Vorapaxar is also contraindicated in patients with pathologic bleeding, such as ICH or peptic ulcer.13 General risk for bleeding. Antiplatelet agents, including vorapaxar, increase the risk for bleeding, including ICH and fatal bleeding. Vorapaxar increases a patient’s risk for bleeding in proportion

to the patient’s underlying bleeding risk. Before initiating vorapaxar therapy, the underlying risk for bleeding should be considered.13 Strong cytochrome P3A inhibitors or inducers. Vorapaxar is eliminated primarily by metabolism, with contributions from cytochrome (CY) P3A4 and CYP2J2. Strong CYP3A inhibitors increase vorapaxar exposure. Vorapaxar should not be used with strong CYP3A inhibitors (eg, ketoconazole, itraconazole, posaconazole, cla rithromycin, nefazodone,

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Drug Update ritonavir, saquinavir, nelfinavir, indinavir, bocep revir, telaprevir, telithromycin, and conivaptan). Strong CYP3A inducers decrease vorapaxar exposure. Vorapaxar should not be used with strong inducers of CYP3A (eg, rifampin, carbamazepine, St. John’s Wort, and phenytoin).13

Use in Specific Populations Pregnancy. There are no adequate and well-controlled studies of vora paxar use in pregnant women. Vorapaxar should only be used during pregnancy if the potential benefit to the mother justifies the potential risk to the fetus.13 Nursing mothers. Nurs ing should be discontinued in patients receiving vorapaxar, or vorapaxar should be discontinued in a nursing mother.13 Renal impairment. No dose adjustment is needed in patients with renal impairment.13 Hepatic impairment. In patients with mild and moderate hepatic impairment, no dose adjustment is required. Based on the increased risk for bleeding

VORAPAXAR REPRESENTS A NEW ANTIPLATELET TREATMENT OPTION FOR PATIENTS AT HIGH RISK FOR MI, STROKE, OR CV DEATH. in patients with severe hepatic impairment, vorapaxar is not recommended in these patients.13 Overdose. There is no known treatment to reverse the antiplatelet effect of vorapaxar; if bleeding occurs after a vora paxar overdose, neither dialysis nor platelet transfusion can be expected to be beneficial. The inhibition of platelet aggregation can be expected for weeks after the discontinuation of normal dosing. There is no standard test available to assess the risk for bleeding in an overdose situation.13

Conclusion Vorapaxar, the first-in-

class PAR-1 antagonist to receive FDA approval, represents a new antiplatelet treatment option for patients at high risk for MI, stroke, or CV death, namely, patients with a history of MI or with PAD. In a clinical trial involving more than 26,000 patients, treatment with vorapaxar, in addition to the standard of care, was shown to reduce the rate of a composite end point of CV death, MI, stroke, and the need for urgent coronary revascularization procedures. The most common adverse reaction reported in patients receiving vorapaxar is bleeding, including life-threatening and fatal bleeding. ❚

References

1. Centers for Disease Control and Prevention. CDC health disparities and inequalities report—United States, 2013. MMWR Morb Mortal Wkly Rep. 2013;62(suppl 3):157-160. 2. Centers for Disease Control and Prevention. Heart disease facts. Updated July 7, 2014. www.cdc.gov/ heartdisease/facts.htm. Accessed June 3, 2014. 3. Centers for Disease Control and Prevention. Stroke fact sheet. Updated July 26, 2013. www.cdc.gov/dhdsp/ data_statistics/fact_sheets/fs_stroke. htm. Accessed June 3, 2014. 4. National Institutes of Health. Facts about peripheral arterial disease (PAD). August 2006. www.nhlbi.nih. gov/health/public/heart/pad/docs/pad_ extfctsht_general_508.pdf. Accessed June 3, 2014. 5. Scandinavian Simvastatin Survival

Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:13831389. 6. Sacks FM, Pfeffer MA, Moye LA, et al; for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009. 7. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357. 8. National Cholesterol Education Program. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Final Report. NIH Publication No. 02-5215. September 2002. www.nhlbi.nih.gov/ files/docs/resources/heart/atp3full.pdf. Accessed August 15, 2014. 9. American Heart Association. Cardiac procedures and surgeries. Updated June 27, 2014. www. heart.org/HEARTORG/Conditions/ HeartAttack/Prevention TreatmentofHeartAttack/CardiacProcedures-and-Surgeries_UCM_ 303939_Article.jsp. Accessed August 15, 2014. 10. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:10451057. 11. Morrow DA, Braunwald E, Bonaca MP, et al; for the TRA 2P–TIMI 50 Steering Committee and Investigators. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366:1404-1413. 12. US Food and Drug Administration. FDA approves Zontivity to reduce the risk of heart attacks and stroke in high-risk patients. Press release. May 8, 2014. www.fda.gov/NewsEvents/ Newsroom/PressAnnouncements/ ucm396585.htm. Accessed May 20, 2014. 13. Zontivity (vorapaxar) tablets [prescribing information]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; May 2014.

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