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TARGET PULLS OUT OF CANADA Ne w 14 NE ind DA W DR ica BI UG tio G R n f A EV or TR IE DV A W To N rP E Drug Topics® Drug Topics ® DrugTopics.com Voice of the Pharmacist Feb r u a r y 2015 FEBRUARY 2015 VOL. 159 NO. 2 C E : NEW AND EMERGING THERAPIES FOR THE TREATMENT OF DIABETES 10 Pharmacy students hit the road 15 Mandatory e-Rx starts in New York 16 Pain management after surgery • OTC: ORAL CARE Promising breakthroughs in cancer, heart failure 2015 PIPELINE REPORT page 22 VOL . 15 9 NO. 2 CREDIT: 2.0 Earn CE credit for this activity at DrugTopics.com/cpe New and emerging therapies THIS SMELLS. for the treatment of diabetes 1 twitter.com/Drug_Topics THIS DOESN’T. Page 40 Which would your patients prefer? facebook.com/DrugTopics NASACORT®. RIGHT ON SHELF. RIGHT NOW. PG .3 5 NOSE-TO-NOSE, WHICH WOULD YOUR PATIENTS PREFER? 1 FLONASE® VS NASACORT® THIS SMELLS THIS DOESN’T THIS STINGS THIS DOESN’T THIS HAS ALCOHOL THIS DOESN’T Recommend Nasacort® Allergy 24HR, the OTC INS without the unpleasant extras. Use as directed. RIGHT ON SHELF. RIGHT NOW. Reference: 1. Flonase Allergy Relief question and answer book. 14-0033AWL. Clifton, NJ: GlaxoSmithKline; 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205434Orig1s000lbl.pdf. Accessed September 18, 2014. FLONASE is a registered trademark, used under license by GlaxoSmithKline Inc. 7025C © 2014 Chattem, Inc. Target pulls out of Canada Ne w 14 Ne ind DA w Dr ica BI ug tio G R n f A ev or TR ie DV A w To N rP E Drug Topics® Drug Topics ® DrugTopics.com Voice of the Pharmacist Feb r u a r y 2015 February 2015 Vol. 159 No. 2 10 P harmacy students hit the road C E : New and emerging therapies for the treatment of diabetes 15 M andatory e-Rx starts in New York 16 P ain management after surgery • OT C : ORAL C ARE Promising breakthroughs in cancer, heart failure 2015 pipeline report page 22 vol . 1 59 no. 2 CREDIT: 2.0 Earn CE credit for this activity at DrugTopics.com/cpe New and emerging therapies for the treatment of diabetes twitter.com/Drug_Topics facebook.com/DrugTopics Page 40 Pg .3 5 Everything you need to compound a single prescription quickly and accurately. Unit-of-Use Compounding Kits are the fast and accurate way for you to compound individual prescriptions for your customers as they wait. Each Kit: • contains pre-weighed, pre-measured ingredients with bar-coded dispensing containers to aid accuracy • saves prep, compounding and cleanup time • facilitates compliance with USP Chapter <795> Each Kit contains everything needed for a single prescription • has a single NDC number that saves time and eliminates waste, also eases third-party reimbursement In fact, Kits make compounding so fast and accurate, they’re changing the way pharmacists think about compounding. To learn more, call 1-800-461-7449 www.cutispharma.com magenta cyan yellow black Mouthwash BLM Mouthwash BXN Dukes’ Mouthwash 8 oz. NDC# 65628-050-01 4 oz. NDC# 65628-050-04 8 oz. NDC# 65628-051-01 8 oz. NDC# 65628-052-01 Mary’s Mouthwash 8 oz. NDC# 65628-053-01 Many more Kits are available. Visit www.CutisPharma.com ES567436_DRTP0215_CV2_FP.pgs 02.06.2015 01:53 ADV ® EDITORIAL ADVISORY BOARD Philip P. Burgess, RPh, MBA Gene Memoli Jr., RPh, FASCP Salvatore J. Giorgianni, Jr. PharmD, BSc, CMHE Chairman Community Pharmacy Foundation Illinois Board of Pharmacy Chicago, Ill. Director Customer Development, Omnicare Cheshire, Conn. Consultant Pharmacist Griffon Consulting Group, Inc. Chair, Men’s Health Caucus, American Public Health Association Advisory Board, Pharmacist Partners, LLC and The Men’s Health Network Perry Cohen, PharmD, FAMCP The Pharmacy Group LLC Glastonbury, Conn. Marvin R. Moore, PharmD Pharmacy manager and co-owner The Medicine Shoppe/ Pharmacy Solutions Inc. Two Rivers, Wisc. Mary E. Inguanti RPh, MPH, FASCP Vice President, Strategic Accounts Integrated Sales, CareFusion San Diego, Calif. David J. Fong, PharmD Brian Romig, RPh, MBA Former community chain store senior pharmacy executive Danville, Calif. Vice President Corporate Pharmacy Director Supply Chain Adventist Health System Altamonte Springs, Fla. Debbie Mack, BS Pharm, RPh Director Pharmacy Regulatory Affairs Wal-Mart Health and Wellness Bentonville, Ark. Jack Rosenberg, PharmD, PhD Anna Garrett PharmD, BCPS Professor Emeritus Pharmacy Practice and Pharmacology Long Island University Brooklyn, N.Y. Frederick S. Mayer, RPh, MPH President Dr. Anna Garrett Asheville, N.C. President Pharmacists Planning Service Inc. San Rafael, Calif. Editorial Mission: Drug Topics, a monthly news magazine guided by an editorial advisory board of pharmacy experts, reports on all phases of community, retail, and health-system issues and trends. We offer a forum for pharmacists to share practical ideas for better pharmacy management and patient care. Stephen W. Schondelmeyer PharmD, PhD Christina Medina, PharmD Director, PRIME Institute College of Pharmacy University of Minnesota Minneapolis, Minn. Manager Professional and College Relations CVS Caremark Hollywood, Fla. CONTENT CONTENT CHANNEL DIRECTOR Julia Talsma CONTENT CHANNEL MANAGER Julianne Stein 440-826-2834 / [email protected] CONTENT EDITOR Mark Lowery 440-891-2705 / [email protected] Robert McGarr Lecia Landis GROUP ART DIRECTOR ART DIRECTOR Georgiann DeCenzo 440-891-2778 / [email protected] VICE PRESIDENT, GROUP PUBLISHER Ken Sylvia 732-346-3017 / [email protected] GROUP PUBLISHER Mike Weiss 732-346-3071 / [email protected] NATIONAL ACCOUNT MANAGER Mark Hildebrand 732-346-3006 / [email protected] NATIONAL ACCOUNT MANAGER Meg Benson DIRECTOR OF MARKETING & RESEARCH SERVICES Gail Kaye 732-346-3042 / [email protected] SALES SUPPORT Hannah Curis UBM ADVANSTAR 732-346-3055 / [email protected] EXECUTIVE VICE-PRESIDENT, LIFE SCIENCES REPRINT SERVICES EXECUTIVE VICE-PRESIDENT 877-652-5295, ext. 121 / [email protected] Outside US, UK, direct dial: 281-419-5725, ext. 121 EXECUTIVE VICE-PRESIDENT LIST ACCOUNT EXECUTIVE PUBLISHING AND SALES EXECUTIVE VICE PRESIDENT SPECIAL PROJECTS DIRECTOR 732-346-3039 / [email protected] 440-891-2792 / [email protected] Rich Fiore Renee Schuster 440-891-2613 / [email protected] PERMISSIONS Maureen Cannon 440-891-2742 or 800-225-4569, ext. 2742 Fax: 440-891-2650 / [email protected] SENIOR PRODUCTION MANAGER Karen Lenzen 218-740-6371 / [email protected] 732-346-3014 / [email protected] CORPORATE DIRECTOR DIRECTOR, OF BUSINESS DEVELPMENT HEALTHCARE TECHNOLOGY SALES Margie Jaxel DIRECTOR Joy Puzzo 440-319-9570 / [email protected] Christine Shappell 732-346-3003 / [email protected] 201-391-2359 / [email protected] ACCOUNT MANAGER, DISPLAY/CLASSIFIED & HEALTHCARE TECHNOLOGY Patrick Carmody CIRCULATION 440-891-2621 / [email protected] ACCOUNT MANAGER, CLASSIFIED/DISPLAY ADVERTISING Joan Maley 440-891-2722 / [email protected] ACCOUNT MANAGER, RECRUITMENT ADVERTISING Joanna Shippoli 440-891-2615 / [email protected] BUSINESS DIRECTOR, EMEDIA Don Berman 212-951-6745 / [email protected] DrugTopics .c om magenta cyan yellow black Rebecca Evangelou EXECUTIVE VICE-PRESIDENT, HUMAN RESOURCES Julie Molleston EXECUTIVE VICE-PRESIDENT, STRATEGY & BUSINESS DEVELOPMENT Mike Alic Tracy Harris VICE-PRESIDENT, GENERAL MANAGER PHARM/SCIENCE GROUP Dave Esola VICE-PRESIDENT, LEGAL AUDIENCE DEVELOPMENT Tom Ehardt Georgiann DeCenzo Chris DeMoulin EXECUTIVE VICE-PRESIDENT, BUSINESS SYSTEMS SR VICE-PRESIDENT PRODUCTION Joe Loggia CHIEF EXECUTIVE OFFICER Michael Bernstein Francis Heid VICE-PRESIDENT, MEDIA OPERATIONS VICE-PRESIDENT, TREASURER & CONTROLLER Adele Hartwick UBM AMERICAS CHIEF EXECUTIVE OFFICER SUBSCRIPTION CUSTOMER SERVICE / ADDRESS CHANGES CHIEF OPERATING OFFICER 888-527-7008 / [email protected] PO Box 6079, Duluth, MN 55806-6079, USA CHIEF FINANCIAL OFFICER Sally Shankland Brian Field Margaret Kohler UBM PLC CONTACT US 24950 COUNTRY CLUB BLVD., SUITE 200, NORTH OLMSTED, OH 44070 MAIN NUMBER: 440-243-8100, MAIN FAX NUMBER: 440-891-2735 CUSTOMER SERVICE: 877-922-2022 EMAIL: [email protected] Tim Cobbold Andrew Crow CHIEF FINANCIAL OFFICER Robert Gray CHAIRMAN Dame Helen Alexander CHIEF EXECUTIVE OFFICER GROUP OPERATIONS DIRECTOR Februar y 2015 DRUG TOPICS ES567044_drtp0215_001.pgs 02.05.2015 20:19 1 ADV CONTENTS F E B R U A R Y 2015 VO L . 1 5 9 N O . 2 DrugTopics.com COVER STORY 2015 Pipeline Report With groundbreaking therapies for cancer and heart failure on the way, the next few years should produce some big wins — and some big winners. 2 015 PIPELINE REPORT Nine crucial seconds PAGE 8 PAGE 22 Derek Borkowski, PharmD Cand. PRESCRIBED READING 10 Mark Jacobs, RPh Pharm school confdential PAGE 10 Inside the paradigm shift Pharmacy school in the 21st century. 15 I-STOP comes to N.Y. New York is just the frst stop for e-Rx of controlled substances. Wherever you live, it’s headed your way. Robert Mabee, RPh Informed consent? PAGE 11 16 Changing the game How one health system shot down skyrocketing drug costs. New CPE mini-series: MTM for the adult patient with diabetes William Winsley, RPh Brought to you by and EPCS for all PAGE 15 Drug Topics and The University of Connecticut School of Pharmacy present a new CPE series for pharmacists ... and it’s FREE. Earn up to 2 hours of CPE credit with each online activity: and related disorders Go online to www.drugtopics.com/cpe Julie Prince, PharmD Drug-price takedown PAGE 16 2 magenta cyan yellow black DRUG TOPICS Februar y 2015 GETTY IMAGES/HH5800 • February 2015: New and emerging therapies for the treatment of diabetes • March 2015: Update on the national guidelines for diabetes management DrugTopics .c om ES567300_drtp0215_002.pgs 02.05.2015 21:34 ADV Available Exclusively from Perrigo Testosterone Gel 1% To AndroGel®1% (Testosterone Gel 1%) The first and only AB rated generic * Not actual size NDC 45802-116-02 NDC 45802-116-65 NDC 45802-116-39 2 x 75 g pumps (12.5 mg per 1.25 g) 30 packets (25 mg per 2.5 g) 30 packets (50 mg per 5 g) Available in a metered-dose pump bottle or unit-dose packets. Order today through your wholesaler or distributor. Learn more about this and other quality generics at Perrigo.com/rx Testosterone Gel 1% is available only by prescription Warning of Secondary Exposure to Testosterone: Virilization has been reported in children who were secondarily exposed to testosterone gel. Children should avoid contact with unwashed or unclothed application sites in men using testosterone gel. Healthcare providers should advise patients to strictly adhere to recommended instructions for use. Indication: Testosterone Gel 1% is used as a replacement therapy in adult males for conditions associated with a deficiency or absence of endogenous testosterone. Safety and efficacy of testosterone gel in males less than 18 years old have not been established. Testosterone Gel 1% is not intended for use in women. Topical testosterone products may have different doses, strengths, or application instructions that may result in different systemic exposure. Important Safety Information What is the most important information I should know about testosterone gel? Testosterone gel can transfer from your body to others. Women and children should avoid contact with the unwashed or unclothed area where testosterone gel has been applied to your skin. Early signs and symptoms of puberty have happened in young children who were accidentally exposed to testosterone through contact with men using testosterone gel. Stop using testosterone gel and call your healthcare provider right away if you see any signs and symptoms in a child or a woman that may have occurred through accidental exposure to testosterone gel. Signs and symptoms of exposure to testosterone gel in children may include: • enlarged genitals or early development of pubic hair • increased erections, sex drive or aggressive behavior Signs and symptoms of exposure to testosterone gel in women may include: • changes in body hair • a large increase in acne To lower the risk of transfer of testosterone gel from your body to others, you should follow these important instructions: • Apply testosterone gel only to areas that will be covered by a short sleeve T-shirt. These areas are your shoulders and upper arms, or stomach area (abdomen), or shoulders, upper arms and stomach area. • Wash your hands right away with soap and water after applying testosterone gel. • After the gel has dried, cover the application area with clothing. Keep the area covered until you have washed the application area well or have showered. • If you expect to have skin-to-skin contact with another person, first wash the application area well with soap and water. • If a woman or child makes contact with the testosterone gel application area, that area on the woman or child should be washed well with soap and water right away. Who should not use testosterone gel? Do not use testosterone gel if you: • have breast cancer • have or might have prostate cancer • are pregnant or may become pregnant or breast-feeding. Testosterone gel may harm your unborn or breast-feeding baby. Women who are pregnant or who may become pregnant should avoid contact with the area of skin where testosterone gel has been applied. Talk to your healthcare provider before taking this medicine if you have any of the above conditions. What are the possible side effects of testosterone gel? Testosterone gel can cause serious side effects including: • If you already have enlargement of your prostate gland your signs and symptoms can get worse while using testosterone gel. This can include: ■ increased urination at night ■ trouble starting your urine stream ■ having to pass urine many times during the day ■ having an urge that you have to go to the bathroom right away ■ having a urine accident ■ being unable to pass urine or weak urine flow • Possible increased risk of prostate cancer. Your healthcare provider should check you for prostate cancer or any other prostate problems before you start and while you use testosterone gel. • In large doses testosterone gel may lower your sperm count. • Swelling of your ankles, feet, or body, with or without heart failure. • Enlarged or painful breasts. • Have problems breathing while you sleep (sleep apnea). • Blood clots in the legs. This can include pain, swelling or redness of your legs. The most common side effects of testosterone gel include: • acne • skin irritation where testosterone gel is applied • lab test changes • increased prostate specific antigen (a test used to screen for prostate cancer) Other side effects include more erections than are normal for you or erections that last a long time. Call your healthcare provider right away if you have any side effects listed above or that does not go away. These are not all the possible side effects of testosterone gel. For more information, ask your healthcare provider or pharmacist. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. *These products are not manufactured or distributed by AbbVie Inc., the marketer of AndroGel® gel. AndroGel® is a registered trademark of Unimed Pharmaceuticals, LLC. ©2015, Perrigo Pharmaceuticals USA PA235 RC AD 1 Please see additional patient information on adjacent page. magenta cyan yellow black ES567445_DRTP0215_003_FP.pgs 02.06.2015 01:54 ADV MEDICATION GUIDE Testosterone Gel (tes-TOS-te-rone gel) CIII Rx Only Read this Medication Guide that comes with testosterone gel before you start using it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is the most important information I should know about testosterone gel? 1. Early signs and symptoms of puberty have happened in young children who were accidentally exposed to testosterone through contact with men using testosterone gel. Signs and symptoms of early puberty in a child may include: • enlarged penis or clitoris • early development of pubic hair • increased erections or sex drive • aggressive behavior Testosterone gel can transfer from your body to others. 2. Women and children should avoid contact with the unwashed or unclothed area where testosterone gel has been applied to your skin. Stop using testosterone gel and call your healthcare provider right away if you see any signs and symptoms in a child or a woman that may have occurred through accidental exposure to testosterone gel. Signs and symptoms of exposure to testosterone gel in children may include: • enlarged penis or clitoris • early development of pubic hair • increased erections or sex drive • aggressive behavior Signs and symptoms of exposure to testosterone gel in women may include: • changes in body hair • a large increase in acne To lower the risk of transfer of testosterone gel from your body to others, you should follow these important instructions: • Apply testosterone gel only to areas that will be covered by a short sleeve T-shirt. These areas are your shoulders and upper arms, or stomach area (abdomen), or shoulders, upper arms and stomach area. • Wash your hands right away with soap and water after applying testosterone gel. • After the gel has dried, cover the application area with clothing. Keep the area covered until you have washed the application area well or have showered. • If you expect to have skin-to-skin contact with another person, first wash the application area well with soap and water. • If a woman or child makes contact with the testosterone gel application area, that area on the woman or child should be washed well with soap and water right away. What is testosterone gel? Testosterone gel is a prescription medicine that contains testosterone. Testosterone gel is used to treat adult males who have low or no testosterone. Your healthcare provider will test your blood before you start and while you are using testosterone gel. It is not known if testosterone gel is safe or effective in children younger than 18 years old. Improper use of testosterone gel may affect bone growth in children. Testosterone gel is a controlled substance (CIII) because it contains testosterone that can be a target for people who abuse prescription medicines. Keep your testosterone gel in a safe place to protect it. Never give your testosterone gel to anyone else, even if they have the same symptoms you have. Selling or giving away this medicine may harm others and is against the law. Testosterone gel is not meant for use in women. Who should not use testosterone gel? Do not use testosterone gel if you: • have breast cancer • have or might have prostate cancer • are pregnant or may become pregnant or breast-feeding. Testosterone gel may harm your unborn or breast-feeding baby. Women who are pregnant or who may become pregnant should avoid contact with the area of skin where testosterone gel has been applied. Talk to your healthcare provider before taking this medicine if you have any of the above conditions. What should I tell my healthcare provider before using testosterone gel? Before you use testosterone gel, tell your healthcare provider if you: • have breast cancer • have or might have prostate cancer • have urinary problems due to an enlarged prostate • have heart problems • have liver or kidney problems • have problems breathing while you sleep (sleep apnea) • have any other medical conditions magenta cyan black Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Using testosterone gel with certain other medicines can affect each other. Especially, tell your healthcare provider if you take: • insulin • corticosteroids • medicines that decrease blood clotting Know the medicines you take. Ask your healthcare provider or pharmacist for a list of these medicines, if you are not sure. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. How should I use testosterone gel? • It is important that you apply testosterone gel exactly as your healthcare provider tells you to. • Your healthcare provider will tell you how much testosterone gel to apply and when to apply it. • Your healthcare provider may change your testosterone gel dose. Do not change your testosterone gel dose without talking to your healthcare provider. • Testosterone gel is to be applied to the area of your shoulders, upper arms, or abdomen that will be covered by a short sleeve t-shirt. Do not apply testosterone gel to any other parts of your body such as your penis, scrotum, or back. • Apply testosterone gel at the same time each morning. Testosterone gel should be applied after showering or bathing. • Wash your hands right away with soap and water after applying testosterone gel. • Avoid showering, swimming, or bathing for at least 5 hours after you apply testosterone gel. • Testosterone gel is flammable until dry. Let testosterone gel dry before smoking or going near an open flame. • Let the application areas dry before putting on a t-shirt. Applying testosterone gel: Testosterone gel comes in a pump or in packets. • Before applying testosterone gel, make sure that your shoulders, upper arms, and abdomen are clean, dry, and there is no broken skin. • The application sites for testosterone gel are the shoulders, upper arms, or abdomen that will be covered by a t-shirt (See Figure A). ( Figure A ) If you are using the testosterone gel pump: • Before using a new bottle of testosterone gel for the first time, you will need to prime the pump. To prime the testosterone gel pump, slowly push the pump all the way down 3 times. • Do not use any testosterone gel that came out while priming. Wash it down the sink to avoid accidental exposure to others. Your testosterone gel pump is now ready to use. • Remove the cap from the pump. Then, position the nozzle over the palm of your hand and slowly push the pump all the way down. Apply testosterone gel to the application site. You may also apply testosterone gel directly to the application site. • Wash your hands with soap and water right away. • Your healthcare provider will tell you the number of times to press the pump for each dose. If you are using testosterone gel packets: • Tear open the packet completely at the dotted line. Squeeze from the bottom of the packet to the top. • Squeeze all of the testosterone gel out of the packet into the palm of your hand. Apply testosterone gel to the application site. You may also apply testosterone gel from the packet directly to the application site. • Testosterone gel should be applied right away. • Wash your hands with soap and water right away. What are the possible side effects of testosterone gel? Testosterone gel can cause serious side effects including: • See “What is the most important information I should know about testosterone gel?” • If you already have enlargement of your prostate gland your signs and symptoms can get worse while using testosterone gel. This can include: ■ increased urination at night ■ trouble starting your urine stream ■ having to pass urine many times during the day ■ having an urge that you have to go to the bathroom right away ■ having a urine accident ■ being unable to pass urine or weak urine flow • Possible increased risk of prostate cancer. Your healthcare provider should check you for prostate cancer or any other prostate problems before you start and while you use testosterone gel. • In large doses testosterone gel may lower your sperm count. • Swelling of your ankles, feet, or body, with or without heart failure. • Enlarged or painful breasts. • Have problems breathing while you sleep (sleep apnea). • Blood clots in the legs or lungs. Signs and symptoms of a blood clot in your leg can include leg pain, swelling or redness. Signs and symptoms of a blood clot in your lungs can include difficulty breathing or chest pain. Call your healthcare provider right away if you have any of the serious side effects listed above. The most common side effects of testosterone gel include: • acne • skin irritation where testosterone gel is applied • lab test changes • increased prostate specific antigen (a test used to screen for prostate cancer) Other side effects include more erections than are normal for you or erections that last a long time. Tell your healthcare provider if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of testosterone gel. For more information, ask your healthcare provider or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store testosterone gel? • Store testosterone gel between 68°F to 77°F (20°C to 25°C). • Safely throw away used testosterone gel in household trash. Be careful to prevent accidental exposure of children or pets. • Keep testosterone gel away from fire. Keep testosterone gel and all medicines out of the reach of children. General information about the safe and effective use of testosterone gel. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use testosterone gel for a condition for which it was not prescribed. Do not give testosterone gel to other people, even if they have the same symptoms you have. It may harm them. This Medication Guide summarizes the most important information about testosterone gel. If you would like more information, talk to your healthcare provider. You can ask your pharmacist or healthcare provider for information about testosterone gel that is written for health professionals. For more information, go to www.perrigo.com or call 1-866-634-9120 What are the ingredients in testosterone gel? Active ingredient: testosterone Inactive ingredients: carbomer 980, ethyl alcohol 67.0%, isostearic acid, purified water and sodium hydroxide. This Medication Guide has been approved by the U.S. Food and Drug Administration. Made in Israel Manufactured By Perrigo Yeruham 80500, Israel Distributed By Allegan, MI 49010 www.perrigo.com Rev 06-14 : 1C200 RC J3 Please see additional patient information on adjacent page. ES567444_DRTP0215_004_FP.pgs 02.06.2015 01:54 ADV Inter@ctive TRENDING NOW Pharmacy incomes hold steady SEE AND HEAR PHARMACISTS, INDUSTRY LEADERS, AND PHARMACY ADVOCATES DISCUSS NEWS AND ISSUES OF IMPORTANCE TO PHARMACISTS. EXCLUSIVE VIDEOS ONLY AVAILABLE THROUGH Drug Topics. Drug Topics’ 2015 salary survey fnds that satisfaction among pharmacists remains high, thanks in part to favorable compensation and benefts packages. http://drugtopics.com/2015DTsalary Disruptive Innovations Alasdair Trotter, a principal at Innosight, explains disruptive innovations and how companies such as Walgreens, CVS, and others are using them to crack new markets and drive revenues. TWITTER.COM/DRUG_TOPICS Follow us on Twitter to receive the latest news and participate in the discussion. A few recent tweets and retweets from and about Drug Topics Meredith. @Princess_Mere11 @Drug_Topics: Merck stops production of #HepC drug due to low demand. bit.ly/BRCGJv Peggy Drunky @PeggyDrunky FDA approves a second #vaccine (#Bexsero; Novartis) to prevent serogroup B #meningococcal disease. 1.usa.gov/1ykTPUE Dave Miller, RPh @IACPRPh IACP President Dale Coker, noted in today’s @Drug_Topics as @iacprx new Board leader. drugtopics.modernmedicine.com/ node/392700 pic.twitter.com/0x2s546KWX SAMPIG: J Perepelkin @RxInterestgroup Should Americans be able to buy cheaper drugs from Canada? drugtopics. modernmedicine.com/drug-topics/ne… via @Drug_Topics Using telepharmacy to improve bottom lines Aaron Jennissen, VP, Pharmacy Operations, Thrifty White Pharmacy, discusses how that chain has used telepharmacy to increase customer loyalty and expand reach. Drug Topics App Have all the benefts Drug Topics offers at your fngertips. The Drug Topics app for iPad and iPhone is now free at the iTunes store. LIKE US! FACEBOOK.COM/DRUGTOPICS DrugTopics .c om magenta cyan yellow black Februar y 2015 DRUG TOPICS ES567372_drtp0215_005.pgs 02.06.2015 00:37 5 ADV CONTENTS F E B R U A R Y 2015 VO L . 1 5 9 N O . 2 CONTINUING EDUCATION What’s happening now at New therapies for diabetes The past two years have seen new medications, a new drug class, and a new route of administration. HereÕs what you need to know about developments in diabetes management. PAGE 40 SOCIAL MEDIA JOIN US ONLINE! Read the latest breaking news and give us your feedback! facebook.com/DrugTopics twitter.com/Drug_Topics DT BLOG 16 HEALTH SYSTEMS Braking runaway drug costs 8 DISPENSED AS WRITTREN Quit kicking that football CLINICAL 9 VOICES Drugs from Canada: Why not? 35 NEW DRUG REVIEW Dabigatran for DVT, PE And now for something completely different This month, the DT Blog has something new up its sleeve: a review of topical treatments for plaque psoriasis. Itching to read it? Go to www.drugtopics.com. 10 STUDENT CORNER Pharmacy students hit the road 36 ANTICOAGULATION THERAPIES Aspirin fzzles out in Japanese study of CVE prevention 11 IN MY VIEW Will King v. Burwell torpedo the ACA? REGULATORY & LEGAL http://drugtopics.com/temptattoo 38 LEGAL COMPLIANCE Feds throw the book at NECC http://drugtopics.com/disruptive 12 VIEW FROM THE ZOO Reality vs. perception 58 FINAL WORD Pharmacists: The best ROI ISSUES & TRENDS WEB EXCLUSIVES Temporary tattoo will monitor glucose levels VIDEO: Disruptive innovations $1M gift for new pharm school http://drugtopics.com/WCUgift 39 ETHICAL DECISION-MAKING The importance of duty to warn DIGITAL EDITION PRODUCT UPDATES 14 UPFRONT Target pulls out of Canada 50 ORAL CARE Put your money where your mouth is 15 UPFRONT IN DEPTH New York: The frst stop for I-STOP 57 NEW PRODUCTS FDA approves Duopa for advanced Parkinson’s disease Subscribe to the monthly digital edition of Drug Topics and receive the journal electronically with live links. Go to http://drugtopics.com/digital. Drug Topics (ISSN# 0012-6616) is published monthly and Drug Topics Digital Edition (ISSN# 1937-8157) is issued every week by UBM Advanstar 131 West First St., Duluth, MN 55806-2065. One-year subscription rates: $61 in the United States & Possessions; $109 in Canada and Mexico; all other countries, $109. Single copies (prepaid only) $10 in the United States; $10 in Canada and Mexico; all other countries, $15. Include $6 per copy for U.S. postage and handling. Periodicals postage paid at Duluth, MN 55806 and additional mailing offces. POSTMASTER: Please send address changes to Drug Topics, P.O. Box 6079, Duluth, MN 55806-6079. Canadian G.S.T. number: R-124213133RT001. Publications Mail Agreement Number 40612608. Return undeliverable Canadian addresses to: IMEX Global Solutions PO Box 25542 London, ON N6C 6B2 CANADA. Printed in the U.S.A. ©2015 Advanstar Communications Inc. All rights reserved. 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Drug Topics welcomes unsolicited articles, manuscripts, photographs and other materials but cannot be held responsible for their safekeeping or return. Library Access Libraries offer online access to current and back issues of Drug Topics through the EBSCO host databases. To subscribe, call toll-free 888-527-7008. Outside the U.S. call 218-740-6477. 6 magenta cyan yellow black DRUG TOPICS Februar y 2015 GETTY IMAGES/RICHARD CANO COUNTER POINTS DrugTopics .c om ES567301_drtp0215_006.pgs 02.05.2015 21:33 ADV Take a bite out of G-CSF acquisition costs Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices. GRANIX® is an option in short-acting G-CSF therapy » A 71% reduction in duration of severe neutropenia vs placebo (1.1 days vs 3.8 days, p<0.0001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1 » The safety of GRANIX was established in 3 Phase III trials, with 680 patients receiving chemotherapy for either breast cancer, lung cancer, or non-Hodgkin lymphoma (NHL)1 » Now offering a new presentation for self-administration Indication » GRANIX is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX. » Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. » Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. » Capillary leak syndrome (CLS): CLS can occur in patients receiving hG-CSFs and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of CLS should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. » Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colony-stimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. » Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain. Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. GRANIX® (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2014. ©2015 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. All rights reserved. GRX-40490 January 2015. 724-41863 DIGITAL C M Y K Job Number: 21079 Revision No: 0 Date: 01/15/15 BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX® (tbo-filgrastim) injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Capillary Leak Syndrome Capillary leak syndrome (CLS) can occur in patients receiving human granulocyte colony-stimulating factors and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. 5.6 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Capillary Leak Syndrome [see Warnings and Precautions (5.5)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.6)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached. 724-41863 DIGITAL Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. Additional Adverse Reactions Other adverse reactions known to occur following administration of human granulocyte colony-stimulating factors include myalgia, headache, vomiting, Sweet’s syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis and thrombocytopenia. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GRANIX in pregnant women. In animal reproduction studies, treatment of pregnant rabbits with tbo-filgrastim resulted in increased spontaneous abortion and fetal malformations at systemic exposures substantially higher than the human exposure. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In an embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2014 Cephalon, Inc., a wholly-owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a registered trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40503 December 2014 This brief summary is based on TBO-004 GRANIX full Prescribing Information. K Job Number: 21079 Revision No: 0 Date: 01/15/15 Counter Points DISPENSED AS WRITTEN Mark Jacobs, RPh, FASCP The future of community pharmacy Truman Lastinger recently posed the question “Is community pharmacy a dying profession?” [DT Blog, December 2014]. Here is how I would answer him. As a profession we worry too much about that elusive provider status. Charlie Brown kept trying to kick the football, to no avail. In the pharmacy profession, we are not that much different. We have been talking about clinical pharmacy and pharmacist services for 20-25 years now. Maybe more. Definition and value The primary problem for the pharmacy profession is not that some insurance company is not giving us money. It is much simpler than that. As a profession, we fail to effectively define what we do, and we fail to demonstrate it. I’m not saying that there aren’t thousands of incredible pharmacists out there doing great work. I’m just saying that collectively we have failed as a profession to define and demonstrate what we do. Second, we have failed to establish value for our work. Out of the thousands of pharmacists mentioned above, only a few hundred or so actually assign value and ask for it. We can get paid for our services; we just don’t believe we should — not enough to charge for it, anyway! Chiropractor and optometrist services were not covered for years, but that didn’t stop chiropractors and optometrists from charging for them. Come to think of it, for many years dental services weren’t covered either. Even now, in 2015, there is limited coverage for many services delivered by dentists. But we still pay for them. I consult with pharmacies all over the United States. In many instances I hear, 8 DRUG TOPICS Februar y 2015 “[He/she’s] in a room with a patient right now,” and I think — wonderful! Then, when I ask whether the pharmacist charges for such services, the answer is a resounding “No.” Many years ago, I worked for a retail chain. In my experience, patients were willing to pay me and did pay me for some of my services. If we plan on sitting around and waiting or lobbying our senators and legislators for provider status, we might just be trying to kick the football for another 20-25 years! Simple answer To my way of thinking, the answer to our problem is relatively simple: Define what you do. Be able to recite it in an elevator speech (30 seconds or less). Then truncate your message to just 9 seconds, because that’s about as long as anyone will remember. Talk about and demonstrate what you do with fervor — first with your staff; then with your patients and their nurses, PAs, NPs, and doctors. Be consistent with your patients. Tell them what you are going to do for them. Then do it. Then show them what you did for them. You may need to write it down for them. Ask them to follow up and see you in a few days, if necessary. Mail-order-pharmacy threat? Poof! Develop a business plan. It does not need to be elaborate — just have one! The response I heard most commonly when I met with patients was “How much do you charge for this?” What will you say when they ask you? If your answer is, “Aw, shucks … nothing!” then as a profession, we have a major problem. It’s up to us When the senators and legislators we lobby hear about what we do, they may have a hard time conceptualizing it, because every time they go to a pharmacy, all they get is a sack. To return to the football analogy — we get sacked a lot! When Charlie Brown tries to kick the football for a measly threepoint field goal, what does Lucy do? The problem is not that we cannot charge for our professional services. Our problem lies within ourselves. We are required to provide basic consultation on proper use and side effects of prescription medication. Beyond that, nothing is stopping us from charging patients for advanced services. We have so many tools available to us. Just take a look at the APhA website. Truman is right. As a profession, we must pursue the change from selling a product to selling a service. I believe we can achieve that goal. Mark Jacobs is a past chair of APhA’s Pharmacy Work Life Issues Committee. He has published a book titled “101 Ways to Improve Your Pharmacy Work Life” and has lectured all over the country on methods for advancing pharmacy practice. DrugTopics .c om Counter Points Voices Attention must be paid Re: “Should Americans be able to buy cheaper drugs from Canada?” [Jan. 21, Mark Lowery, www. drugtopics.com]: Why should U.S. pharmacies and citizens pay higher prices than Canada does for drugs manufactured in the United States? Permitting the purchase of meds from Canada hurts U.S. businesses, particularly the pharmacies that border Canada. It also creates a nightmare for FDA and others to protect U.S. citizens from fraud and possibly tainted meds — and at a cost to these agencies probably higher than any savings. How will counseling and education occur? Also, generic Viagra is available in Canada, but not in the U.S. How will this be controlled? Individuals in leadership roles should be addressing the rising costs of generics (a much larger problem as it continues to happen, because insurance companies will pass on the increased costs of these generics to all of us via premiums and such), and develop legislation that protects our own people from unscrupulous and unfair practices. Congress needs to pay attention to us. Anonymous POSTED AT WWW.DRUGTOPICS.COM Cure the disease Importing drugs from Canada is treating just the symptoms, not the underlying disease. Fix our pricing problem and we don’t have to worry about Canada. There’s no reason the United States should be paying for the rest of the world and then go ahead and pay Canada to make an end run around our problem. Why don’t we learn from Canada’s success at not being robbed by Big Pharma, and cure our underlying disease? Joseph Jorgenson POSTED AT WWW.DRUGTOPICS.COM If we can’t do it, how can they? If it is not legal for a licensed U.S. pharmacy and its licensed pharmacists to purchase products from Canada to provide to their customers, why should it be legal for the unlicensed general public to purchase these products? Do these Senators plan to allow U.S. pharmacies to make these DrugTopics .c om magenta cyan yellow black purchases as well, so that the business remains in the U.S.? Or is this just another way to destroy the U.S. economy by sending U.S. dollars out of the country? And what kind of jurisdiction will U.S. regulators such as FDA and DEA have on these “Canadian” drugs? DOUGLAShei POSTED AT WWW.DRUGTOPICS.COM Unbridled greed I frmly believe Senators Klobuchar and McCain do not go far enough. A better bill would allow purchase of medications from the E.U. or, alternatively, mandate American price ceilings no higher than the average E.U. price. The cost of drugs in the U.S. refects nothing more than unbridled greed of executives who have no sense of shame or loyalty to the country that made them all very rich. Anonymous Outrageous profts I can see the wholesalers’ cost and then the charge either to the patient or insurance on the prescriptions I fll, and for the most part the percent proft is outrageous. I believe the company I work for is taking this proft, along with the manufacturers. I’d not only buy from Canada but from India, Mexico, etc., wherever I could get a better price. The issue about the quality of the drugs, in my opinion, is baloney — just a tactic to prevent “regular” folks from getting the drug and a price break. I’ve personally seen drugs coming from India, for example, packaged with the Burroughs Welcome label and all its manufacturing information. Most of the drug companies don’t reside in the U.S. So, in a way, most of the products we use are imports already! Anonymous POSTED AT WWW.DRUGTOPICS.COM No jobs in Florida Re: “New pharmacy school planned for Miami” [Jan. 23, Mark Lowery, www. drugtopics.com]: Shame on you, Mr. Michel. [Jack Michel, president of Larkin Community Hospital, which will build the school.] Obviously you are all about the money and not the well-being of future pharmacy students. Wake up! There are no jobs for pharmacists in Florida. We already graduate close to 1,000 students a year in this state and no one is retiring, so there will be no jobs for new pharmacists. Stop ruining our profession! Anonymous POSTED AT WWW.DRUGTOPICS.COM Down go the wages I agree! Too many pharmacists chasing too few jobs. ACPE is causing a glut which in the long run will drive down wages. Alfonso Deluca POSTED AT WWW.DRUGTOPICS.COM That bubble’s gonna blow Re: “Family donates $1 million for new Continued on pg. 21 POSTED AT WWW.DRUGTOPICS.COM Februar y 2015 DRUG TOPICS ES567364_drtp0215_009.pgs 02.06.2015 00:27 9 ADV Counter Points STUDENT CORNER Derek Borkowski, PharmD Candidate 2018 Pharmacy education shifts the paradigm When I went home for winter break at the end of my frst semester in pharmacy school, I found that my friends who were nursing students knew more names and uses of drugs than I did. This startled me until I realized that I was being exposed to far more than just this one aspect of pharmacy practice. Here are a few highlights of my experience so far. Public health On only our fourth day of class, firstyear pharmacy and medical students were bussed out to rural Minnesota communities. We spent a day at different locations in our respective towns, talking with people about each community’s characteristics and needs. Back at school, we made presentations about the towns we visited, focusing on eight critical assessment domains. Then we engaged in a semester-long project, using similar criteria to evaluate our own hometowns. Pharmacists have great potential to make an impact in their communities. This starts with identifying underserved populations and unmet needs, and then taking steps to address them. In Duluth, for example, one unique area of attention is the underserved Native American population. In areas highly populated with Spanish speakers, increasing numbers of pharmacy schools are adding Pharmacy Spanish to their curricula to enable future pharmacists to provide better care for these patients. Whether the focus is on educating young children about safe use of medications, providing programs on drug abuse, or putting on fu clinics and health fairs, across the country examples abound to show that meeting community needs is a core component of every pharmacy school curriculum. Healthcare system Early on, when I worked as a retail pharmacy technician, I found myself 10 magenta cyan yellow black DRUG TOPICS Februar y 2015 overwhelmed when I attempted to plug a patient’s insurance card information into the computer to bill for a prescription. After I helplessly watched the pharmacist do it for me, I asked whether I would learn how to do that in pharmacy school. He chuckled and said, “Of course not.” As if navigating the healthcare system weren’t difficult enough for trained professionals, patients with far less experience are burdened with this challenge every day. We are taught that as pharmacists, we have a duty to advocate for patients dealing with this system. First-semester courses have included both the history and contemporary state of the U.S. healthcare system (including the ACA and a wide range of current payer models) and have examined international healthcare systems. We will continue to revisit this topic from various perspectives throughout the curriculum. Patient focus The profession has adopted pharmaceutical care as the practice of a pharmacist, and pharmacy schools are updating curricula to prepare student pharmacists to practice. This starts with a philosophy of practice that includes the pharmacist’s responsibility to meet society’s medication-related needs through identifcation, prevention, and resolution of drug-therapy problems. In our frst-semester pharmaceutical care course we began assessing real patients and patient cases using a systematic patient-care process designed to ensure that medications (whether Rx, OTC, or herbal) are indicated, effective, safe, and convenient for the patient, and that all nonpharmacological and referral alternatives be considered. All of this is done while keeping the patient at the center of the decision-making process. Innovation Collaboration As studies show, “medical homes” or a team-based approach to healthcare provide the best outcomes for patients, and pharmacists have a lot to contribute to both patient care and cost savings. Collaboration with other professionals is a key focus of the professional curriculum. Already, in my frst semester, I have participated in a semester-long course with students from the other health professions on campus that focused on understanding each discipline’s unique contribution to patient care and on working together to optimize outcomes. So far, my most important take-away in pharmacy school has been that as pharmacists we must strive to practice at the top of our education, which will inevitability exceed the top of our license. Only by working toward practices and policies that encompass our full education can we drive the innovation that broadens the benefits that pharmacy offers to patients and society as a whole. Derek Borkowski is a first-year PharmD student at the University of Minnesota College of Pharmacy, Duluth. Contact him at [email protected]. DrugTopics .c om ES566957_drtp0215_010.pgs 02.05.2015 19:28 ADV Counter Points IN MY VIEW Robert L. Mabee, RPh, JD, MBA Is the ACA treating America without informed consent? In the practice of medicine, informed consent is essential. Before treating a patient, the provider must make sure the patient understands what is going to be done and consents to the treatment. Failure to obtain informed consent is a basis for a claim of negligence as medical malpractice. Lying to a patient or intentionally misleading a patient is gross negligence in many jurisdictions and might be the basis for criminal charges. The case can be made that the ACA was passed without the informed consent of voters because their legislators were misled. While some naïve supporters in Congress freely admitted they had never even read the act before voting for it, there is also evidence to suggest that they were systematically and intentionally misled, conduct that could constitute gross negligence. Back to court In its initial decision, the Supreme Court, through Justice Roberts, found that the ACA was constitutional as a tax. Justice Roberts made it clear that the Court was not ruling on the wisdom of the legislation. This spring the Court will revisit the legislation in its consideration of King v. Burwell, to analyze its structure and decide whether the language should be interpreted literally. At issue is the possible denial of a tax credit — “premium assistance credit amount” — to anyone enrolled in an exchange set up by the federal government, because that is not an “exchange established by the State.” Challengers argue that the language was intentional, to motivate the states to enact their own exchanges. Professor Jonathan Gruber, an MIT economist hired by the Administration and paid $400,000 to help draft the ACA, made a comment supporting that interpretation, but later tried to walk it back. However, at least four videos have recorded Gruber stating that DrugTopics .c om magenta cyan yellow black the draft legislation attempted to obscure the fact that the mandate was a tax. The majority on the Court were not deceived. The Court called it a tax. Issues and appearances The Administration may have a struggle on its hands. In the frst case, the Supreme Court was obligated to fnd that the law was constitutional, if possible, and did so by fnding that it was a tax. In King v. Burwell, the Administration is asking the Court to fx it. Normally, the Court will look at legislative history to determine the intent of a law or to clarify ambiguities in drafting. The ACA has little or no real legislative history, and its language is clear. Congressional actions are normally granted the presumption of regularity. The troubled history of this legislation does not appear to support such a presumption. Professor Gruber’s public statements that the legislation was designed to mislead voters might be construed as an admission against interest. Fraudulent inducement in civil matters can require rescission of a contract. Obtaining money under false pretenses could be construed as a felony. Unfortunately, the actions of these drafters at the very least raise the appearance of impropriety. While the Court has already stated that it will not rule on the wisdom of the legislation, it will not want to countenance the appearance of impropriety, much less participate in perpetuating a fraud. Not the optimal signature Some observers believe that from the beginning the Administration was willing to sacrifce the presumption of regularity and avoid transparency to get this legislation passed. Using fraudulent inducements to put the IRS in charge of a sixth of our economy and our medical records may not represent the signature legislation that this Administration wants as its legacy. Many have questioned the demographics, therapeutics, and economics of the ACA. Exempting the ruling elites and unionized bureaucrats from this legislation is beyond unacceptable and demonstrates how little faith they have in the ACA or their ability to administer the act. Unique among providers Pharmacists have always been viewed as an accessible and reliable source of accurate healthcare information. They routinely explain therapeutic interaction and the real cost of care, and present the bill, less any insurance payment, directly to the patient. If the ACA collapses, as some foresee, it will create significant problems for millions of patients who need healthcare and deserve honest and accurate information.Let us hope that the government follows the example set by pharmacy. Robert L. Mabee is a pharmacist and attorney practicing in Sioux Falls, S.D. He also holds an MBA. Contact him at [email protected]. Februar y 2015 DRUG TOPICS 11 ES566958_drtp0215_011.pgs 02.05.2015 19:28 ADV Counter Points VIEW FROM THE ZOO David Stanley, RPh And the reality vote goes to … independent pharmacy I think it’s time for a pep talk. For more than a generation now, we’ve heard all about the challenges facing the drugstore business. Declining reimbursements from third-party payers, erosion of our professionalism by the faceless corporate bureaucrat, ever-growing mounds of red tape to slash through just to get the increasing volume of prescriptions out the door — I could go on all year, and many others will. And recently, in this very magazine, Truman Lastinger asked, “Is community pharmacy a dying profession?” [DT Blog, December 2014]. Here’s my answer — and a big piece of evidence: No, and $6.7 billion. That’s the amount of money the “Big Three” drugstore operators made last year by running drugstores. Yes, CVS also made a chunk of its proft through one of the country’s largest pharmacy beneft managers, but that’s not an argument you can make about Walgreens and the $1.9 billion it earned, at roughly $225,000 proft per store. Even perennial laggard Rite Aid has found its way back to proftability. And how are the chains earning this giant pot of cash? By buying things and selling them for more than they paid. Just the way the community pharmacist does. What’s really being promoted? So how do the industry big boys manage to be so competitive and proftable in a perpetually challenging business climate? Give any of their executives a shot of truth serum, and they’ll freely admit they don’t compete on price. Loyalty cards and advertised specials aside, any customer who is primarily price-sensitive is likely to end up at a big-box retailer. The “Big Three” sell themselves to consumers with convenience. They scout out the best locations in town so that everyone will see their drive-through windows on the way home from work. They offer a product mix, so that customers who do 12 magenta cyan yellow black DRUG TOPICS Februar y 2015 leave their cars will be able to “pick up a few things” while they’re in the store getting their Rxs. And in case folks notice that they’re paying more for those few things than they would at the Target across town, the chains pick locations that will make it awfully inconvenient for them to get back into their cars and drive all the way there. to talk to a pharmacist, but I can usually solve your problem and get you off the line in less time than it takes to listen to the flu ads in the roboannouncements. Heck, I can give you a fu shot in less time than it usually takes to conduct a routine business transaction at the corner of Happy and Healthy. Who really delivers? What’s the real perception? But there’s a glitch. While the big chains promote convenience, we all know they don’t always deliver. Take a good look at those drive-throughs and you’ll see the vehicle backup. Inside, one check-out lane is open — and 10 people are in line. Behind the Rx counter, the pace is frenzied. And the store is so understaffed that the employees — from the manager on duty to the part-time stock clerk — are all trying to do three things at once. It won’t take you long to see that the industry M.O. is to lure people in with the appearance of convenience, while in actuality it is gauging how much aggravation they will take, once inside, and still hand over their money. This is my reason for optimism. The independent community pharmacy can deliver what the giant chains only pretend to offer. Under the chains’ definition of convenience, you may have to wait on hold for 40 minutes The fact that so many people are willing to spend so much money chasing after the idea of a convenient shopping experience gives me hope, because my pharmacy — and almost every independent drugstore in the country — can make it happen far better than the chains can. If you don’t believe me, just go look up the latest pharmacy rankings in Consumer Reports, which rate independent drugstores far and away above the “Big Three.” So the only question that stands between the independent community pharmacy and its share of that giant pot of money spent by pharmacy customers every year is whether the perception of convenience is greater than the reality. As long as I’m on the side of reality, I like my chances. So should you. David Stanley is a pharmacy owner, blogger, and professional writer in northern California. Contact him at [email protected]. DrugTopics .c om ES566956_drtp0215_012.pgs 02.05.2015 19:28 ADV Up front INDUSTRY NEWS & ANALYSIS Target to shut 133 stores in Canada, open 15 in U.S. Target Corp. announced mid-January its plans to shut down its Canadian operations, totaling 133 stores and 107 retail pharmacy franchises. Two weeks later, Target announced its decision to expand in the United States, planning 15 new stores with some smaller formats for urban areas. “Smaller formats like TargetExpress and CityTarget offer customized assortments and services to meet the needs of guests who are increasingly moving into urban centers,” said Tina Tyler, Target’s executive vice president and chief stores offcer. Target plans to open TargetExpress stores in the greater Washington, D.C., area and in Chicago, and CityTargets in Boston and Brooklyn, N.Y., in 2015. As for the Canadian store closures, Target created a safety net for its 17,600 employees in the form of an Employee Trust, worth $59 million (U.S.). Each employee is entitled to a minimum of 16 weeks of compensation, even if the worker is not required for the entire wind-down period. However, Target offered little information about the effect of the closure on its 107 retail pharmacy franchises, 14 of which are located in Quebec. Target ignored repeated requests for comment. HONOR MEDAL AWARDED Palliative care innovator wins Remington Honor Medal Award Calvin H. Knowlton, BS Pharm, MDiv, PhD, has been named this year’s Remington Honor Medal award winner. He will be recognized next month at the American Pharmacists Association (APhA) annual meeting and exposition in San Diego. Knowlton, known for his “out-ofthe-box” thinking, was nominated by Calvin H. Knowlton a colleague for the development of a practice model for hospice patients. He founded Hospice Pharmacia/excelleRx, a medication management and distribution company that specializes in palliative care, about 20 years ago. “In this practice model, pharmacists work in a transdisciplinary environment with nurses, physicians, and other hospice and palliative care practitioners to select drug therapies that optimize clinical, humanistic, and economic outcomes,” stated one of his colleagues. “His efforts single-handedly elevated the level of prescribing practices for these incredibly complex patients.” 14 magenta cyan yellow black DRUG TOPICS Februar y 2015 More than 200 pharmacists and 200 pharmacy technicians will be affected by the decision to close all 133 TCC stores. Mark J. Wong, general counsel for Target Canada Co. (TCC), provided a statement to the court on behalf of an application by TCC for bankruptcy protection. In the Jan. 14 affdavit, Wong stated that each franchise is independent and wholly owned by a licensed pharmacist. “Franchisee-pharmacists and [their] employees will not receive the compensation Target has announced,” confrmed Genevieve Gregoire, communications advisor for Metro, the owner of the Brunet trademark, which was used in conjunction with the Target trademark in the 14 pharmacies in Quebec. Franchisee pharmacies will operate for a limited time, Target’s statement noted. Target gave them a deadline of Feb. 27 to leave, according to a report published online at www.thestar.com. Eighty-one pharmacist franchisees recently joined the Pharmacy Franchisee Association of Canada and are hiring legal counsel to fght for more time to move their pharmacies to other locations. They also are seeking fnancial compensation. — Julia Talsma, Content Channel Director A man on a mission Another colleague nominated Knowlton based on his passion to advance the role of the pharmacist in optimizing care for vulnerable patients, such as the elderly. Knowlton took medication management to new heights with the PACE (Programs of All-inclusive Care of the Elderly) model of care and CareKinesis, a company he founded in 2009 to promote medication safety and the application of the science of personalized medicine. “Starting with this extremely high-risk group [PACE enrollees], he is a man on a mission to make a measurable impact on the abysmal epidemic of iatrogenesis in the US (third leading cause of death), of which a larger proportion is due to medications. Accomplishing this mission elevates pharmacy as not only a major player in reducing medication misadventures, but also the player with the best tools to do the job,” his colleague wrote. Ten companies, many honors Knowlton is also the founder and CEO of Tabula Rasa Healthcare, parent company of CareKinesis, the 10th company he has founded. He was named the 2003 and 2013 Ernst & Young Entrepreneur of the Year in the Greater Philadelphia area, and has served as president of the American College of Apothecaries, APhA, and the American Pharmacists Association Foundation. — Julia Talsma, Content Channel Director DrugTopics .c om ES566969_drtp0215_014.pgs 02.05.2015 19:37 ADV Issues & Trends Up front In Depth Fred Gebhart, Contributing Editor New York moves to e-prescribing for all Rxs P harmacists across New York are processing some of their last paper prescriptions. As of March 27, all Rxs flled by New York pharmacists must be electronic, including those for controlled substances. With a few minor exceptions, paper is about to become history in one of the largest Rx markets in the country. “Mandatory electronic prescribing is a bigger change for prescribers than it is for pharmacists and pharmacies,” said Tracy Russell, executive director of the Pharmacists Society of the State of New York. “Pharmacies will have to adjust their internal workfow to accept the vast majority of their prescriptions electronically, but that’s the only major change from the pharmacy side.” The change isn’t so simple for prescribers, however. “Many prescribers are comfortable with electronic scripts, but the technology has not been there for electronic prescribing of controlled substances, or EPCS,” said Sean Kelly, MD, emergency physician at Beth Israel Deaconess Medical Center in Boston and chief medical officer for proSean Kelly vider technology firm Imprivata. “Most prescribers in New York have been using electronic systems for most of their prescriptions and writing paper scripts for controlled substances. The New York mandate for EPCS will lead to other states taking the same step.” A matter of public health The switch from paper to EPCS is a matter of public health and safety, Kelly DrugTopics .c om magenta cyan yellow black continued. Like every state, New York has a growing problem with prescription drug abuse. Paper Rxs make it easy for patients to shop multiple prescribers and pharmacies. Shady prescribers and pharmacies can divert narcotics with little fear of discovery. EPCS provides a direct evidence trail from prescriber to pharmacy, pharmacist, and patient. “I applaud New York for having the nerve to implement EPCS,” said William Winsley, MS, RPh, former president of the National Association of Boards of Pharmacy and former executive director of the Ohio State Board of Pharmacy. “All 49 other states are going William Winsley to be watching. I expect to see other states following suit, but nobody is going to commit until we see how New York goes.” Tight controls The New York system is known as I-STOP (Internet System for Tracking Over-Prescribing). I-STOP was created by the state’s Bureau of Narcotic Enforcement (BNE) to meet all DEA requirements for EPCS. The primary burden of implementation falls on prescribers and electronic health record vendors, Russell said. Vendors must create systems that meet DEA requirements for certifcation and authentication of individual prescribers. Prescribers must be certified for EPCS by BNE and maintain at least two types of authentication. DEA regulations allow for three types of online authentication: a physical device such as a key fob or card; something that only the prescriber knows such as a password; and individual biometric data such as a retina pattern. Prescribers must use two of the three forms of authentication for EPCS. Authenticators may not be shared between individuals. And each EPCS must be sent to a specific pharmacy, chosen by the patient. If that pharmacy cannot fill the script, the prescriber must cancel the original and write a new EPCS for another pharmacy. Daily report The filling pharmacy files a daily report with BNE, listing all controlled substance scripts flled. The daily report includes a unique Rx number, prescriber identifcation, patient information, and controlled substances dispensed. If the patient presents a paper prescription for a controlled substance, the pharmacy can fll it but must note the nonstandard Rx in its BNE report. The agency can take action against prescribers who fail to use EPCS. “It is painful to be a prescriber in New York right now, but other states will beneft.” “New York has forced vendors to create a system that works,” Kelly said. “It is painful to be a prescriber in New York right now, but other states will beneft from New York’s experience. With this system up and running, other states will be able to consider their own laws in a different light, because the necessary technology will already be in place.” Februar y 2015 DRUG TOPICS 15 ES566968_drtp0215_015.pgs 02.05.2015 19:37 ADV Health Systems Julie Simcik Prince, PharmD, BCPS, and Danton Dungy, MD When IV acetaminophen costs shot up, one health system did some new math Chandler Regional Medical Center is a 339-bed not-for-proft community hospital in Chandler, Ariz. The center is part of the Dignity Health System, the ffth-largest hospital system in the United States. Like all healthcare providers, Dignity Health must be vigilant in the face of escalating drug costs. Through the roof In May 2014, Mallinckrodt Pharmaceuticals purchased Cadence Pharmaceuticals, the manufacturer of injectable acetaminophen (Ofrmev). At the time of purchase, Mallinckrodt increased the cost of injectable acetaminophen from $14.60 to $35.05 for each 1-g vial. This was a 140% increase beyond the 37% price increase implemented by Cadence during the three years before the company’s acquisition. Dignity Health resolved to reduce its use of injectable acetaminophen. Members of the system’s Clinical Pharmacy Group spent a month researching and discussing the literature. They then developed a draft Intravenous (IV) Acetaminophen Guideline, which permitted use of IV acetaminophen outside the perioperative area when the patient was unable to tolerate oral (PO) medications. For patients who were candidates for IV acetaminophen, duration was limited to 24 hours. At Chandler Regional, use of IV acetaminophen was restricted to its orthopedic surgeon, who was using post-operative (post-op) acetaminophen 1 g IV Q 8 h for two doses in all his patients. A lack of available literature comparing IV vs. PO acetaminophen in orthopedic surgery convinced Chandler Regional’s clinical pharmacy coordinator and orthopedic surgeon to conduct an internal retrospective study comparing post-op acetaminophen 1 g IV Q 8 h for two doses and acetaminophen 1 g PO Q 8 h for two doses. The study With the vote on the IV Acetaminophen Guideline looming, time constraints required Chandler Regional to limit its study to 62 patients, 31 in each treatment 16 magenta cyan yellow black DRUG TOPICS Februar y 2015 group. Patients were similar in sex, age, weight, and type of surgery. Except for the two postop acetaminophen 1-g doses, all patients received the same post-op multimodal pain therapy. Four patients in the IV acetaminophen group and seven patients in the PO acetaminophen group were on opioid medication(s) at home. Outcome data includDanton Dungy, MD, and Julie Prince, PharmD, conceived and ed total opioid use on post-op conducted the study for Chandler Regional. Day 0 and Day 1; use of antiemetics on post-op Day 0 and in the two groups: 2.68 days for the IV Day 1; and hospital length of stay. acetaminophen group and 2.97 for the PO acetaminophen group. Findings Outcome data showed no major differences between the two treatment groups in post-op opioid use on Day 0 or Day 1: On post-op Day 0, the IV acetaminophen group used 41.6 mg of PO morphine equivalents. The PO acetaminophen group used 27.6 mg of PO morphine equivalents. Post-op Day 0 saw a total of 14 mg more PO morphine equivalents used in the IV acetaminophen group. On post-op Day 1, the IV acetaminophen group used 24.7 mg and the PO acetaminophen group used 24.6 mg of PO morphine equivalents. Similarly, there was no difference in as-needed (PRN) antiemetic use on post-op Day 0 or Day 1. The IV acetaminophen group used 6 doses of PRN antiemetics on postop Day 0 and 6 doses on post-op Day 1. The PO acetaminophen group used 8 doses of PRN antiemetics, post-op Day 0, and 4 doses, post-op Day 1. Average length of stay was similar Implementation and savings On the basis of the above study, the hospital endorsed Dignity Health’s Guidelines in September 2014, and Chandler Regional’s orthopedic surgeon substituted PO acetaminophen for scheduled post-op IV acetaminophen. Expenses have decreased. Before implementation of the IV Acetaminophen Guideline, Chandler Regional spent $23,308.17 per month on IV acetaminophen. In December 2014, three months after the Guideline was implemented, Chandler spent roughly $10,500 less, with a total IV acetaminophen cost of $12,938.65. Clinical Pharmacy Coordinator Julie Prince and orthopedic surgeon Danton Dungy practice at Chandler Regional Medical Center in Chandler, Ariz. Contact Julie Prince at Julie. [email protected]. DrugTopics .c om ES566970_drtp0215_016.pgs 02.05.2015 19:37 ADV NOW AVAILABLE For patient savings and more information, visit HysinglaER.com WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION Addiction, Abuse, and Misuse HYSINGLA ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing HYSINGLA ER, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of HYSINGLA ER. Monitor for respiratory depression, especially during initiation of HYSINGLA ER or following a dose increase. Instruct patients to swallow HYSINGLA ER tablets whole; crushing, chewing, or dissolving HYSINGLA ER tablets can cause rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions (5.2)]. Accidental Ingestion Accidental ingestion of even one dose of HYSINGLA ER, Please read Brief Summary of Full Prescribing Information on the following pages, including Boxed Warning. especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions (5.2)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of HYSINGLA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)]. Cytochrome P450 3A4 Interaction The concomitant use of HYSINGLA ER with all cytochrome P450 CYP3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving HYSINGLA ER and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.11), Drug Interactions (7.1), and Clinical Pharmacology (12.3)]. ©2014 Purdue Pharma L.P., Stamford, CT 06901-3431 A8971-AVAIL-A 11/2014 BRIEF SUMMARY OF PRESCRIBING INFORMATION (For complete details please see the Full Prescribing Information and Medication Guide.) WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND CYTOCHROME P450 3A4 INTERACTION Addiction, Abuse, and Misuse HYSINGLA™ ER exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing HYSINGLA ER, and monitor all patients regularly for the development of these behaviors or conditions [see Warnings and Precautions (5.1)]. Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression may occur with use of HYSINGLA ER. Monitor for respiratory depression, especially during initiation of HYSINGLA ER or following a dose increase. Instruct patients to swallow HYSINGLA ER tablets whole; crushing, chewing, or dissolving HYSINGLA ER tablets can cause rapid release and absorption of a potentially fatal dose of hydrocodone [see Warnings and Precautions (5.2)]. Accidental Ingestion Accidental ingestion of even one dose of HYSINGLA ER, especially by children, can result in a fatal overdose of hydrocodone [see Warnings and Precautions (5.2)]. Neonatal Opioid Withdrawal Syndrome Prolonged use of HYSINGLA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available [see Warnings and Precautions (5.3)]. Cytochrome P450 3A4 Interaction The concomitant use of HYSINGLA ER with all cytochrome P450 CYP3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving HYSINGLA ER and any CYP3A4 inhibitor or inducer [see Warnings and Precautions (5.11), Drug Interactions (7.1), and Clinical Pharmacology (12.3)]. 4 CONTRAINDICATIONS HYSINGLA ER is contraindicated in patients with: • Significant respiratory depression • Acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment • Known or suspected paralytic ileus and gastrointestinal obstruction • Hypersensitivity to any component of HYSINGLA ER or the active ingredient, hydrocodone bitartrate 5 WARNINGS AND PRECAUTIONS 5.1 Addiction, Abuse, and Misuse HYSINGLA ER contains hydrocodone, a Schedule II controlled substance. As an opioid, HYSINGLA ER exposes users to the risks of addiction, abuse, and misuse [see Drug Abuse and Dependence (9.1)]. As extended-release products such as HYSINGLA ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of hydrocodone present. Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed HYSINGLA ER and in those who obtain the drug illicitly. Addiction can occur at recommended doses and if the drug is misused or abused. Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing HYSINGLA ER, and monitor all patients receiving HYSINGLA ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of HYSINGLA ER for the proper management of pain in any given patient. Abuse or misuse of HYSINGLA ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of the hydrocodone and can result in overdose and death [see Drug Abuse and Dependence (9.1), and Overdosage (10)]. Opioid agonists are sought by drug abusers and people with addiction disorders and are subject to criminal diversion. Consider these risks when prescribing or dispensing HYSINGLA ER. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the proper disposal of unused drug [see Patient Counseling Information (17)]. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product. 5.2 Life-Threatening Respiratory Depression Serious, life-threatening, or fatal respiratory depression has been reported with the use of modified-release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status [see Overdosage (10.2)]. Carbon dioxide (CO2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids. While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of HYSINGLA ER, the risk is greatest during the initiation of therapy or following a dose increase. Closely monitor patients for respiratory depression when initiating therapy with HYSINGLA ER and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of HYSINGLA ER are essential [see Dosage and Administration (2.1, 2.2)]. Overestimating the HYSINGLA ER dose when converting patients from another opioid product can result in fatal overdose with the first dose. Accidental ingestion of even one dose of HYSINGLA ER, especially by children, can result in respiratory depression and death due to an overdose of hydrocodone. 5.3 Neonatal Opioid Withdrawal Syndrome Prolonged use of HYSINGLA ER during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid withdrawal syndrome in adults, may be life-threatening if not recognized and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn. 5.4 Interactions with Central Nervous System Depressants Hypotension, profound sedation, coma, respiratory depression, and death may result if HYSINGLA ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids). When considering the use of HYSINGLA ER in a patient taking a CNS depressant, assess the duration use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin HYSINGLA ER is made, start with a lower HYSINGLA ER dose than usual (i.e., 20-30% less), monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant [see Drug Interactions (7.2)]. 5.5 Use in Elderly, Cachectic, and Debilitated Patients Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance compared to younger, healthier patients. Monitor such patients closely, particularly when initiating and titrating HYSINGLA ER and when HYSINGLA ER is given concomitantly with other drugs that depress respiration [see Warnings and Precautions (5.2)]. 5.6 Use in Patients with Chronic Pulmonary Disease Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression for respiratory depression, particularly when initiating therapy and titrating with HYSINGLA ER, as in these patients, even usual therapeutic doses of HYSINGLA ER may decrease respiratory drive to the point of apnea [see Warnings and Precautions (5.2)]. Consider the use of alternative non-opioid analgesics in these patients if possible. 5.7 Use in Patients with Head Injury and Increased Intracranial Pressure In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the possible respiratory depressant effects of opioid analgesics and their potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, opioid analgesics can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries. Monitor patients closely who may be susceptible to the intracranial effects of CO2 retention, such as those with evidence of increased intracranial pressure or impaired consciousness. Opioids may obscure the clinical course of a patient with a head injury. Avoid the use of HYSINGLA ER in patients with impaired consciousness or coma. 5.8 Hypotensive Effect HYSINGLA ER may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is an added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines or other agents which compromise vasomotor tone. Monitor these patients for signs of hypotension after initiating or titrating the dose of HYSINGLA ER. In patients with circulatory shock, HYSINGLA ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of HYSINGLA ER in patients with circulatory shock. 5.9 Gastrointestinal Obstruction, Dysphagia, and Choking In the clinical studies with specific instructions to take HYSINGLA ER with adequate water to swallow the tablet, 11 out of 2476 subjects reported difficulty swallowing HYSINGLA ER. These reports included esophageal obstruction, dysphagia, and choking, one of which had required medical intervention to remove the tablet [see Adverse Reactions (6)]. Instruct patients not to pre-soak, lick, or otherwise wet HYSINGLA ER tablets prior to placing in the mouth, and to take one tablet at a time with enough water to ensure complete swallowing immediately after placing in the mouth [see Patient Counseling Information (17)]. Patients with underlying gastrointestinal disorders such as esophageal cancer or colon cancer with a small gastrointestinal lumen are at greater risk of developing these complications. Consider use of an alternative analgesic in patients who have difficulty swallowing and patients at risk for underlying gastrointestinal disorders resulting in a small gastrointestinal lumen. 5.10 Decreased Bowel Motility HYSINGLA ER is contraindicated in patients with known or suspected gastrointestinal obstruction, including paralytic ileus. Opioids diminish propulsive peristaltic waves in the gastrointestinal tract and decrease bowel motility. Monitor for decreased bowel motility in post-operative patients receiving opioids. The administration of HYSINGLA ER may obscure the diagnosis or clinical course in patients with acute abdominal conditions. Hydrocodone may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis. 5.11 Cytochrome P450 CYP3A4 Inhibitors and Inducers Since the CYP3A4 isoenzyme plays a major role in the metabolism of HYSINGLA ER, drugs that alter CYP3A4 activity may cause changes in clearance of hydrocodone which could lead to changes in hydrocodone plasma concentrations. The clinical results with CYP3A4 inhibitors show an increase in hydrocodone plasma concentrations and possibly increased or prolonged opioid effects, which could be more pronounced with concomitant use of CYP3A4 inhibitors. The expected clinical result with CYP3A4 inducers is a decrease in hydrocodone plasma concentrations, lack of efficacy or, possibly, development of an abstinence syndrome in a patient who had developed physical dependence to hydrocodone. If co-administration is necessary, caution is advised when initiating HYSINGLA ER treatment in patients currently taking, or discontinuing, CYP3A4 inhibitors or inducers. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Drug Interactions (7.1)]. 5.12 Driving and Operating Machinery HYSINGLA ER may impair the mental and physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Peak blood levels of hydrocodone may occur 14 – 16 hours (range 6 – 30 hours) after initial dosing of HYSINGLA ER tablet administration. Blood levels of hydrocodone, in some patients, may be high at the end of 24 hours after repeated-dose administration. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of HYSINGLA ER and know how they will react to the medication [see Clinical Pharmacology (12.3)]. 5.13 Interaction with Mixed Agonist/Antagonist Opioid Analgesics Avoid the use of mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) in patients who have received, or are receiving, a course of therapy with a full opioid agonist analgesic, including HYSINGLA ER. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. 5.14 QTc Interval Prolongation QTc prolongation has been observed with HYSINGLA ER following daily doses of 160 mg [see Clinical Pharmacology (12.2)]. This observation should be considered in making clinical decisions regarding patient monitoring when prescribing HYSINGLA ER in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QTc interval. HYSINGLA ER should be avoided in patients with congenital long QT syndrome. In patients who develop QTc prolongation, consider reducing the dose by 33 – 50%, or changing to an alternate analgesic. 6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the labeling: • Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)] • Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)] • Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)] • Interactions with Other CNS Depressants [see Warnings and Precautions (5.4)] • Hypotensive Effects [see Warnings and Precautions (5.8)] • Gastrointestinal Effects [see Warnings and Precautions (5.9, 5.10)] 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 1,827 patients were treated with HYSINGLA ER in controlled and open-label chronic pain clinical trials. Five hundred patients were treated for 6 months and 364 patients were treated for 12 months. The clinical trial population consisted of opioid-naïve and opioid-experienced patients with persistent moderate to severe chronic pain. The common adverse reactions (≥2%) reported by patients in clinical trials comparing HYSINGLA ER (20-120 mg/day) with placebo are shown in Table 2 below: Table 2: Adverse Reactions Reported in ≥2% of Patients during the Open-Label Titration Period and Double-Blind Treatment Period: Opioid-Naïve and Opioid-Experienced Patients Open-label Titration Period MedDRA Preferred Term Nausea Constipation Vomiting Dizziness Headache Somnolence Fatigue Pruritus Tinnitus Insomnia Decreased appetite Influenza Double-blind Treatment Period (N=905) (%) Placebo (N=292) (%) HYSINGLA ER (N=296) (%) 16 9 7 7 7 5 4 3 2 2 1 1 5 2 3 2 2 1 1 <1 1 2 1 1 8 3 6 3 2 1 1 0 2 3 2 3 The adverse reactions seen in controlled and open-label chronic pain studies are presented below in the following manner: most common (≥5%), common (≥1% to <5%), and less common (<1%). The most common adverse reactions (≥5%) reported by patients treated with HYSINGLA ER in the chronic pain clinical trials were constipation, nausea, vomiting, fatigue, upper respiratory tract infection, dizziness, headache, somnolence. The common (≥1% to <5%) adverse events reported by patients treated with HYSINGLA ER in the chronic pain clinical trials organized by MedDRA (Medical Dictionary for Regulatory Activities) System Organ Class were: Ear and labyrinth disorders tinnitus Gastrointestinal disorders abdominal pain, abdominal pain upper, diarrhea, dry mouth, dyspepsia, gastroesophageal reflux disease General disorders and administration chest pain, chills, edema site conditions peripheral, pain, pyrexia Infections and infestations Injury, poisoning and procedural complications Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders bronchitis, gastroenteritis, gastroenteritis viral, influenza, nasopharyngitis, sinusitis, urinary tract infection fall, muscle strain decreased appetite arthralgia, back pain, muscle spasms, musculoskeletal pain, myalgia, pain in extremity Nervous system disorders lethargy, migraine, sedation Psychiatric disorders anxiety, depression, insomnia Respiratory, thoracic and mediastinal cough, nasal congestion, disorders oropharyngeal pain Skin and subcutaneous tissue disorders hyperhidrosis, pruritus, rash Vascular disorders hot flush, hypertension Other less common adverse reactions that were seen in <1% of the patients in the HYSINGLA ER chronic pain clinical trials include the following in alphabetical order: abdominal discomfort, abdominal distention, agitation, asthenia, choking, confusional state, depressed mood, drug hypersensitivity, drug withdrawal syndrome, dysphagia, dyspnea, esophageal obstruction, flushing, hypogonadism, hypotension, hypoxia, irritability, libido decreased, malaise, mental impairment, mood altered, muscle twitching, edema, orthostatic hypotension, palpitations, presyncope, retching, syncope, thinking abnormal, thirst, tremor, and urinary retention. 7 DRUG INTERACTIONS 7.1 Drugs Affecting Cytochrome P450 Isoenzymes Inhibitors of CYP3A44 Co-administration of HYSINGLA ER with ketoconazole, a strong CYP3A4 inhibitor, significantly increased the plasma concentrations of hydrocodone. Inhibition of CYP3A4 activity by inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may prolong opioid effects. Caution is advised when initiating therapy with, currently taking, or discontinuing CYP3A4 inhibitors. Evaluate these patients at frequent intervals and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. Inducers of CYP3A4 CYP3A4 inducers may induce the metabolism of hydrocodone and, therefore, may cause increased clearance of the drug which could lead to a decrease in hydrocodone plasma concentrations, lack of efficacy or, possibly, development of a withdrawal syndrome in a patient who had developed physical dependence to hydrocodone. If co-administration with HYSINGLA ER is necessary, monitor for signs of opioid withdrawal and consider dose adjustments until stable drug effects are achieved [see Clinical Pharmacology (12.3)]. 7.2 Central Nervous System Depressants The concomitant use of HYSINGLA ER with other CNS depressants including sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and HYSINGLA ER for signs of respiratory depression, sedation and hypotension. When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced [see Warnings and Precautions (5.4)]. 7.3 Interactions with Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) and partial agonist analgesics (buprenorphine) may reduce the analgesic effect of HYSINGLA ER or precipitate withdrawal symptoms in these patients. Avoid the use of mixed agonist/antagonist and partial agonist analgesics in patients receiving HYSINGLA ER. 7.4 MAO Inhibitors HYSINGLA ER is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics. No specific interaction between hydrocodone and MAO inhibitors has been observed, but caution in the use of any opioid in patients taking this class of drugs is appropriate. 7.5 Anticholinergics Anticholinergics or other drugs with anticholinergic activity when used concurrently with opioid analgesics may increase the risk of urinary retention or severe constipation, which may lead to paralytic ileus. Monitor patients for signs of urinary retention and constipation in addition to respiratory and central nervous system depression when HYSINGLA ER is used concurrently with anticholinergic drugs. 7.6 Strong Laxatives Concomitant use of HYSINGLA ER with strong laxatives (e.g., lactulose), that rapidly increase gastrointestinal motility, may decrease hydrocodone absorption and result in decreased hydrocodone plasma levels. If HYSINGLA ER is used in these patients, closely monitor for the development of adverse events as well as changing analgesic requirements. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of HYSINGLA ER use during pregnancy. Prolonged use of opioid analgesics during pregnancy may cause neonatal opioid withdrawal syndrome. In animal reproduction studies with hydrocodone in rats and rabbits no embryotoxicity or teratogenicity was observed. However, reduced pup survival rates, reduced fetal/pup body weights, and delayed ossification were observed at doses causing maternal toxicity. In all of the studies conducted, the exposures in animals were less than the human exposure (see Animal Data). HYSINGLA ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Clinical Considerationss Fetal/neonatal adverse reactions Prolonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly [see Warnings and Precautions (5.3)]. Data Animal Data No evidence of embryotoxicity or teratogenicity was observed after oral administration of hydrocodone throughout the period of organogenesis in rats and rabbits at doses up to 30 mg/kg/day (approximately 0.1 and 0.3-fold, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). black However, in these studies, reduced fetal body weights and delayed ossification were observed in rat at 30 mg/kg/day and reduced fetal body weights were observed in in rabbit at 30 mg/kg/day (approximately 0.1 and 0.3fold, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons). In a pre- and post-natal development study pregnant rats were administered oral hydrocodone throughout the period of gestation and lactation. At a dose of 30 mg/kg/day decreased pup viability, pup survival indices, litter size and pup body weight were observed. This dose is approximately 0.1-fold the human hydrocodone dose of 120 mg/ day based on AUC exposure comparisons. 8.2 Labor and Delivery Opioids cross the placenta and may produce respiratory depression in neonates. HYSINGLA ER is not recommended for use in women immediately prior to and during labor, when use of shorter acting analgesics or other analgesic techniques are more appropriate. HYSINGLA ER may prolong labor through actions which temporarily reduce the strength, duration and frequency of uterine contractions. However, this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor. 8.3 Nursing Mothers Hydrocodone is present in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue HYSINGLA ER, taking into account the importance of the drug to the mother. Infants exposed to HYSINGLA ER through breast milk should be monitored for excess sedation and respiratory depression. Withdrawal symptoms can occur in breast-fed infants when maternal administration of an opioid analgesic is stopped, or when breast-feeding is stopped. 8.4 Pediatric Use The safety and effectiveness of HYSINGLA ER in pediatric patients have not been established. Accidental ingestion of a single dose of HYSINGLA ER in children can result in a fatal overdose of hydrocodone [see Warnings and Precautions (5.2)].] HYSINGLA ER gradually forms a viscous hydrogel (i.e., a gelatinous mass) when exposed to water or other fluids. Pediatric patients may be at increased risk of esophageal obstruction, dysphagia, and choking because of a smaller gastrointestinal lumen if they ingest HYSINGLA ER [see Warnings and Precautions (5.9)]. 8.5 Geriatric Use In a controlled pharmacokinetic study, elderly subjects (greater than 65 years) compared to young adults had similar plasma concentrations of hydrocodone [see Clinical Pharmacology (12.3)]. Of the 1827 subjects exposed to HYSINGLA ER in the pooled chronic pain studies, 241 (13%) were age 65 and older (including those age 75 and older), while 42 (2%) were age 75 and older. In clinical trials with appropriate initiation of therapy and dose titration, no untoward or unexpected adverse reactions were seen in the elderly patients who received HYSINGLA ER. Hydrocodone may cause confusion and oversedation in the elderly. In addition, because of the greater frequency of decreased hepatic, renal, or cardiac function, concomitant disease and concomitant use of CNS active medications, start elderly patients on low doses of HYSINGLA ER and monitor closely for adverse events such as respiratory depression, sedation, and confusion. 8.6 Hepatic Impairment No adjustment in starting dose with HYSINGLA ER is required in patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment may have higher plasma concentrations than those with normal hepatic function. Initiate therapy with 1/2 the initial dose of HYSINGLA ER in patients with severe hepatic impairment and monitor closely for adverse events such as respiratory depression [see Clinical Pharmacology (12.3)]. 8.7 Renal Impairment No dose adjustment is needed in patients with mild renal impairment. Patients with moderate or severe renal impairment or end stage renal disease have higher plasma concentrations than those with normal renal function. Initiate therapy with 1/2 the initial dose of HYSINGLA ER in these patients and monitor closely for adverse events such as respiratory depression [see Clinical Pharmacology (12.3)]. 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance HYSINGLA ER contains hydrocodone bitartrate, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. HYSINGLA ER can be abused and is subject to misuse, abuse, addiction and criminal diversion. The high drug content in the extended-release formulation adds to the risk of adverse outcomes from abuse and misuse. 9.2 Abuse All patients treated with opioids require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use. Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high,” or the use of steroids for performance enhancement and muscle build up. Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal. “Drug-seeking” behavior is very common to addicts and drug abusers. Drug seeking tactics include, but are not limited to, emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of “loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, people with untreated addiction, and criminals seeking drugs to sell. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control. Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction. HYSINGLA ER can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs. Abuse may occur by taking intact tablets in quantities greater than prescribed or without legitimate purpose, by crushing and chewing or snorting the crushed formulation, or by injecting a solution made from the crushed formulation. The risk is increased with concurrent use of HYSINGLA ER with alcohol or other central nervous system depressants. Risks Specific to Abuse of HYSINGLA ER HYSINGLA ER is for oral use only. Abuse of HYSINGLA ER poses a risk of overdose and death.. Taking cut, broken, chewed, crushed, or dissolved HYSINGLA ER increases the risk of overdose and death. With parenteral abuse, the inactive ingredients in HYSINGLA ER can result in death, local tissue necrosis, infection, pulmonary granulomas, and increased risk of endocarditis and valvular heart injury. Parenteral drug abuse is commonly associated with transmission of infectious diseases, such as hepatitis and HIV. Abuse Deterrence Studies Summary The in vitro data demonstrate that HYSINGLA ER has physical and chemical properties that are expected to deter intranasal and intravenous abuse. The data from the clinical abuse potential studies, along with support from the in vitro data, also indicate that HYSINGLA ER has physicochemical properties that are expected to reduce intranasal abuse and oral abuse when chewed. However, abuse of HYSINGLA ER by the intravenous, intranasal, and oral routes is still possible. Additional data, including epidemiological data, when available, may provide further information on the impact of HYSINGLA ER on the abuse liability of the drug. Accordingly, this section may be updated in the future as appropriate. HYSINGLA ER contains hydrocodone, an opioid agonist and Schedule II controlled substance with an abuse liability similar to other opioid agonists, legal or illicit, including fentanyl, hydromorphone, methadone, morphine, oxycodone, and oxymorphone. HYSINGLA ER can be abused and is subject to misuse, addiction, and criminal diversion [See Warnings and Precautions (5.1) and Drug Abuse and Dependence (9)]. 9.3 Dependence Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects. Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, or mixed agonist/antagonist analgesics (pentazocine, butorphanol, nalbuphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage. HYSINGLA ER should be discontinued by a gradual downward titration [see Dosage and Administration (2.6)]. If HYSINGLA ER is abruptly discontinued in a physically dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate. Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Warnings and Precautions (5.3) and Use in Specific Populations (8.3)]. 10 OVERDOSAGE 10.1 Symptoms Acute overdosage with opioids is often characterized by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and, sometimes, pulmonary edema, bradycardia, hypotension, and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations [see Clinical Pharmacology (12.2)]. 10.2 Treatment In the treatment of HYSINGLA ER overdosage, primary attention should be given to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Employ other supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques. The opioid antagonist naloxone hydrochloride is a specific antidote against respiratory depression that may result from opioid overdosage. Nalmefene is an alternative opioid antagonist, which may be administered as a specific antidote to respiratory depression resulting from opioid overdose. Since the duration of action of HYSINGLA ER may exceed that of the antagonist, keep the patient under continued surveillance and administer repeated doses of the antagonist according to the antagonist labeling, as needed, to maintain adequate respiration. Opioid antagonists should not be administered in the absence of clinically significant respiratory or circulatory depression. Administer opioid antagonists cautiously to persons who are known, or suspected to be, physically dependent on HYSINGLA ER. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. In an individual physically dependent on opioids, administration of the usual dose of the antagonist will precipitate an acute withdrawal syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. If a decision is made to treat serious respiratory depression in the physically dependent patient, administration of the antagonist should be initiated with care and by titration with smaller than usual doses of the antagonist. CAUTION DEA FORM REQUIRED Healthcare professionals can telephone Purdue Pharma’s Medical Services Department (1-888-726-7535) for information on this product. Purdue Pharma L.P. Stamford, CT 06901-3431 ©2014, Purdue Pharma L.P. U.S. Patent Numbers: 6,488,963; 6,733,783; 8,309,060; 8,361,499; 8,529,948; 8,551,520; 8,647,667 and 8,808,740. This brief summary is based on Hysingla ER Prescribing Information 303511-0B, Revised 11/2014 (A) ES567464_DRTP0215_A17_FP.pgs 02.06.2015 01:55 ADV Up front IN MEMORIAM Dean of Wegmans School of Pharmacy mourned Scott Swigart, founding dean of the Wegmans School of Pharmacy at St. John Fisher College in Rochester, N.Y., created quite a legacy during his nearly 10-year tenure at the college. Swigart, 58, succumbed to pancreatic cancer on December 23, 2014, after a lengthy illness. “Scott was a spirited presence on campus and a true friend. His leadership of the Wegmans School of Pharmacy created a culture that fostered student success and growth of the Scott Swigart school,” said Dr. Donald E. Bain, president of St. John Fisher College. “His zeal for life and his passion for his career went hand in hand, and his absence on our campus and in our community will be felt for some time. He was loved by many and will be missed by all. ” The Fisher School of Pharmacy became an extension of Swigart’s family over the past year, as he underwent treatment for cancer. Faculty, staff, and students created purple “Team Swigart” pins, bracelets, and T-shirts, which were worn daily by members of the Fisher community. Last November, Swigart himself led “Team Swigart” at the Step-it-Up Walk for the ACCREDITATION Innovative patient-care services recognized by CPPA Last month, Marv Moore, PharmD, received good news from the Center for Pharmacy Practice Accreditation (CPPA). His Two Rivers Medicine Shoppe, located in Two Rivers, Wis., was accredited under CPPA’s community pharmacy practice standards, becoming the third pharmacy to receive this recognition. Moore, who is the president and owner of the Two Rivers pharmacy franchise, said he was pleased to head one of the frst community pharmacies in the country to meet CPPA’s rigorous accreditation standards. “For years, we have been committed to providing the best possible care to our patients, and this important accreditation validates that we are on the right track,” said Moore, an editorial Marvin Moore advisor to Drug Topics. Accreditation is important to Moore, who ensures that his staff follows best practice guidelines for providing safe and effective patient care. His team offers health screenings, medication therapy management, and medication counseling personalized to meet patients’ specifc needs. 18 magenta cyan yellow black DRUG TOPICS Februar y 2015 Pancreatic Cancer Association of Western New York, raising the most money of any participating teams. A strong leader Under Swigart’s leadership, the school experienced tremendous growth, and year after year its graduates achieve some of the most successful licensure-exam pass rates in the state, a school announcement stated. “In addition, he has nurtured a strong community-minded atmosphere in the School of Pharmacy. Teams of faculty and students regularly travel on domestic and international medical mission trips to provide free medical care to underserved populations and hold an annual Day of Service, among a variety of other service activities,” the statement said. Before coming to Fisher, Swigert spent fve years as a professor and founding dean at the Lloyd L. Gregory School of Pharmacy at Palm Beach Atlantic University. Before that, he held positions as assistant dean and head of the Department of Pharmacy Practice at Nova Southeastern University College of Pharmacy in Ft. Lauderdale, Florida; and headed the Department of Pharmacy Practice at Ferris State University College of Pharmacy in Big Rapids, Mich. Swigart is survived by his wife, Cindy; his daughter, Kim, a 2011 graduate of the Wegmans School of Pharmacy; and his son, Scott, a junior at Fisher. — Christine Blank, Contributing Editor Emphasis on improved care “I felt that the [accreditation] process would help us look for gaps in our current policy and procedures, and guide us in how to best fll in those gaps,” he said in an article in The Journal of the Pharmacy Society of Wisconsin. “[Also] it is important to recognize that some pharmacies have put an emphasis on improving the quality of patient care they provide and have invested in providing innovative patientcare services,” he said. “I believe that becoming accredited is a way to show that we have one of these practices here in Two Rivers.” Moore believes that the day is coming when payers will note accredited pharmacies and include them in their networks. In the future, payers may offer patients incentives to seek healthcare providers who offer quality patient-care services, he said. The accreditation process begins with a self-assessment survey of current policies and practices. CPPA reviews the survey and schedules an on-site observation visit to ensure that criteria for accreditation have been met, after which it notifes the pharmacy by letter of any issues found. Then an action plan must be implemented to meet these accreditation issues. The nonproft CPPA was launched in 2012 by the American Pharmacists Association, the National Association of Boards of Pharmacy, and the American Society of Health-System Pharmacists. Go to www.pharmacypracticeaccredit.org for more information. — Julia Talsma, Content Channel Director DrugTopics .c om ES566971_drtp0215_018.pgs 02.05.2015 19:37 ADV Clinical Lynda Charters Managing diabetic retinopathy: Annual ocular evaluations are key As long as they remain asymptomatic, patients with type 2 diabetes can easily forget about the devastating systemic consequences of the disease. And this comfort level may be their downfall, because diabetic retinopathy (DR) is a sneaky, sight-stealing thief that can burst onto the scene with little or no advance warning. DR does not develop in every Symptoms and signs patient with diabetes. However, the The disease is characterized by a numestimated prevalence of DR in the United ber of symptoms and signs. Patients States from 2005 to 2008 was a substan- should be alert for the appearance tial 28.5% in diabetic adults, and the of floaters or strands in their vision; prevalence of vision-threatblurred or distorted central ening DR was 4.4%, said vision; and transient visual Mary Elizabeth Hartnett, blurring resulting from lens MD, professor, Department of swelling in uncontrolled diaOphthalmology, Moran Eye betes. Center, University of Utah, These symptoms are Salt Lake City. frequently present only One way pharmacists in advanced retinopathy, can promote patient educawhich underscores the need Mary Hartnett tion is by reminding patients for all patients with diabetes of the inherent visual risks to undergo screening exams. associated with diabetes and emphasizing Clinical fndings include the presthe importance of regular ocular evalu- ence of microaneurysms, fame-shaped ations to rule out the presence of DR or hemorrhages, cotton-wool spots, into facilitate early intervention to prevent traretinal microvascular abnormalities progression. (IRMA), retinal edema/exudates, and venous beading, said Michael Allingham, MD, PhD, assistant professor of How diabetes may ophthalmology, Duke University Eye affect vision Diabetes affects the retinal vasculature Center, Durham, N.C. and the existing normal retinal blood vessels in several ways. Types of diabetic retinopathy Sometimes diabetes causes retinal Types of DR are characterized as noncapillary damage and leakiness in the proliferative and proliferative. macula and leads to retinal swelling, In mild disease, nonproliferative DR known as macular edema, which can (NPDR) presents as a few microaneureduce central vision. rysms. In moderate disease, it appears Other times the retinal capillaries as hemorrhages, microaneurysms, and are damaged outside the macula, and exudates. And in severe instances, those the retina is starved for oxygen and same characteristics can appear in all nutrients. This can lead to release of four ocular quadrants; as venous beadsubstances that promote blood vessel ing in two quadrants minimally; or as growth into the vitreous. IRMA in one quadrant. In both cases, certain growth factors, Proliferative DR (PDR) is characterized such as vascular endothelial growth by neovascularization, preretinal hemorfactor (VEGF), can be involved, Hart- rhage, vitreous hemorrhage, and traction nett said. retinal detachment, Allingham said. DrugTopics .c om magenta cyan yellow black Diabetic macular edema (DME), one of the most important visionthreatening forms of DR, results from a combination of chronic microvascular damage to the retinal endothelium and probably a variety of other cellular types, including neurons, glial cells, and pericytes that culminates in fuid accumulation in the macula and affects the ability to read fne print and the central vision, said Allingham. He also noted that it is not uncommon for some patients with diabetes to have both near-normal central vision and very advanced peripheral retinopathy that requires treatment. Screening Because DR develops over an extended period, with many affected patients having diabetes for between 10 and 20 years or more before DR develops, the key to managing ocular complications in patients with diabetes is regular ocular evaluations. “The real challenge with these patients is that they can have advanced asymptomatic DR. We recommend that patients with diabetes have eye examinations at least yearly to screen for the presence of DR,” Hartnett said. Another wrinkle when dealing with this patient group, according to Allingham, is that millions of individuals have diabetes but don’t know it. “Diabetes can be so insidious that people can write off the symptoms for extended periods before diagnosis. For these reasons, most retina specialists recommend at least a complete dilated fundus examination for all patients with Continued on pg. 20 Februar y 2015 DRUG TOPICS 19 ES566985_drtp0215_019.pgs 02.05.2015 19:41 ADV Clinical Managing diabetic retinopathy Continued from pg. 19 newly diagnosed diabetes. Most general ophthalmologists can perform this examination in asymptomatic individuals,” he said. Guidelines published by the American Academy of Ophthalmology recommend yearly monitoring for patients without retinopathy. Because signs of DR do not develop for an extended period of time, some screening guidelines have been changing, Allingham added, in response to the shortage of ophthalmologists and patient reluctance to undergo dilated eye examinations without a clear visionrelated problem. For example, he said, the Department of Veterans’ Affairs (VA) has instituted a photographic screening service in which patients can show up at a participating VA facility and have a color fundus photograph taken; if an abnormality is identified, the patient can be referred for a full examination by an ophthalmologist. This evaluation simplifes the process by allowing the fundus photograph to be substituted for a dilated fundus examination. Monitoring Hartnett and Allingham adhere to much the same course of management. Upon diagnosis of DR, the frequency of subsequent ocular evaluations depends on the severity of the disease. When NPDR is mild, no specifc treatment is indicated and patients should be reevaluated every nine months. In the case of moderate disease, they should be monitored every four to six months. With severe-to-very-severe NPDR or PDR with new abnormal blood vessels growing on the optic nerve or iris, early treatment can be considered, or evaluations every two to three months at most. “The clinical monitoring is based on estimating the patient’s risk of progressing to a treatable or vision-threatening form of diabetes,” Allingham said. Treatment There is no evidence-based ophthalmic treatment for NPDR, said Allingham. 20 magenta yellow black DRUG TOPICS Februar y 2015 Patients are observed. Standard recommendations emphasize serum glucose and blood pressure control to reduce the risk of ocular and systemic complications. For PDR, there is no FDA-approved pharmacologic agent. Panretinal photocoagulation (PRP) is used to perform thermal laser ablation of the peripheral and nonperfused retina. “Patients with high-risk PDR are considered to have crossed a threshold in which patients are at high risk for vision loss,” he said. Patients with PDR also can benefit from the use of anti-VEGF drugs. “VEGF is a driving force in PDR. Clinical studies have shown that the incidence of progression to PDR or requiring treatment for PDR is reduced in patients receiving intravitreal anti-VEGF therapy for other indications. This is an active research area. We cannot state defnitively that anti-VEGF drugs are part of the treatment for PDR, but there is mounting evidence that they can play a role,” he said. Ranibizumab (Lucentis; Genentech Inc.) and afibercept (Eylea; Regeneron Pharmaceuticals) have received FDA approval for treatment of macular edema, in 2012 and 2014 respectively. Bevacizumab (Avastin; Genentech Inc.) is used off-label to treat DME. While anti-VEGF treatment seems to work for PDR, PRP applied to the peripheral retina remains the mainstay of treatment, said Hartnett. An anti-VEGF drug can be used initially or in combination with laser; following full PRP, patients can be monitored often without anti-VEGF treatment. DME can be treated with a number of pharmacologic agents, with anti-VEGF drugs now the frst-line treatment. Historically, the gold standard treatment for more than 30 years was thermal laser (focal or grid laser macular photocoagulation). This approach stabilizes vision but does not improve vision in most patients. Intravitreal steroid injections (triamcinolone acetonide; Kenalog; Bristol-Myers Squibb) are also effcacious for treating DME, but are associated with glaucoma and cataract development, Allingham said. The latest studies have indicated that intravitreally injected anti-VEGF drugs are beneficial for DME in conjunction with possible laser treatment, Hartnett noted. Another option for DME is the steroid implant dexamethasone (Ozurdex; Allergan), which recently received FDA approval and is also used for treating retinal vein occlusion, he added. Team approach Because diabetes affects every organ system, numerous clinicians may be involved in controlling the disease. Pharmacists who are aware of patients who have had diabetes for an extended period of time should recommend that they undergo yearly ocular examinations with an ophthalmologist or optometrist. “The best approach that a clinician can have for patients with diabetes is to strongly encourage good serum glucose control with an A1c under 7, blood pressure, and cholesterol — the ABCs of monitoring diabetes. A good management plan happens with a good team. Clinical care now requires teamwork among various specialties,” Hartnett said. Such team management includes close working relationships between an endocrinologist, a primary care physician or nurse practitioner, an ophthalmologist, a cardiologist, a nephrologist, a nutritionist, and perhaps an exercise trainer, she said. She noted that patients with diabetes may have a silent infection or injury that disrupts glycemic control, so it is important for their feet or legs to be checked for sores and dental evaluations made for tooth abscesses. To stop progression, it is important to identify those patients who are asymptomatic, as well as to emphasize the need for annual eye exams in newly diagnosed patients with diabetes. Lynda Charters is a medical writer in Framingham, Mass. DrugTopics .c om ES566984_drtp0215_020.pgs 02.05.2015 19:41 ADV Counter Points Voices Continued from pg. 9 pharmacy school in Miss.” [Jan. 16, Mark Lowery, www. drugtopics.com]; Amazing. This is the frst I’ve heard of another new school, and I live in nearby Alabama. A recent article I read in the New Republic, titled “The pharmacy school bubble is about to burst,” quotes a prediction of “20% unemployment of new grads by 2018.” Even now, new grads we see fnd it mandatory to have done at least one or two residencies, and all of our residents are getting BCPS certifcation. Has there ever been a more suicidal profession in the healthcare industry? Anonymous POSTED AT WWW.DRUGTOPICS.COM You’re kidding, right? Re: “Meredith named dean of B.U. pharmacy school” [Jan. 8, Mark Lowery, www.drugtopics.com]; Are you serious? Just what we need, another new pharmacy school, at a time when 27 pharmacy departments are being closed, as reported by another article in this magazine. Wake up, kids! Become a physician assistant. Anonymous Quarters give more bang for the buck With the six-to-seven-year programs that exist now, there’s plenty of opportunity to pick up a social sciences background (if the student doesn’t already have a degree in the feld). We had a couple of social science courses in my pharmacy curriculum, which, because they were poorly placed in the second professional year, were attended by fve designated note-takers while everyone else was studying med chem, pharmacology, and clinical pharmacy. The classes weren’t meeting anyone’s needs at the time (early 1980s). I think Dennis would have had plenty of opportunity to audit the social sciences if his college/university had been on a quarter system instead of a semester system. The semester system signifcantly reduces a student’s options for additional courses, giving that degree less “bang for the buck.” Anonymous POSTED AT WWW.DRUGTOPICS.COM We want to hear from you Printed and e-mailed letters should be brief and include the writer’s name, address, daytime phone number, and date of the issue you are referencing: Editor, Drug Topics, 24950 Country Club Blvd., Suite 200, North Olmsted, OH 44070-5351. E-mail: [email protected]. Letters may be edited for length, style, content, and clarity at our discretion. POSTED AT WWW.DRUGTOPICS.COM Food for thought Re: “What I wish I had learned in pharmacy school” [Jan. 7, Dennis Miller, www.drugtopics.com]; I have to agree, especially about all calculus, literature, and physics classes! When I did pharmacy, there was a program where you could get dual degree in food science and pharmacy! I actually think that some more nutrition classes might be valid, as well. Anonymous POSTED AT WWW.DRUGTOPICS.COM Get ahead with psych I can certainly attest to the usefulness of a psychology background, and not just a semester. I got a degree in psychology before pharmacy school (as well as a few years working on a psych unit). I can honestly say I use it every day of my life. Mr. J Blossom POSTED AT WWW.DRUGTOPICS.COM Don’t forget about business management I enjoyed this article and would like to add that a few courses in business management would be essential for a more well-rounded graduate. We should be cognizant of the fact that healthcare is a business, yet many practitioners are clueless about modern business practices. Anonymous POSTED AT WWW.DRUGTOPICS.COM DrugTopics .c om magenta cyan yellow black Februar y 2015 DRUG TOPICS 21 ES567828_drtp0215_021.pgs 02.06.2015 04:19 ADV Cover Story 2015 PIPELINE REPORT Josh Baxt New drugs raise hopes Groundbreaking therapies on the way for cancer, heart failure T racking new therapies as they wind their way through development, regulatory approval, and payer acceptance can be like waiting for paint to dry — and then repainting in a different color. It’s a slow process and far from linear. This is especially true for drugs with groundbreaking potential, disruptive therapies that completely upend markets and patient care. The lag time between that frst fickering glimmer of hope and an accepted therapy can be measured in decades. And, all too often, agents that seem hopeful in the lab and early clinical trials fzzle on further investigation. But then there are those rare moments when the stars align and truly astounding therapies make their way into the world, providing improved care and big returns. In the next few years, cancer immunotherapies seem likely to enter the pantheon of big winners. And they may not be alone. Besides the buzz around a cure for hepatitis C virus, there are exciting drugs for heart failure and cholesterolemia coming into play. On a smaller scale, companies are embracing new therapies for rare diseases. Stem cells are making real forays into late-stage trials. This year’s pipeline report will check in on these emerging technologies, as well as potential therapies to address metabolic and neurodegenerative diseases. There’s a lot to like in the pipeline and more than a little competitive drama to make it really interesting. Immuno-oncology: The elegant solution For Trekkers, there’s nothing better than watching a Klingon or Romulan ship lose its invisibility cloak and get blasted out of space. On the cellular level, similar action is driving the excitement around programmed death 1 (PD-1)/programmed 22 magenta cyan yellow black DRUG TOPICS Februar y 2015 Editor’s Note: This article was first published in the November 2014 issue of Pharmaceutical Executive, another UBM Advanstar publication. It has been updated to refect the most current information available at press time. death ligand 1 (PD-L1) checkpoint inhibitors: the opportunity to reveal cancer and unleash the immune system against it. “There’s genuine enthusiasm among oncology experts,” said Seamus Fernandez, managing director of Major and Specialty Pharmaceuticals at Leerink Partners. “There’s evidence of activity in more than fve different tumors and signals of activity in as many as 14. We forecast a $36 billion immuno-oncology market by 2025.” That’s a large pie, and there’s been a lot of jostling to get the biggest piece. Bristol-Myers Squibb’s cytotoxic T lymphocyte antigen-4 (CTLA-4) inhibitor Yervoy (ipilimumab) was frst out of the gate, but several other agents are poised to hit the market as well. Last September, Merck’s PD-1 blocker Keytruda (pembrolizumab) received accelerated approval from FDA to treat melanoma, and the company is conducting trials of the drug for non-small cell lung cancer (NSCLC) and other indications. In its World Preview 2014 Outlook report, EvaluatePharma forecasts Keytruda sales of $4.06 billion by 2020. That’s a great start, but it’s unclear whether Merck’s advantage will hold out over the long haul. The competition will be ferce in the PD-1/PD-L1 space. With a huge potential market, this could be the equivalent of the Oklahoma land rush for the usual pharma titans. However, StephaContinued on pg. 24 DrugTopics .c om ES567010_drtp0215_022.pgs 02.05.2015 20:05 ADV Now patients covered by any private insurance can get ACCU-CHEK® test strips at preferred co-pay levels. 1 INTRODUCING THE NEW The NEW ACCU-CHEK Preferred Savings program eliminates the guesswork about a patient’s insurance coverage for diabetes test strips. Applicable savings are automatically applied at your terminal or by simply entering your patient’s ACCU-CHEK Preferred Savings card as secondary insurance. Whether newly diagnosed or disrupted by a formulary change, your patient now has access to ACCU-CHEK test strips at a low cost.1 Visit accu-chek.com/preferred for details. 1 The ACCU-CHEK Preferred Savings program is not valid for test strip prescriptions paid, in whole or in part, by any government healthcare programs, including Medicare, Medicaid, or Medicare Advantage, or for patients in Massachusetts. Limitations and maximum discounts apply. ACCU-CHEK, ACCU-CHEK SMARTVIEW, ACCU-CHEK COMPACT, and ACCU-CHEK AVIVA are trademarks of Roche. © 2015 Roche. 316-54160-0115 magenta cyan yellow black ES567461_DRTP0215_A23_FP.pgs 02.06.2015 01:55 ADV Cover Story 2015 Pipeline report Continued from pg. 22 Table 1. C A N C E R DRUG NAME; COMPANY DRUG INDICATION FDA STATUS Pembrolizumab (Keytruda) for injection; Merck Pembrolizumab is a human programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approved Sept. 2014 Nivolumab (Opdivo) injection; Bristol-Myers Squibb Nivolumab is a human programmed death receptor-1 (PD-1)-blocking antibody indicated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approved Dec. 2014 MPDL3280A; Genentech/Roche MPDL3280A is an engineered anti-PDL1 antibody in clinical trials for the treatment of patients with metastatic bladder cancer, metastatic melanoma, non-small cell lung cancer (NSCLC), and advanced renal cell carcinoma (RCC). Phase 3 (bladder) Phase 3 (melanoma) Phase 1b (NSCLC) Phase 2 (RCC) MEDI-4736; MedImmune/ AstraZeneca MEDI-4736 is a human monoclonal antibody directed against programmed cell death ligand 1 (PD-L1). It is in clinical trials for the treatment of patients with locally advanced, unresectable NSCLC (Stage III) following completion of treatment with chemoradiotherapy and no evidence of tumor progression. Phase 3 Blinatumomab (Blincyto); Amgen Blinatumomab is a bispecifc CD19-directed CD3 T-cell engager (BiTE) antibody construct Approved product that is approved for the treatment of patients with Philadelphia chromosome-negaDec. 2014 tive relapsed or refractory B-cell precursor acute lympoblastic leukemia (ALL). Veliparib; AbbVie Veliparib is an investigational oral poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP) inhibitor being evaluated in multiple tumor types, including phase 3 studies in nonsmall cell lung cancer and breast cancer. Phase 3 Rucaparib; Clovis/Pfzer Rucaparib is an oral poly (adenosine diphosphate [ADP]-ribose) polymerases (PARP) inhibitor being investigated for the treatment of patients with ovarian cancer. Phase 2 Palbociclib; Onyx/Pfzer Palbociclib, an oral CDK 4/6 inhibitor, is being investigated for the frst-line treatment for postmenopausal women with estrogen receptor positive (ER+) human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer who have not received previous systemic treatment for their advanced disease. NDA fled and accepted Oct. 2014 nie Hawthorne, senior director at Kantar Health, noted that, for now in melanoma, Keytruda is in the driver’s seat compared to BMS’s PD-1 inhibitor Opdivo (nivolumab), which FDA approved last December, three months behind Keytruda in the United States. “It’s a big advantage for Merck, being frst-to-market,” said Hawthorne. “Based on the available data, they both look really effcacious, and they’re fairly well tolerated compared to Yervoy. BMS’s saving grace might be the combination of Opdivo and Yervoy they are studying. The survival data we’ve seen for it so far is really impressive, and that could trump Merck’s lead.” Hawthorne’s point was underscored late last September when BMS released data at the European Society for Medical Oncology (ESMO) showing that Opdivo achieved a 32% response rate against advanced melanoma in patients who had previously been treated with Yervoy. The control group, which received traditional chemo, had an 11% response. While Keytruda was frst in the United States, Opdivo was approved for melanoma in Japan in July 2014, under a deal with BMS partner Ono Pharmaceuticals. The ESMO data only supports BMS’s showing in the United States. FDA gave 24 magenta cyan yellow black DRUG TOPICS Februar y 2015 Opdivo fast-track designation in melanoma, NSCLC, and renal cell carcinoma (RCC), and breakthrough-therapy designation for Hodgkin’s lymphoma. Last September, BMS announced that both FDA and the European Medicines Agency (EMA) accepted Opdivo for accelerated review for melanoma. FDA approved Opdivo for advanced melanoma December 22, 2014. In the next few years, cancer immunotherapies seem likely to enter the pantheon of big winners. “Opdivo is the most valuable pipeline drug in development at the moment,” said Lisa Urquhart, editor of Evaluate’s editorial team, EP Vantage. “The data from studies is showing some impressive advances in both overall survival and disease progression.” EvaluatePharma pegs Opdivo’s potential sales at $6 billion by 2020. That’s in melanoma. Opdivo may even have a more Continued on pg. 26 DrugTopics .c om ES567011_drtp0215_024.pgs 02.05.2015 20:05 ADV NEXAFED IS THE # 1 CHOICE AMONG PHARMACISTS WHO RECOMMEND METH-RESISTANT PSE PRODUCTS.1 The wait is over. NEXAFED SINUS PRESSURE + PAIN IS NOW AVAILABLE. Nexafed is proud to introduce the first extension of its line of meth-resistant pseudoephedrine (PSE) products—Nexafed Sinus Pressure + Pain. 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All rights reserved. 14NEX006.13 magenta cyan yellow black ES567462_DRTP0215_025_FP.pgs 02.06.2015 01:55 ADV Cover Story 2015 Pipeline report Continued from pg. 24 clear-cut advantage in being frst-to-market for NSCLC, where BMS has already submitted its drug for approval while Merck is still completing Phase 3 trials. A crowded field The PD-1/PD-L1 approach is generating a lot of enthusiasm for good reason. Early results have shown great effcacy in many indications, including underserved areas, such as bladder and head-and-neck cancers. The possibility of producing an agent that can target multiple cancers is raising heart rates throughout the pharma industry. “These drugs are all across the board,” said Hawthorne. “I’m not sure there’s a tumor type that’s not being touched: renal cell cancer, head and neck, bladder, and Hodgkin’s lymphoma. It’s just an indication of how huge and impactful these could be for patients.” Again, this is underscored by Merck results, also released at ESMO, which showed a 24% response rate for Keytruda against bladder cancer. Genentech/Roche’s PD-L1 offering, MPDL3280A (RG-7446), is in trials for NSCLC, melanoma, RCC, and bladder cancer. The company received breakthrough designation for this last indication. EvaluatePharma puts sales at $2.93 billion by 2020, while the Thomson Reuters Cortellis database puts them at $1.2 billion by 2019. MedImmune/AstraZeneca is also in the race with PD-L1 drug MEDI-4736, primarily targeting NSCLC. Also shared at ESMO, a small 18-person study showed a 28% response to MEDI-4736 combined with the CTLA-4-directed antibody tremelimumab. Cortellis projects MEDI-4736 sales at close to $1.1 billion by 2019. “We’re just at the tip of the iceberg for immuno-oncology, but the enthusiasm is certainly warranted because of the kinds of responses and the tumors being opened up,” said Fernandez. “The feld is about as exciting and confusing as you could possibly imagine.” The combo conundrum With these fantastic response rates in aggressive cancers, how will PD-1/PD-L1 inhibitors redefne patient care? As monotherapies? In combination with other types of immuno-oncology drugs? Or will they be combined with the new generation of targeted chemotherapies? “The best-case scenario, these agents are working in 35 to 50% of melanoma patients as single agents,” said Fernandez. “Worst-case scenario, maybe they’re working in 15 or 20%. There’s a strong conviction that multiple mechanisms are going to be relevant in various different tumors.” How this will play out is subject to much debate. If Fernandez’s more optimistic scenario proves accurate, these checkpoint agents could be extremely successful monotherapies, which could have a profound impact on standards of care. 26 magenta cyan yellow black DRUG TOPICS Februar y 2015 “This could be very disruptive,” said Hawthorne. “Whereas you’re used to treating lung cancer with cisplatin or carbotaxol frst line, you might get Opdivo, and that could push those drugs out.” Hawthorne anticipates that both clinical and commercial factors will drive companies to test their more traditional therapies in combination with the emerging checkpoint inhibitors. “If the drug has the potential to displace you, then it makes sense to go in combination with it,” said Hawthorne. In addition, there’s the long-term possibility of pairing a PD-1/PD-L1 with emerging immunotherapies that target different mechanisms. Just over the horizon, chimeric antigen receptor (CAR-T) therapies could make a big impact. Unlike PD-1/PD-L1 inhibitors, which unchain immunity, CAR-Ts activate the immune system, which offers intriguing possibilities, as well as possible dangers. “My wariness would be around the potential side effects,” said Hawthorne. “If you’re simultaneously up-regulating the immune system and taking the brakes off, that could go kind of crazy.” At this point, Novartis is first in the CAR-T line with CTL019, which received breakthrough designation from FDA in July 2014 for acute lymphoblastic leukemia (ALL). The drug is currently in Phase 2 trials. However, CAR-T therapy may not have an easy path. A Juno Therapeutics/Memorial Sloan-Kettering study for aggressive non-Hodgkin’s lymphoma (NHL) was suspended recently after two patients died from cytokine release syndrome, one of the apparent risks of taking the brakes off the immune system. While the study was only delayed, this event underscores potential concerns about CAR-T therapies. Another interesting immuno-oncology therapy is Amgen’s blinatumomab, a bi-specifc T-cell engager (BiTE). Blinatumomab received breakthrough-therapy designation for ALL in July 2014, and Amgen fled for early approval, which it received in December. At Leerink Partners’ Healthcare Insights Conference in July, a number of experts expressed their belief that this drug is an interesting proof-of-concept; however, they were also concerned about neurotoxicity. Thomson Reuters puts potential sales at $325 million by 2019. There are too many immunotherapies to list here, which is great news for cancer patients. Ultimately, PD-1/PD-L1 may form the backbone for a variety of combinations. This is based on effcacy, as well as a complementary mechanism of action, but there’s also a practical measure. With so many different combinations, it would be virtually impossible to test them all. “The stakes get a lot more interesting and a lot more confusing,” said Fernandez. “We are going to see a signifcant number of mixed successes and disappointments as we move forward with these different combinations.” Continued on pg. 28 DrugTopics .c om ES567009_drtp0215_026.pgs 02.05.2015 20:05 ADV NOW AVAILABLE Valsartan Tablets, USP AB rated for Diovan® Tablets* ® NDC # Strength Size 31722-745-30 40 mg 30 ct 31722-746-90 80 mg 90 ct 31722-747-90 160 mg 90 ct 31722-748-90 320 mg 90 ct 40 mg 160 mg 80 mg 320 mg Camber Pharmaceuticals is committed to bringing the highest quality products to market and improving the quality of life for patients with cost-effective medications. Our strong supply chain from APIs, to intermediates, to finished dosages, has enabled Camber to be one of the fastest growing generic pharmaceutical manufacturers in the US. 732.529.0430 | camberpharma.com *Diovan® is a registered trademark of Novartis. © 2015 Camber Pharmaceuticals, Inc. Product images not to scale. magenta cyan yellow black ES567442_DRTP0215_027_FP.pgs 02.06.2015 01:54 ADV Cover Story 2015 Pipeline report Continued from pg. 26 Table 2. H E A RT FA I LU R E DRUG NAME; COMPANY DRUG INDICATION FDA STATUS LCZ696; Novartis LCZ696 is a combination agent of valsartan, an angiotensin receptor blocker, and sacubitril, the neprilysin inhibitor, being investigated for heart failure. Phase 3 Serelaxin; Novartis Serelaxin is an investigational drug for the treatment of acute heart failure (AHF), targeting the relaxin receptor. Phase 3 Alirocumab; Sanof/Regeneron Alirocumab is a human monoclonal antibody proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor designed for the treatment of hypercholesterolemia. Phase 3 Evolocumab; Amgen Evolocumab is a human monoclonal antibody PCSK9 inhibitor designed for the treatment of hypercholesterolemia. Phase 3 Bococizumab; Pfzer Bococizumab is an injectable monoclonal antibody PCSK9 inhibitor, under investigation for the treatment of hypercholesterolemia. Phase 3 Anacetrapib; Merck Anacetrapib is an oral inhibitor of cholesteryl ester transfer protein (CETP) inhibitor, in development for the treatment of atherosclerosis. Phase 3 Evacetrapib; Eli Lilly Evacetrapib is an oral inhibitor of cholesteryl ester transfer protein (CETP) inhibitor, in development for the prevention of cardiovascular events in high-risk vascular disease. Phase 3 Targeted oncology agents While immunotherapies may hold the greatest upside, various more traditional treatments are still in the oncology pipeline. First on the list are the poly ADP ribose polymerase (PARP) inhibitors, which encourage cancer-cell death by limiting this DNA-repair enzyme. They include veliparib from AbbVie; rucaparib from Clovis Oncology/Pfzer; Lynparza (olaparib) from AstraZeneca; and BMN-673 from BioMarin. Their oral administration makes them particularly exciting. Veliparib is being developed for triple-negative breast cancer and NSCLC. The drug showed a 52% response rate against breast cancer in a study that combined it with carboplatin and paclitaxel. AbbVie recently announced a pivotal Phase 3 study for patients with advanced breast cancer. The company is also conducting a Phase 2 trial for NSCLC. Thomson Reuters projects sales at $350 million by 2019. Meanwhile, in a Phase 2 study, rucaparib showed a 93% disease-control rate in BRCA-positive ovarian cancer. Thomson has rucaparib at $414 million by 2019. Clovis has also earned breakthrough status for its epidermal growth factor receptor (EGFR) blocker CO-1686 for lung cancer. At the 2014 ASCO Annual Meeting, Clovis unveiled excellent progression-free survival in a combo Phase 1/2 study. The company will have major competition from AstraZeneca’s AZD9291, which targets both EGFR and the resistance mutation T790. The drug is currently in pivotal trials. AstraZeneca is partnering with Roche; they plan to fle with regulators in the latter part of this year. Thomson Reuters estimates $761 million in sales in 2019. Then there are the cell cycle regulating cyclin-dependent kinase 4 (CDK4) and CDK6 inhibitors, which show great potential for adjuvant treatment. At the front of the pack is Onyx/Pfzer’s palbociclib. Pfzer recently submitted a new drug application (NDA), for use of 28 magenta cyan yellow black DRUG TOPICS Februar y 2015 palbociclib in combination with letrozole to treat advanced ERpositive, HER2-negative breast cancer. Data submitted at the AACR Annual Meeting showed a progression-free survival of 20.2 months. EvaluatePharma predicts that palbociclib will have worldwide sales in the $2.95 billion range by 2020. The Thomson Reuters Cortellis database puts sales at $2.02 billion in 2019. Another CDK4/CDK6 candidate is Eli Lilly’s abemaciclib for metastatic breast cancer and NSCLC. Cortellis forecasts $306.2 million for that drug. A revolution in heart failure Heart failure is an underserved health area that is continuing to grow. Decision Resources Group recently estimated that it will expand from $2.9 billion in 2013 to $8.9 billion in 2023. Breakthroughs have been limited for some years, so the feld is wide open for promising therapeutics. “Heart failure is very common and getting more common, very expensive in terms of co-morbidities, and really underserved,” said Les Funtleyder, a healthcare portfolio manager at E Squared Asset Management. Few drugs are generating more enthusiasm than Novartis’ heart-failure and hypertension treatment LCZ696. The drug has novel mechanisms, combining sacubitril to preserve peptides that lower blood pressure and valsartan to improve vasodilation. There haven’t been any major improvements in heart failure therapies in decades. EvaluatePharma puts sales at $1.3 billion by 2020, while Thomson Reuters has them at $1.8 billion in 2019. Both estimates may be conservative. Data from a pivotal Phase 3 trial showed the drug reduced the risk of death by 20%, compared to an angiotensinconverting-enzyme (ACE) inhibitor, as well as dramatically reducing the risk of hospitalization. There’s a lot of excitement that this new drug could supplant ACE inhibitors and ARBs. “We’re forecasting $6 billion of peak sales, but that number DrugTopics .c om ES567013_drtp0215_028.pgs 02.05.2015 20:05 ADV Cover Story Table 3. D I A B E T E S DRUG NAME; COMPANY DRUG INDICATION FDA STATUS Toujeo; Sanof Toujeo (insulin glargine [rDNA origin] injection, 300 U/mL) is an investigational basal insulin for the treatment of type 1 and type 2 diabetes. NDA accepted July 2014 Basaglar; Lilly/Boehringer Basaglar (insulin glargine injection) received tentative approval from FDA due to litigation fled from Sanof, claiming patent infringement. Basaglar is indicated for improvement of glycemic control in adults with type 2 diabetes and in combination with mealtime insulin in adults and children with type 1 diabetes. Tentative approval Insulin peglispro; Lilly/Boehringer Insulin peglispro is an investigational, once-daily basal insulin for the treatment of type 1 and type 2 diabetes. Phase 3 Trulicity; Lilly Trulicity is a glucagon-like peptide (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Approved Sept. 2014 IDegLira; Novo Nordisk IDegLira is a combination of liraglutide (Victoza) and long-lasting insulin degludec (Tresiba) in development for type 2 diabetes. Phase 3 Omarigliptin; Merck Omarigliptin is a long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, administered once weekly, and is under investigation for treatment of type 2 diabetes. Phase 3 could be low by a factor of 50% or even a 100%,” said Fernandez. “LCZ696 could be a Plavix-like product.” This enthusiasm appears to be widespread. “LCZ696 has been described as a game changer, and there are some that believe that because of its mortality beneft it should become the standard of care, replacing ACE inhibitors and ARBs, especially given its very clean safety profle,” said Urquhart. “The market was also quick to wake up to its potential after the Paradigm-HF trial was stopped early in March because of its conclusive benefts.” By contrast, Novartis’ other heart-failure drug has hit hard times. Last May, the FDA rejected Novartis’ biologics license application (BLA) for serelaxin. A synthetic human relaxin 2 hormone, serelaxin has received breakthrough designation, but FDA needed more effcacy data for approval and found issues in the trial design. Novartis has been conducting a large Phase 3 trial and hopes that the results, expected in 2016, will sway FDA. Serelaxin is a tantalizing prospect for both Novartis and analysts, and not only for the possible one-two punch of the combination with LCZ696. Because acute heart failure is a serious unmet need, clinicians are looking for successors to beta blockers, developed in the 1960s, and ACE inhibitors, developed in the ’80s. “There hasn’t been a product to advance in-hospital treatment for heart failure in somewhere between 30 and 50 years,” said Fernandez. Fernandez views serelaxin as a dark horse. However, if Novartis can get past the regulatory hurdles, Leerink Partners projects serelaxin’s worth potential at $2 to $3 billion. By contrast, EvaluatePharma puts its sales at $484 million by 2018. have great potential and faws. The PCSK9 inhibitors seem to have a cleaner path towards approval. However, administration and compliance could be an issue. “You’re introducing an injectable and an antibody to treat an asymptomatic condition,” said Fernandez. “People tend to be less compliant.” Leerink Partners believes there’s a potential $10 billion worldwide market by 2030 for the four leading PCSK9 inhibitors from Amgen and Sanof/Regeneron — the obvious leaders — followed by Pfzer and Lilly. The investment bank projects $4 billion by 2020. Sanof/Regeneron’s alirocumab and Amgen’s evolocumab seem pretty evenly matched, and the market may respond in kind. EvaluatePharma puts sales by 2018 at around $1 billion and $777 million, respectively. Pfzer’s bococizumab showed great results in a Phase 2b trial, signifcantly reducing LDL in patients also treated with statins. EvaluatePharma puts their sales at $231 million by 2018. CETP inhibitors are administered orally but must contend with the long shadows of Pfzer’s torcetrapin, which, unfortunately, had deadly side effects, and Roche’s dalcetrapib, which simply wasn’t effective. However, Merck’s anacetrapib and Lilly’s evacetrapib seem to be better at raising HDL and lowering LDL, and are worth watching. Thomson Reuters has anacetrapib sales at $759 million by 2019 and evacetrapib sales at $373 million in the same time period. “There’s more consistency on the PCSK9 side,” said Fernandez. “We don’t have the same evidence with CETP inhibitors. However, if they work — and they may simply work by lowering LDL — they are oral products and might be the larger class.” Raising HDL, lowering LDL Diabetes and obesity There’s a lot of work being done on LDL cholesterol, and a lot of skepticism to match. There might be a battle coming up between proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors and cholesteryl ester transfer protein (CETP) inhibitors — or there might not. Both approaches In the immediate future, it seems as if the diabetes market will be more evolutionary than revolutionary, governed by refnements in insulin delivery rather than major breakthroughs. Still, there are improvements to be made and healthy profts on top of that. Case in point, Sanof’s Toujeo (insulin glargine), a refor- DrugTopics .c om magenta cyan yellow black Februar y 2015 DRUG TOPICS 29 ES567007_drtp0215_029.pgs 02.05.2015 20:04 ADV Cover Story Table 4. N E U ROD E G E N E R AT I V E D I S E A S E S DRUG NAME; COMPANY DRUG INDICATION FDA STATUS Brexpiprazole; Otsuka/Lundbeck Brexpiprazole is serotonin-dopamine activity modulator (SDAM) under investigation for the treatment of schizophrenia and as an adjunct therapy for the treatment of major depression. NDA fled Sept. 2014 Ocrelizumab; Genentech/Roche Ocrelizumab is a humanized anti-CD20 monoclonal antibody in development for the treatment of relapsing-remitting and primary progressive multiple sclerosis. Phase 3 Zinbryta; AbbVie/Biogen Idec Zinbryta (daclizumab) is an IL-2 receptor inhibitor, administered once monthly, in development for relapsing-remitting multiple sclerosis. Phase 3 Plegridy; Biogen Idec Plegridy (peginterferon beta-1a) subcutaneous injection was FDA approved for the treatment of relapsing forms of multiple sclerosis. Approved August 2014 mulated long-lasting insulin, could preserve the company’s income stream as Lantus loses patent protection. The FDA accepted Toujeo’s NDA in July, and approval is expected in the frst half of this year. EvaluatePharma’s projection comes in at $1.4 billion in sales by 2018. Thomson Reuters forecasts $1.6 billion by 2019. Lilly/Boehringer’s insulin glargine, Basaglar, received tentative FDA approval in August 2014, but Sanof is claiming patent infringement. As a result, approval has been delayed for up to 30 months while the case makes its way through the courts. EvaluatePharma projects $401 million in sales by 2018. Lilly/Boehringer is also working on insulin peglispro, an insulin analog for type 1 and type 2 diabetes. A recently concluded trial showed daily therapy compared favorably to treatment with insulin glargine. Lilly plans to submit insulin peglispro early this year. EvaluatePharma estimates sales of $406 million by 2018. Focusing on type 2 diabetes, Lilly’s long-acting glucagonlike peptide-1 (GLP-1) agonist Trulicity (dulaglutide) received FDA approval last September. GLP-1 is a hormone that balances blood sugar, making it a particularly tempting target for type 2 diabetes treatments. With EvaluatePharma projecting sales of $912 million by 2018, Trulicity could be bad news for Novo Nordisk and AstraZeneca. “We think Trulicity could be a $1.5 billion drug and a meaningful competitor to Novo’s Victoza,” noted Fernandez. “I think it’s going to do a lot of damage to AstraZeneca’s Bydureon.” However, Novo has big plans for Victoza (liraglutide), which has recently been found safe and effective against obesity. Last September, an FDA panel voted to recommend the drug for approval for that indication. In December, FDA approved Victoza for chronic weight management. Perhaps more interesting, Novo has combined liraglutide with long-lasting insulin degludec (Tresiba) to create IDegLira for type 2 diabetes. Recent data have shown the combination works better than liraglutide and insulin degludec do alone. Thomson Reuters puts IDegLira at $815 million by 2019. EvaluatePharma estimates $517 million by 2018. Merck’s omarigliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor to treat type 2 diabetes, is continuing through fairly massive Phase 3 trials. Taken weekly, the drug may reduce 30 magenta cyan yellow black DRUG TOPICS Februar y 2015 glucose as well as daily treatments. EvaluatePharma pegs sales at $412 million by 2018. Zafgen’s obesity drug Beloranib, which modulates fatty acid metabolism, is turning heads. A Phase 2 trial in 2013 produced rapid weight loss in severely obese patients and was well tolerated. An effective weight-loss drug with few side effects could have tremendous potential. This is defnitely one to watch. Neurodegenerative diseases It would be wonderful to highlight a number of promising agents that could improve cognitive function in Alzheimer’s disease patients. Billions have been spent on such treatments, most of them targeting amyloid plaque, and none of them has come through. “There are so many bodies on the side of the road, it’s almost as if the safe thing is to bet against any drug trying to affect cognitive function in Alzheimer’s disease,” said Ritu Baral, senior analyst and managing director, Biotechnology Equity Research, at Cowen and Co. While there’s no joy on the disease-modifying side, there are other efforts to mitigate some of the symptoms associated with Alzheimer’s and other neurodegenerative conditions. Avanir’s AVP-923, which combines ordinary dextromethorphan with the heart-rhythm treatment quinidine, may have promise to treat the agitation associated with Alzheimer’s. Avanir released positive Phase 2 results last September and is meeting with FDA and EMA to discuss next steps. “Agitation is the No. 1 driver behind hospitalization and institutionalization for Alzheimer’s disease,” said Baral. “Agitation and aggression make it impossible to care for patients in the home setting.” Otsuka and Lundbeck are working on brexpiprazole for schizophrenia and major depressive disorder (MDD), as well as Alzheimer’s-related agitation. FDA has accepted its NDA as a schizophrenia treatment and as an adjunct treatment for MDD; the PDUFA date is set for July 2015. Thomson Reuters predicts potential sales of $1.43 billion by 2019. EvaluatePharma pegs sales at $763 million by 2018. The pipeline is more promising in multiple sclerosis (MS), because these drugs can target the underlying immune response. For example, ocrelizumab, Genentech/Roche’s CD20 DrugTopics .c om ES567005_drtp0215_030.pgs 02.05.2015 20:04 ADV Cover Story Table 5. R A R E D I S E A S E S DRUG NAME; COMPANY DRUG INDICATION FDA STATUS Kalydeco (ivacaftor)/lumacaftor (VX-809) is a combination drug, under investigation Kalydeco/lumacaftor; for the treatment of patients 12 years and older with cystic fbrosis and two copies Vertex of the most common mutation of cystic fbrosis, F508del. NDA fled Nov. 2014 ALXN-1215; Alexion ALXN-1215 (asfotase alfa) is a human recombinant tissue, nonspecifc alkaline phosphatase fusion protein in development for the treatment of hypophosphatasia—a severe and often deadly metabolic bone disease. Phase 3 Migalastat; Amicus Migalastat is an investigational pharmacological chaperone for the treatment of Fabry disease. Phase 3 inhibitor for relapsing-remitting MS, is currently in Phase 3 trials and has been shown to reduce infammatory brain lesions. Ocrelizumab is projected by EvaluatePharma to sell around $355 million by 2018. Thomson Reuters is a bit more bullish at $578 million by 2019. Meanwhile AbbVie and Biogen Idec are working on the IL-2 receptor inhibitor Zinbryta (daclizumab), which treats relapsing-remitting MS. Recent data showed patients on the drug experienced a significant reduction in relapse when compared to Avonex, which had $3 billion in sales in 2013. EvaluatePharma projects $320 million by 2018 for Zinbryta, while Thomson Reuters goes higher at $829 million by 2019. Biogen Idec’s Plegridy was recently approved in the United States as a weekly replacement for daily Avonex. However, analysts are not universally enthusiastic about its prospects. “The drug is approved in Europe and was supposed to be the natural, longer-acting successor to Avonex, which came off patent last year,” said Urquhart at EvaluatePharma. “However, the lure of fortnightly dosing over weekly Avonex does not appear to be foating too many boats, and consensus sales forecasts for the drug have fallen signifcantly recently. At the moment, they are $537 million in 2018, nowhere near the $3 billion Avonex pulled in last year.” Also, there may be a little hope for patients with Huntington’s disease. Early last year, Raptor announced positive 18-month results on a three-year Phase 2/3 trial for RP103. In the study, total motor score progression was shown to be 32% slower in the RP103 group. An extended and delayedrelease formulation of cysteamine bitartrate, RP103 recently received orphan-drug designation from the European Commission. While it’s still early in the process, good news is scant in Huntington’s disease, so this one is something to watch. Rare diseases Orphan-disease therapies are becoming more and more popular with both big pharma and biotech companies. The combination of exclusivity and a more streamlined path to market have made them increasingly appealing. But while the orphan-drug market has seen astronomical growth, there’s been increasing pushback from payers over the prices for these medications. Given that cost containment is a central tenet of healthcare reform, it’s unclear how six-fgure prices will fare in the long run. To complicate the picture, patient DrugTopics .c om magenta cyan yellow black advocacy groups have become increasingly engaged and will fght any measures that limit access. Given this environment, will payers balk at the growing slice of the pie going to specialty medications? No answers yet, but the implications are big. At the top of the growing list of orphan drugs, Vertex may have a genuine blockbuster with its combination of lumacaftor and Kalydeco (ivacaftor) for cystic fbrosis (CF). Recent Phase 3 results have been positive, though not overwhelming, showing that the combo does improve lung function, just not as much as everyone would like. Still, the drug has received FDA’s breakthrough-therapy designation and approval would dramatically increase the number of CF patients who could be treated with Vertex therapies. Right now, Kalydeco helps only around 4% of CF patients, while the combination would cover approximately 50%. Thomson Reuters puts potential sales at $3.7 billion by 2019. Vertex is expected to file in the United States and Europe by the end of 2015. Alexion acquired Enobia in 2012 and with it came asfotase alfa (ALXN-1215), which treats hypophosphatasia, an often deadly form of rickets. Alexion scooped up breakthrough therapy designation in 2013 for the enzyme-replacement drug. A recently concluded study showed that fve-year survival on the drug was 89%, compared to 27% for patients who received no treatment. The company submitted a rolling BLA in April. Thomson Reuters puts potential sales at $578 million by 2019. A number of agents are in the pipeline to treat Duchenne muscular dystrophy (DMD), which currently has few therapeutic options. One of these is Translarna (ataluren) from PTC. The small-molecule drug, which treats nonsense mutations in the dystrophin protein, was recently given conditional approval by the European Commission. Prosensa’s RNA drug drisapersen, an exon-skipping therapy, appears to be back from the dead. A Phase 3 study showed little advantage over placebo; however, additional data convinced FDA to take another look. Drisapersen now has breakthrough status, and the company is moving forward with an NDA. Sarepta, which also takes an exon-skipping approach, is seeking early approval for its RNA drug eteplirsen, also for treatment of DMD. The company has experienced a bad combination of up-and-down trial results and corporate boardroom drama, but appears to be poised to submit the NDA for its DMD therapy. When approved, drisapersen and eteplirsen should be direct competitors. Februar y 2015 DRUG TOPICS 31 ES567012_drtp0215_031.pgs 02.05.2015 20:05 ADV Cover Story Fabry disease is caused by mutations in the alphagalactosidase A enzyme, which leads to fat buildup and a variety of painful and debilitating symptoms. There are a few approved Fabry treatments (Fabrazyme and Replagal), but they require weekly infusions that are especially diffcult for children. However, Amicus has developed a small-molecule drug, migalastat, that could help patients with less severe disease. “One of the things people forget about enzyme-replacement therapies is that they require a signifcant amount of chair time,” said Ritu Baral. “This has the potential to be a game changer in Fabry treatment because of its oral delivery.” Migalastat is designed to treat people who have some enzyme activity; that may be as many as 50% of Fabry patients. The drug has had an up-and-down path and GlaxoSmithKline pulled out of its deal with Amicus, but improved Phase 3 results have put the drug back on track. Thomson Reuters estimates sales at $99 million. BioMarin has a promising therapy for Pompe disease, a lysosomal storage disorder that causes weakness and respiratory issues. BMN-701 has received FDA orphan-drug designation and is in Phase 3 trials. Thomson Reuters puts potential sales at $163 million by 2019. Stem cells Stem cells have been long on potential but short on immediate beneft. However, that may be gradually changing, as a number of therapies are making their way through Phase 3 trials. Though it’s diffcult to gauge what kind of impact these therapeutics will have on health or markets, this might be the tip of the iceberg, and we may fnally see some actual stemcell therapies make their way to patients. While the majority of press has been devoted to the handwringing around embryonic stem cells and the blinding coolness of induced pluripotent stem cells, the therapies closest to market often rely on more differentiated cells. These treatments are a bit sparse on data and projections, but they’re interesting to watch and are a likely harbinger of bigger things to come. One good example is Revascor (CEP-41750), Teva/Mesoblast’s adult mesenchymal stem cell treatment for heart failure, which is currently in a pivotal 1,730-patient Phase 3 trial. Outcomes won’t be available for some time, but previous results have been encouraging, although they have come from small samples. While it won’t be the blockbuster Novartis’ LCZ696 is expected to be, Revascor could make a signifcant impact. Gamida Cell is moving forward with its Phase 3 trial for StemEx, a therapy for blood cancers, such as leukemia and lymphoma. The therapy has orphan-drug designation and fast-track status, and is intended for patients who cannot fnd a marrow donor. Gamida has been changing partners lately, with Teva dropping out and Novartis being an on-off-on suitor. In earlier stages, both Stem Cells Inc. and Asterias are working on treatments for chronic spinal cord injuries; Asterias is picking up where Geron left off. In addition, a number of early-phase studies are investigating the possibility of inhibiting 32 magenta yellow black DRUG TOPICS Februar y 2015 cancer stem cells, which may provide a well of slow-growing cells that continuously reinvigorate certain tumors. Celgene has invested heavily in therapies that address cancer stem cells. Odds and ends Ebola dominated the news last year, and there’s palpable hope that new treatments will rescue the world from a fullblown pandemic. Mapp, Sarepta, and Tekmira are collaborating with the World Health Organization, Wellcome Trust, and other organizations to begin trials in West Africa. In addition, OncoSynergy has received orphan-drug designation for OS2966, which targets CD29 to treat glioblastoma and other aggressive cancers. But CD29 also plays a role in Ebola, and the company is planning a trial. Another area that’s gaining ground is antibiotics. The provisions of the Generating Antibiotic Incentives Now (GAIN) Act are driving innovation in antibacterials in the same way that the Orphan Drug Act supported work on rare diseases. One interesting example is Cempra’s solithromycin, which is in trials for community-acquired pneumonia and other infections. Thomson Reuters projects sales of $200 million by 2019. Biosimilars are knocking on the door, but many questions remain about how they’ll fare in the U.S. market. Sandoz has fled a BLA for its version of Neupogen (flgrastim), and an FDA advisory committee recommended approval in early January. Celltrion is right behind it with a biosimilar for Remicade. However, regulatory approval may be the easy part. Biosimilars still face patent battles, prospective price discounts remain hostage to the uncertainty around trial development costs, and there’s no guarantee that physicians will switch patients to these newer versions of established drugs. On the distant horizon, there is keen interest in microbiota, the human body’s friendly bacteria. Pfzer is partnering on drug candidates with Second Genome, a leader in this area, and a host of startup ventures are coming out of the woodwork. This could be an interesting area for approval candidates in 2020. Payer politics As Gilead well knows from its Sovaldi experience, developing a groundbreaking therapy and gaining FDA approval do not guarantee blockbuster nirvana. Gilead has been a popular punching bag for Sovaldi’s perceived high price, but it is hardly unique. A number of emerging therapies are generating sticker shock, particularly in oncology. How will payers push back? There’s a lot of discussion, but no clear consensus has emerged. Some payers are asking for evidence of value, and there are trends toward referencing across borders and closed formularies. This will be a complicated societal issue, as drug companies, payers, and consumers wrestle with the question: How much is too much? Josh Baxt is a freelance science and healthcare writer. He can be reached at [email protected]. DrugTopics .c om ES567006_drtp0215_032.pgs 02.05.2015 20:04 ADV Rosacea: The physical and emotional toll By Scott Kober, MBA, CCMEP R osacea is a chronic cutaneous disorder that primarily affects the central face, including the cheeks, eyes, nose, chin, and forehead. It is important to note that there is not a specific characteristic or set of characteristics that define rosacea. Rather, there are specific features that vary in presentation and magnitude among patients (Table 1).1 Although the pathophysiology of rosacea is not yet completely understood, it is believed to involve both the innate and adaptive immune systems. Patients with rosacea often have abnormal regulation of the neurovascular system. Vascular abnormalities, microbial activity, and pilosebaceous gland abnormalities may also exacerbate the condition.2 Clinical studies have shown that patients with rosacea have a high concentration of cathelicidin-derived peptide (LL-37), which can contribute to inflammation.3 Recent research has also focused on the possible influence of Demodex mites on the pathophysiology of rosacea, showing that Demodex density is almost 6 times higher in patients with rosacea than it is in the normal population.4 Rosacea affects up to 10% of the general population, with the greatest prevalence in individuals aged 30 to 50 years. Although most common in light-skinned individuals of Northern European descent, rosacea is not exclusive to Caucasians and can be seen, albeit with less frequency, in Asians, Hispanics, African-Americans, and other demographic groups.5 There is certainly a physical burden associated with rosacea, but the emotional impact of the condition is often even more substantial. Whereas acne is often considered almost a rite of passage for teenagers, many adult rosacea patients avoid going out in public due to psychological Published as a promotional supplement to February 2015 factors. A recent National Rosacea Society (NRS) survey of more than 400 rosacea sufferers showed that 75% had low self-esteem, 70% were “embarrassed” by their condition, and 56% felt robbed of pleasure/happiness.6 In 2002, the NRS identified 4 distinct subgroups of rosacea. Although there may be some overlapping characteristics of these subtypes, the classifications have helped with diagnosis and initial treatment plans:5 Erythematotelangiectatic rosacea: Mainly characterized by flushing and persistent central facial erythema. Telangiectases are common, but not essential for diagnosis. Most common rosacea subtype. Papulopustular rosacea: Characterized by persistent central facial erythema with transient papules or pustules (or both) in a central facial distribution. Papules and pustules may also occur periodically. Resembles acne, except for the presence of comedones. Phymatous rosacea: Characterized by thickening skin, irregular surface nodularities, and enlargement. Predominantly present in male patients. Ocular rosacea: Characterized by watery or bloodshot eyes, foreign body sensation, burning/stinging, dryness, itching, light sensitivity, blurred vision, telangiectases of the conjunctiva and lid margin, or lid and periocular erythema. In addition to rosacea classifications, the NRS also developed a standard grading system to provide a common reference for diagnosis, treatment, and assessment of results in clinical practice. This grading system is commonly used in clinical trials to allow for comparability of results. A modified version of an available grading scorecard is included in Table 2.7 It gives a general overview of the delineation between severity ratings. The determination of rosacea severity is helpful, but it is important for clinicians to do more than simply perform a visual assessment of a patient’s condition as they consider initial steps of treatment. For example, a patient may present with symptoms consistent with mild rosacea, but if they report significant issues with social and/or professional embarrassment due to their appearance, more-aggressive therapy may be warranted. It is also important to keep in mind that despite the general conditioning of many clinicians to expect more psychological strain in women with rosacea, many men with rosacea also report a significant emotional burden. Determining initial treatment options Many patients with rosacea will try over-thecounter medications indicated for the treatment of acne prior to seeking a clinician’s evaluation. Unfortunately, many of these medications will exacerbate rather than ameliorate a rosacea patient’s inflammation. Patients with rosacea have very sensitive skin that results in a prickly or painful feeling with use of certain agents. It is important for clinicians seeing a patient for the first time to gather a thorough medication history that will help determine initial therapeutic steps. At baseline, a gentle skin care and photoprotective regimen should be recommended for all rosacea patients with centrofacial erythema, regardless of the presence of papulopustular lesions. Generally, a sunscreen with an SPF of at least 30 is recommended for protecting against incidental sun exposure.1 Patients who present with centrofacial erythema but without papules or pustules can ROSACEA TYPES AND TREATMENTS SUBTYPES: SYMPTOMS: 1: Erythematotelangiectatic Rosacea (Facial Redness) 2: Papulopustular Rosacea (Bumps and Pimples) 3: Phymatous Rosacea (Skin Thickening) 4: Ocular Rosacea (Eye Irritation) Flushing and persistent redness, may include visible blood vessels, stinging, burning, and swelling Bumps (papules) or pimples (pastules) that come and go, includes red patches Excess tissue often results in enlargement of the nose and irregular surface nodules (bump-like lesions) Watery or bloodshot eyes, tearing and burning, swollen eyelids, recurrent styes EXAMPLES: Courtesy of: National Rosacea Society Published as a promotional supplement to Drug Topics | © 2015 February/2015 magenta cyan yellow black Sponsored by ES562559_DRTP0215_INSERT1_FP.pgs 01.30.2015 03:46 ADV Rosacea: The physical and emotional toll Table 1 Primary features Features of rosacea Secondary features Flushing (transient erythema) Burning or stinging Nontransient erythema Phymatous changes Papules and pustules Plaque Telangiectasia Dry appearance Edema a patient’s rosacea severity at baseline. Common side effects include headache, nausea, and vomiting. These side effects have been shown to appear less frequently in the antiinflammatory 40-mg dose compared to the antimicrobial 100mg dose.12 of antibiotics but in other instances may require additional topical or systemic therapies. Setting treatment goals References Coming up next In part 2 of this series, we’ll take a closer look at the newest treatment option for the inflammatory component of rosacea—ivermectin— and discuss how it may fit into the overall treatment armamentarium. Ocular manifestations Peripheral location Source: Ref 1 Television advertisements often serve as false idols for patients Table 2 Severity grading of rosacea papules and pustules with rosacea, promising “Results Rosacea severity Papules/pustules Plaques within 24 hours!” or “Skin as Mild Few None clear as you could ever imagModerate Several None ine!” Unfortunately, this often Severe Many Present creates a wildly inflated sense Source: Ref 7 of expectations among patients that can be difficult to temper. It is vital for rooften be managed with use of a once-daily sacea patients to understand that, with anyalpha agonist, which will demonstrate an initial thing prescribed for them, improvements are effect within 30 to 60 minutes of application not going to occur overnight. and peak after 3 to 4 hours. Intense pulsed In the majority of phase 2 and 3 clinical light or laser therapy may also be incorporated trials for agents approved by FDA or in lateinto the treatment plan.8 stage clinical trials, patients are treated for The majority of research in rosacea has fo12 to 16 weeks.9,10,13,14 Although patients cused on the treatment of inflammatory papules and pustules, which can be more difficult to manage. There are currently 2 topical agents approved by FDA for the treatment of inflammatory lesions of rosacea: metronidazole (MTZ; twice-daily 0.75% gel, cream, or lotion, and once-daily 1% gel or cream) and azelaic acid (AZA; twice-daily 15% gel). Also available is modified-release doxycycline 40 mg once daily, a systemic therapy.9,10 MTZ and AZA are most commonly used initially in patients with mild or moderate disease, whereas doxycycline is often initiated in patients with more severe rosacea. Use of a combination regimen of a topical agent with doxycycline is a popular option for some patients. Recent survey data of 300 dermatologists showed that this combination approach is used as initial therapy in 83.7% of patients with moderate-to-severe papulopustular rosacea.11 The overall safety and tolerability profiles of MTZ and AZA are favorable, with the most common adverse events related to local reactions. AZA may cause neurosensory symptoms after application, but these are usually transient and remit within 1 to 2 weeks after initiating a regimen.9 The submicrobial dose of doxycycline was designed to provide anti-inflammatory effects with no antibiotic activity, even with prolonged duration of use for several months. It has been shown to be equally efficacious regardless of can expect to see some improvement in their symptoms within a few weeks of therapy (assuming adherence to the prescribed regimen), it may take 6 to 8 weeks for significant improvement to occur. Even then, there may not be complete resolution of background erythema or inflammatory lesions. Some patients will develop an immediate skin reaction to topical medications, but for those who can tolerate them, a 6- to 8-week trial at minimum should be prescribed to gauge efficacy.8 This can be difficult for some patients who want a more-immediate panacea, which is why a frank, upfront discussion is vital to calm overzealous expectations. Because rosacea is a lifelong condition that may wax and wane over the course of a patient’s lifetime, it is also important to discuss long-term maintenance for patients who do get relief from the use of 1 or more medications. Unfortunately, there are few long-term studies in the published literature that address maintenance of disease control beyond 6 months, so it often up to clinician judgment and patient tolerance to determine the best course of action for lifelong maintenance of rosacea symptoms.8 Many clinicians will see the same patients multiple times during the course of their lifetime to deal with rosacea flares. These flares can sometimes be managed with a short course Published as a promotional supplement to Drug Topics | © 2015 February/2015 magenta cyan yellow black 1. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 1: a status report on the disease state, general measures, and adjunctive skin care. Cutis. 2013;92(5):234–240. 2. Chang BP-Y, Kurian A, Barankin B. Rosacea: an update on medical therapies. Skin Therapy Lett. 2014;19(3):1–4. 3. Del Rosso JQ, Gallo RL, Kircik L, et al. Why is rosacea considered to be an inflammatory disorder? The primary role, clinical relevance, and therapeutic correlations of abnormal innate immune response in rosacea-prone skin. J Drugs Dermatol. 2012;11(6):694–700. 4. Casas C, Paul C, Lahfa M, et al. Quantification of Demodex folliculorum by PCR in rosacea and its relationship to skin innate immune activation. Exp Dermatol. 2012;21(12):906–910. 5. Wilkin J, Dahl M, Detmar M, et al. Standard classification of rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 2002;46(4):584–587. 6. National Rosacea Society. Coping with rosacea: managing psychosocial aspects of rosacea. www. rosacea.org/patients/materials/coping/managing. php#Managing. Accessed December 24, 2014. 7. Wilkin J, Dahl M, Detmar M, et al. Standing grading system for rosacea: Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea. J Am Acad Dermatol. 2004;50(6):907–912. 8. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 5: a guide on the management of rosacea. Cutis. 2014;93(3):134–138. 9. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 2: a status report on topical agents. Cutis. 2013;92(6):277–284. 10. Del Rosso JQ, Thiboutot D, Gallo R, et al. Consensus recommendations from the American Acne & Rosacea Society on the management of rosacea, part 3: a status report on systemic therapies. Cutis. 2014;93(1):18–28. 11. Del Rosso JQ. Patterns of use of topical and oral therapies in the treatment of different subtypes of rosacea. Presented at the 11th Annual South Beach Symposium; April 11–15, 2013: Miami Beach, FL. 12. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7(6):573–576. 13. Del Rosso JQ, Webster GF, Jackson M, et al. Two randomized phase III clinical trials evaluating antiinflammatory dose doxycycline (40-mg doxycycline, USP capsules) administered once daily for treatment of rosacea. J Am Acad Dermatol. 2007;56(5):791– 802. 14. Stein L, Kircik L, Fowler J, et al. Efficacy and safety of ivermectin 1% cream in treatment of papulopustular rosacea: results of two randomized, doubleblind, vehicle-controlled pivotal studies. J Drugs Dermatol. 2014;13(3):316–323. Sponsored by ES562558_DRTP0215_INSERT2_FP.pgs 01.30.2015 03:46 ADV Clinical NEW DRUG REVIEW Diana M. Sobieraj, PharmD Dabigatran approved for treatment of venous thromboembolism I n April 2014 FDA approved dabigatran (Pradaxa; Boehringer Ingelheim) for the treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE) in patients who have been treated with a parenteral anticoagulant for fve to 10 days, as well as for the reduction in the risk of recurrent DVT and PE in those previously treated. Dabigatran was originally approved in 2010 for stroke prevention in patients with nonvalvular atrial fbrillation. As an oral direct thrombin inhibitor, dabigatran inhibits both clot-bound and free thrombin, as well as thrombin-induced platelet aggregation. Dabigatran is contraindicated in patients with active bleeding, history of hypersensitivity to dabigatran, or mechanical heart valves. Efficacy The effcacy of dabigatran for treatment of DVT and PE is based on four randomized controlled trials (RCTs). RE-COVER and RE-COVER II evaluated dabigatran 150 mg by mouth twice daily vs. warfarin adjusted to an INR of 2.0 to 3.0 for six months as initial VTE treatment, each after initial parenteral anticoagulation. Over 4,000 patients with DVT, PE, or both were included in total. Both RCTs found dabigatran noninferior to warfarin, based on the outcome of symptomatic, recurrent, objective VTE and related deaths. The pooled hazard ratio (HR) in comparison to warfarin was 1.09 (0.76 to 1.57). The RE-MEDY and RE-SONATE trials evaluated extended duration of treatment with dabigatran 150 mg by mouth twice daily vs. warfarin adjusted to an INR of 2.0 to 3.0 (REMEDY) or vs. placebo (RE-SONATE), for at least an additional six months of treatment, in patients who completed an initial VTE treatment course of at least three months. The RE-MEDY trial evaluated more than 2,000 patients and found dabigatran to be noninferior to warfarin for the primary outcome of recurrent or fatal VTE [HR 1.44 (0.78 to 2.64)]. The RE-SONATE trial evaluated more than 1,200 patients and found that dabigatran signifcantly reduced the risk of recurrent VTE in comparison to placebo [HR 0.08 (0.02 to 0.25)]. II [HR 0.82 (0.45 to 1.48) and HR 0.69 (0.36 to 1.32), respectively]. The composite outcome of major bleeding or clinically relevant nonmajor bleeding (CRNMB) was signifcantly reduced with dabigatran vs. warfarin in both trials [HR 0.63 (0.47 to 0.84) and HR 0.67 (0.56 to 0.81), respectively]. In the extended-duration studies, the risk of major bleeding with dabigatran was not significantly different from that of warfarin [HR 0.52 (0.27 to 1.02)] or placebo (0% in placebo, 0.3% in dabigatran). Although the risk of the composite bleeding outcome of major bleeding or CRNMB was signifcantly lower with extended treatment of dabigatran vs. warfarin [HR 0.54 (0.41 to 0.71], the risk was signifcantly higher with dabigatran in comparison to placebo [HR 2.92 (1.52 to 5.60)]. Across the active intervention trials, the incidence of gastrointestinal events in the dabigatran and warfarin groups was similar (24.7% on dabigatran vs. 22.7% on warfarin). The incidence of dyspepsia and gastritis-like symptoms in patients taking dabigatran was 7.5% and 3.0% compared to 5.5% and 1.7% in patients taking warfarin. Dosing In patients with a creatinine clearance (CrCl) of 30 mL/min or greater, the dabigatran dose for VTE treatment is 150 mg by mouth twice daily after fve to 10 days of parenteral anticoagulation. The drug should not be used in patients with a CrCl less than 30 mL/min or in patients on hemodialysis for this indication. In addition, in patients with a CrCl less than 50 mL/min who are taking a pg-p (permeability glycoprotein) inhibitor or in any patient taking a pg-p inducer, the use of dabigatran for VTE treatment should be avoided. The capsule should be swallowed whole and not chewed, crushed, or opened. The package insert provides detailed recommendations for switching patients to or from dabigatran and another anticoagulant and offers suggestions for methods of discontinuation before surgery and other procedures. Safety The risk of major bleeding for dabigatran vs. warfarin was not signifcantly different in either RE-COVER or RE-COVER DrugTopics .c om magenta cyan yellow black Diana M. Sobieraj is assistant professor of Pharmacy Practice, University of Connecticut School of Pharmacy, Storrs, Conn. Februar y 2015 DRUG TOPICS 35 ES566998_drtp0215_035.pgs 02.05.2015 20:04 ADV Clinical ANTICOAGULATION THERAPIES Anna D. Garrett, PharmD, BCPS Aspirin fails in Japanese primary prevention study R esults from a new Japanese trial showed no beneft in low-dose, once-daily aspirin in the primary prevention of cardiovascular events in patients with multiple risk factors. The Japanese Primary Prevention Project (JPPP) included 14,464 patients from 60 to 85 years of age, who had hypertension, dyslipidemia, or diabetes mellitus. They were randomized to receive either aspirin 100 mg daily or placebo. Median follow-up was 6.5 years. No benefit was seen for the composite endpoint of nonfatal myocardial infarction (MI), nonfatal stroke, or death from cardiovascular causes. There were signifcant reductions in MI and transient ischemic attack (TIA), but this beneft came with a signifcant increase in serious bleeding events. The overall rate of events was much lower than anticipated in the study, and it did not reach statistical signifcance. The authors concluded that further analysis is needed to identify patients who may beneft most from aspirin. More studies are ongoing (ARRIVE, ASCEND, ASPREE, and ACCEPT-D), which are assessing primary prevention in predominantly Western populations. Source: Ikeda Y, Shimada K, Teramoto T, et al. Low-dose aspirin for primary prevention of cardiovascular events in Japanese patients 60 years or older with atherosclerotic risk factors. JAMA 2014;312(23):2510–2520. Intracranial hemorrhage risk lower with novel oral anticoagulants Randomized studies have shown a decreased risk of intracranial hemorrhage (ICH) with use of novel oral anticoagulants (NOACs). However, it is unclear whether the magnitude of beneft is similar for all NOACs that are currently available. A recent meta-analysis sought to quantify the rates of ICH using both conventional and Bayesian statistics. Six studies (one of dabigatran, two of rivaroxaban, three of apixaban) enrolling a total of 57,491 patients were included for analysis. The data showed that each of the three drugs reduced the risk of ICH, with Bayesian indirect comparison analysis not revealing a signifcant difference between the specifc medications. The authors concluded that all the novel oral anticoagulants are associated with an overall reduced risk 36 magenta cyan yellow black DRUG TOPICS Februar y 2015 of ICH when used for stroke prevention in patients with atrial fibrillation and that any of the currently available medications may be considered frst-line for patients at high risk for ICH. Source: Chatterjee S, Sardar P, Biondi-Zoccai G, et al. New oral anticoagulants and the risk of intracranial hemorrhage: Traditional and Bayesian meta-analysis and mixed treatment comparison of randomized trials of new oral anticoagulants in atrial fbrillation. JAMA Neurol. 2013;70(12):1486–1490. Bleeding risk increased with dabigatran in atrial fibrillation It’s not clear whether dabigatran is associated with higher risk of bleeding than warfarin sodium in real-world clinical practice. A recent study used Medicare data to compare dabigatran and warfarin bleeding risks. The retrospective cohort study used pharmacy and medical claims in 2010 to 2011 from a 5% random sample of Medicare benefciaries. The authors identifed participants as those newly diagnosed with atrial fbrillation (AF) from October 1, 2010, through October 31, 2011, and who started dabigatran (1302) or warfarin (8102) treatment within 60 days of the AF diagnosis. Bleeding events were categorized as major or minor by anatomical site. Major bleeding events included intracranial hemorrhage, hemoperitoneum, and inpatient or emergency department stays for hematuria or gastrointestinal or other hemorrhage. Dabigatran was associated with a higher risk of bleeding relative to warfarin, with hazard ratios of 1.30 for any bleeding event, 1.58 for major bleeding, and 1.85 for gastrointestinal bleeding. The risk of intracranial hemorrhage was higher among warfarin users, with a hazard ratio of 0.32 for dabigatran compared with warfarin. The risk of major bleeding among dabigatran users was especially high for African Americans and patients with chronic kidney disease. Source: Hernandez I, Baik SH, Piñera A, et al. Risk of bleeding with dabigatran in atrial fbrillation. JAMA Intern Med. Published online November 3, 2014. http://archinte.jamanetwork.com/ article.aspx?articleid=1921753. Accessed December 30, 2014. Anna D. Garrett is a clinical pharmacist and president of Dr. Anna Garrett (www.drannagarrett.com). Her mission is to help women in midlife maximize their mojo! Contact her at [email protected]. DrugTopics .c om ES566997_drtp0215_036.pgs 02.05.2015 20:04 ADV THIS SMELLS. 1 THIS DOESN’T. Which would your patients prefer? NASACORT®. RIGHT ON SHELF. RIGHT NOW. Reference: 1. Flonase Allergy Relief question and answer book. 14-0033AWL. Clifton, NJ: GlaxoSmithKline; 2014. http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/205434Orig1s000lbl.pdf. Accessed September 18, 2014. 7021 © 2014 Chattem, Inc. magenta cyan yellow black FLONASE is a registered trademark, used under license by GlaxoSmithKline Inc. ES567443_DRTP0215_A37_FP.pgs 02.06.2015 01:54 ADV Regulatory & Legal LEGAL COMPLIANCE Ned Milenkovich, PharmD, JD Murder and other criminal charges filed against NECC executives I n December 2014, the United States Attorney’s Offce charged 14 New England Compounding Center (NECC) employees, among them the owner and seven other pharmacists, with crimes that included racketeering and mail fraud. The charges stem from NECC’s compounding and distribution of thousands of doses of contaminated injectable steroid medications that were ultimately linked to a fungal meningitis outbreak, frst reported in 2012, that resulted in 64 patient deaths and 751 cases of illness. The federal government has also seized $18.3 million held in various bank accounts associated with the company’s principals. Racketeering and murder The NECC pharmacy executives face a 131-count indictment, including 25 counts of second-degree murder. Although the requirements for second-degree murder charges vary by state, second-degree murder generally requires willful or extreme disregard for life or awareness that such wrongful conduct would cause death. The indictment also lists 78 acts of racketeering, in which the defendants shipped the drugs interstate as part of a scheme to defraud their customers and the patients of those customers by making materially false representations of compliance with Massachusetts pharmacy laws. For instance, one pharmacy technician had voluntarily surrendered his Massachusetts license in a disciplinary action a year before he was employed by NECC. NECC sold its compounded drugs through a sales force and marketing materials that asserted the pharmacy’s compli- 38 magenta cyan yellow black DRUG TOPICS Februar y 2015 ance with USP-797’s standards for sterile compounded drugs. However, the indictment demonstrates multiple instances of noncompliance with USP-797. For example, company pharmacists did not verify the effectiveness of NECC’s sterilization process and routinely attempted to sterilize drug lots in the autoclave for approximately fve minutes less than the minimum time stipulated by USP-797. The sales force also provided quality assurance report cards with false environmental monitoring results. In reality, NECC had actionable environmental defciencies that it did not remediate. Nonsterile ingredients NECC’s high-risk compounding business allegedly used nonsterile ingredients to make sterile drugs. According to the indictment, the pharmacy used expired and expiring ingredients, created fake expiration dates, mixed lots to conceal expiring or untested lots, and changed lot numbers. If the company received a notifcation from an independent laboratory that a drug was nonsterile, NECC did not notify its customers or recall the drugs. NECC employees also falsifed cleaning records and sent samples from stock solutions for sterility testing, as opposed to flled vials of drugs. Conspiracy to defraud The indictment also charges the defendants with conspiracy to defraud the United States for their role in operating as a drug manufacturer distributing compounded drugs in bulk, rather than a state-regulated pharmacy dispensing drugs pursuant to valid, patient-specifc prescriptions. As a drug manufacturer, the pharmacy would fall under the regulatory oversight of the Food and Drug Administration (FDA). On three occasions, NECC told FDA that it compounded only patient-specifc prescriptions. However, NECC permitted specifc customers to provide it with fake patient names or the names of a previous month’s patients. The pharmacy executives reused names, and created fake prescriptions based on the names of celebrities, medical staff, and fctional characters, including Wonder Woman, Filet O’fsh, Bill Clinton, and Bud Weiser. NECC also regularly waived the requirement for patient-specifc prescriptions for its customer’s frst orders. NECC not only shipped drugs without patient names; it told its sales force to tell customers that it would not include patientspecifc names on the drug labels. Executives at the highest levels were involved; NECC’s national sales director warned the sales force in an e-mail not to use words such as “backfill” when discussing the need to provide patient names for orders. The indictment’s extensive descriptions of NECC’s actions serve as a warning to compounding pharmacies that fail to follow sterile compounding standards and perform bulk dispensing of compounded drugs without patientspecifc prescriptions. This article is not intended as legal advice and should not be used as such. When legal questions arise, pharmacists should consult with attorneys familiar with the relevant drug and pharmacy laws. Ned Milenkovich is a principal at Much Shelist and vice chair of the Illinois State Board of Pharmacy. Contact him at 312-521-2482 or at [email protected]. DrugTopics .c om ES566996_drtp0215_038.pgs 02.05.2015 20:04 ADV magenta cyan yellow black ES567439_DRTP0215_B37_FP.pgs 02.06.2015 01:53 ADV Regulatory & Legal ETHICAL DECISION-MAKING IN PHARMACY Kenneth R. Baker, BS Pharm, JD The importance of the pharmacist in everyday practice S peaking of ethics, Socrates said, “It is no small matter, it is how we ought to live.” Once in a while something reminds us of the importance of pharmacists in everyday practice. The Indiana case of Kolozsvari v. Doe1 is such a reminder. In brief, the story is this. Christine was told she had to have a colonoscopy. Christine’s doctor prescribed the pre-prep laxative OsmoPrep, sodium phosphate-based tablets. Sodium phosphate products such as OsmoPrep, now designated REMS drugs, pose a risk of renal failure. This risk may be heightened when combined with factors that stress the kidneys. Adding to the risk is the concurrent use of ACE inhibitors, such as lisinopril, which Christine took for her blood pressure. OsmoPrep carries a warning “regarding the drug’s potential for causing kidney damage as a result of possible interactions with lisinopril.”1 The computer in Christine’s pharmacy provided such a warning when her prescription was flled. Patient asked After taking the OsmoPrep, Christine found that her colonoscopy had to be rescheduled, which meant that she had to take a second dose of the laxative. She informed her doctor’s offce that “. . . she had experienced some tingling in her fngers and forearms and asked whether these sensations might be related to the OsmoPrep.” 1 In response, someone from the doctor’s offce “told DrugTopics .c om magenta cyan yellow black her that these were not caused by the OsmoPrep.”1 Christine took the second OsmoPrep prescription to the pharmacy and asked again about these symptoms. “The technician consulted with [the pharmacist], who said that OsmoPrep did not cause the tingling sensation.”1 After the second round of OsmoPrep, Christine was admitted to the emergency room with symptoms of kidney failure. The court said, “The damage to her kidneys requires that Christine undergo dialysis for the rest of her life or receive a kidney transplant, and she has been placed on a transplant waiting list.” Failure to warn The only question for the court at this phase of the case was whether the pharmacist and pharmacy could be sued for failure to warn Christine and/or her physician of the risk of taking the drugs. The court ruled in the affrmative, saying, “We hold that [the pharmacy and the pharmacist] had a duty of care to Christine either to warn Christine of the side effects of OsmoPrep or to withhold the medication in accordance with [Indiana law].”1 The court did not rule on what caused the kidney failure; that was for the trial jury to determine. We are looking at this case only as a reminder of the life-saving professional and ethical role pharmacists can exercise for its patients. It reminds us of the importance of the role of the pharmacist. Reference 1. Kolozsvari v. Doe, Ind App, 943 N.E.2d 823 (2011). The facts cited are from the Court opinion. Since this was a motion for summary judgment, the facts were stated in favor of the nonmoving party, in this case the plaintiff Kolozsvari. There was no conclusion in the case as to whether the OsmoPrep caused or led to the kidney failure. This would have to be proved in the trial that followed this opinion. The question here was only one of duty, not ultimate liability. Since this was a motion for summary judgment, the defenses of the pharmacy and pharmacist were not considered in this opinion but would be presented in the trial. Could the pharmacist and the pharmacy be sued for failure to warn Christine and her physician of the risk? These articles are not intended as legal advice and should not be used as such. When a legal question arises, the pharmacist should consult with an attorney familiar with pharmacy law in his or her state. Ken Baker is a pharmacist and an attorney. He teaches ethics at the Glendale, Arizona, campus of Midwestern University, and risk management for the University of Florida. He consults in the areas of pharmacy error reduction, communication, and risk management. Mr. Baker is an attorney of counsel with the Arizona law firm of Renaud Cook Drury Mesaros, PA. E-mail him at [email protected]. Februar y 2015 DRUG TOPICS 39 ES567008_drtp0215_039.pgs 02.05.2015 20:05 ADV CREDIT: 2.0 Continuing Education EARN CE CREDIT FOR THIS ACTIVITY AT WWW.DRUGTOPICS.COM AN ONGOING CE PROGRAM OF THE UNIVERSITY OF CONNECTICUT SCHOOL OF PHARMACY AND DRUG TOPICS educationaL oBJectiVeS Goal: To discuss new and emer ging medications for the treatment of diabetes. After participating in this activity, pharmacists will be able to: ● Describe the pertinent pharmacological properties of new agents for the treatment of diabetes ● Discuss the place in therapy for new agents for the treatment of diabetes ● Identify emerging therapies for the treatment of diabetes New and emerging therapies for the treatment of diabetes ACPE# 0009-9999-15-015-H01-P Grant Funding: None Activity Fee: There is no fee for this activity.. Initial release date: 2/10/2015 Expiration date: 2/10/2017 To obtain CPE credit, visit www.drugtopics.com/cpe and click on the “Take a Quiz” link. This will direct you to the UConn/Drug Topics website, where you will click on the Online CE Center. Use your NABP E-Profle ID and the session code: 15DT15-WKX27 to access the online quiz and evaluation. First-time users must pre-register in the Online CE Center. Test results will be displayed immediately and your participation will be recorded with CPE Monitor within 72 hours of completing the requirements. For questions concerning the online CPE activities, e-mail: [email protected]. Marissa Salvo, PharmD, BCACP ASSISTANT CLINICAL PROFESSOR, UNIVERSITY OF CONNECTICUT SCHOOL OF PHARMACY, STORRS, CONN. Gretchen Stern, PharmD CLINICAL PHARMACIST, bRIGHAM AND WOMEN’S HOSPITAL, bOSTON, MASS. Christina Palazzo PHARMD CANDIDATE 2015, UNIVERSITY OF CONNECTICUT SCHOOL OF PHARMACY, STORRS, CONN. Abstract Diabetes medication options continue to evolve. Over the past two years, not only were numerous new diabetes medications approved, but there was also the advent of an entirely new drug class and a new route of insulin administration. It is essential for pharmacists to keep up to date with ongoing advances in diabetes management. Furthermore, pharmacists are well positioned and well trained to collaborate with other healthcare providers to individualize patient care plans. The contributions of pharmacists are necessary and should take into account medication-related factors, available clinical evidence, and most importantly, patient preferences. Faculty: Marissa Salvo, Pharmd, BcacP, gretchen Stern, Pharmd, and christina Palazzo, Pharmd candidate 20215 Dr. Salvo is an assistant clinical professor at the University of Connecticut School of Pharmacy, Storrs, Conn. Dr. Stern is a clinical pharmacist at brigham and Women’s Hospital, boston, Mass. Ms. Palazzo is a 2015 PharmD candidate at the University of Connecticut School of Pharmacy, Storrs, Conn. Faculty Disclosure: Dr. Salvo and Ms. Palazzo have no actual or potential confict of interest associated with this article. Dr. Stern has some shares of Target stock. Disclosure of Discussions of Off-Label and Investigational Uses of Drugs: This activity may contain discussion of unlabeled/unapproved use of drugs in the United States and will be noted if it occurs. The content and views presented in this educational program are those of the faculty and do not necessarily represent those of Drug Topics or University of Connecticut School of Pharmacy. Please refer to the offcial information for each product for discussion of approved indications, contraindications, and warnings. 40 magenta cyan yellow black Drug topics Februar y 2015 IMAGE: GETTY IMAGES / RICHARD CANO The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Pharmacists are eligible to participate in the knowledge-based activity, and will receive up to 0.2 CEUs (2 contact hours) for completing the activity, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statements of credit are available via the online system and your participation will be recorded with CPE Monitor within 72 hours of submission. DrugTopics .c om ES567070_drtp0215_040.pgs 02.05.2015 20:31 ADV continuing education A s advances continue to be made in treatment approaches for diabetes, pharmacists must not only know about the new medications available on the market, but they must also evaluate the evidence for each medication to determine how they should be used in patient care. Many factors must be considered when healthcare providers are selecting appropriate medication(s) to manage a patient’s diabetes. The pharmacist has a unique role in this process as part of the multidisciplinary patient care team. This article will review newly available diabetes medications and discuss some diabetes medications that may soon undergo U.S. Food and Drug Administration (FDA) review. (Note: new insulin pump technology is outside the scope of this article.) New medications joining existing drug classes Dipeptidyl peptidase-4 inhibitors. Dipeptidyl peptidase-4 (DPP-4) inhibitors are commonly used for diabetes management because of their many advantages, including their neutral effect on body weight, low risk of hypoglycemia, enhanced beta-cell function, and good overall tolerability.1 DPP-4 inhibitors can be used as monotherapy or in combination with metformin, thiazolidinediones, sulfonylureas, or insulin. Alogliptin, the newest DPP-4 inhibitor (Table 1), slows the inactivation of incretin hormones, causing an increase in bloodstream concentration, and reduces fasting and postprandial plasma glucose concentrations in a glucose-dependent manner.2 Like sitagliptin and linagliptin, alogliptin is classifed as a nonpeptidomimetic, meaning it has a greater selectivity for DPP-4 compared to peptidomimetics. Peptidomimetics, such as vildagliptin and saxagliptin, generally have a greater selectivity for DPP-8 and DPP-9 than for DPP-4, which results in a greater potential for side effects. pause&ponder How would you compare and contrast the currently available gLP-1 Ras? DrugTopics .c om magenta cyan yellow black TAbLE 1 CharaCTeriSTiCS Of alOGliPTin Indication Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Tablet strengths 6.25 mg, 12.5 mg, 25 mg Dosing 25 mg by mouth daily with or without food Hemoglobin A1c lowering effect (as monotherapy) –0.6% to –1.0% Renal impairment (CrCl) ≥60 mL/min: no adjustment ≥30 to <60 mL/min: 12.5 mg by mouth daily ≥15 to <30 mL/min: 6.25 mg by mouth daily ESRD (<15 mL/min or requiring hemodialysis): 6.25 mg by mouth daily Hepatic impairment Use caution; however, no dose adjustment needed Contraindications Hypersensitivity reaction to alogliptin Precautions Pancreatitis or hepatic failure (obtain baseline LFTs and monitor); use with other medications causing hypoglycemia Common adverse effects Headache, nasopharyngitis, upper respiratory infection Drug combinations Alogliptin plus metformin Alogliptin plus pioglitazone Abbreviations: CrCl, creatinine clearance; ESRD, end-stage renal disease; LFTs, liver function tests Source: Ref 2 Alogliptin does not have any signifcant drug interactions, whereas caution must be used when saxagliptin is administered with drugs metabolized by CYP3A4.3 A unique characteristic of alogliptin compared to other DPP-4 inhibitors is its ability to reduce low-density lipoprotein cholesterol (LDL-C), triglycerides, and postprandial lipemia; other DPP-4 inhibitors are thought to be lipid neutral. This fnding suggests that alogliptin may have potential antiatherogenic properties.1 When alogliptin is used, it is important to evaluate renal and liver function at baseline and throughout treatment. Pharmacists should counsel patients about the signs and symptoms of pancreatitis and the need to report the occurrence of these symptoms. Although alogliptin alone will not induce hypoglycemia, doses of sulfonylurea or insulin may need to be lowered when alogliptin is added.2 Glucagon-like peptide-1 receptor agonists. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are injectable medications indicated for the treatment of type 2 diabetes mellitus. Generally, this medication class decreases hemoglobin A1c (HbA1c) by 1% to 1.5% through several mechanisms, including increased glucosedependent insulin production, decreased inappropriate glucagon production, slowed gastric emptying, and improved satiety.4,5 The GLP-1 RAs are especially useful for prandial glucose control; however, the longacting agents are effective in decreasing fasting glucose levels.4 because GLP-1 RAs increase insulin production during periods of increased exogenous glucose intake, hypoglycemia is relatively uncommon when these agents are used, but hypoglycemia can occur when GLP-1 RAs are used in combination with sulfonylurea or insulin therapy.4 If GLP-1 RA therapy is added to a sulfonylurea or insulin, consider frequent glucose monitoring during initiation and titration of the GLP-1 RA, along with empiric dose reduction of the hypoglycemic-inducing medication. Gastrointestinal (GI) side effects, commonly manifested as nausea, vomiting, and diarrhea, are the primary adverse effects of GLP-1 RA therapy. The frequency of these effects varies among the GLP-1 RAs, but studies have generally reported GI-related adverse events, which have occurred in 10% to 50% of patients.5 In trials, the dropout rate because of GI-related symptoms was approximately 5%.4 The GI-related effects are likely caused by delayed gastric emptying and central appetite suppression. After one to two months of therapy, symptoms may become more tolerable. The atFebruar y 2015 Drug topics 41 ES567065_drtp0215_041.pgs 02.05.2015 20:30 ADV Continuing Education TABLE 2 NEW & EMERGING THERAPIES FOR DIABETES TREATMENT OVERVIEW OF CURRENTLY AVAILABLE GLP-1 RAS Generic name Dosing Route Site of action Common side effects Hemoglobin A1c-lowering effects Albiglutide 30-50 mg weekly Dulaglutide 0.75-1.5 mg weekly Subcutaneous Satiety center, GI tract, liver Nausea, diarrhea, injection site pain, headache –1% Exenatide 5-10 mcg twice daily Exenatide ER 2 mg weekly –1.5% Liraglutide 0.6-1.8 mg daily –1.5% –1.5% –1% Abbreviations: ER, extended release; GI, gastrointestinal; GLP-1 RAs, glucagon-like peptide-1 receptor agonists Source: Ref 6-10 tenuation of symptoms is thought to be the result of patients recognizing when they are full. Liraglutide, immediate-release exenatide, albiglutide, and dulaglutide have titration schedules to help mitigate GI-related adverse effects.6-9 When GLP-1 RAs were first introduced, many clinicians believed that the weight neutral and often weight loss associated with these agents were due solely to the adverse effect profile. However, in long-term studies and clinical practice, weight loss or maintenance has been found to continue after GI-related symptoms become tolerable.4 This is especially noteworthy as GLP1 RAs may be a valuable add-on therapy for patients who are taking agents associated with weight gain. Several class-wide contraindications include a family or medical history of medullary thyroid carcinoma or a history of multiple endocrine neoplasia syndrome type 2.6-8,10 Hepatic impairment does not seem to affect drug concentrations of GLP-1 RAs, with the exception of liraglutide.8 For patients with renal impairment, doses should be cautiously started or escalated, because of a higher risk of GI-related adverse events.6-8,10 Liraglutide and exenatide have additional warnings recommending against their use in patients with a creatinine clearance (CrCl) <50 mL/min (liraglutide) or CrCl <30 mL/min (exenatide).8-10 In the past year, several new GLP-1 RAs have received FDA approval and entered the market, including albiglutide, dulaglutide, and the once-weekly exenatide pen.6,7,10 Although all GLP-1 RAs work similarly, each 42 DRUG TOPICS Februar y 2015 agent has unique characteristics, mostly due to their formulations. Table 2 provides an overview of the currently available GLP1 RAs.6-10 Albiglutide is a once-weekly subcutaneous injection that was approved by the FDA in April 2014. The starting dose of albiglutide is 30 mg once weekly injected without regard to meals. Albiglutide can be increased to 50 mg once weekly if further HbA1c reduction is required. Both strengths are formulated in a pen dosage form and require reconstitution by the patient before use.7 Pharmacists should be familiar with the product’s use and storage in order to ensure patients are receiving the most benefit from the product. To reconstitute this product, the pen must be twisted until the cartridge clicks. The pen should be slowly shaken, and the medication should then be propped upright in a glass for 15 or 30 minutes, depending on the strength. Once this time has elapsed, the pen should be lightly shaken. The liquid should be slightly yellow with a large air bubble on top. The needle should then be attached and the cartridge should be twisted until there is a click. The pen will then be ready for use.7 The medication can be injected into subcutaneous tissue of the abdomen, thigh, or upper arm. The patient can repeatedly use the same body region for injections; however, the patient should rotate the exact injection site. This also applies if the patient is using insulin. Once the needle penetrates the skin, the patient should push the plunger until he or she hears a click. The device should then be held in place for 5 seconds before it is removed from the injection site. Proper disposal of the pen in a sharps container is required. If a patient misses a dose and realizes it within three days of the missed dose, the dose should be administered as soon as possible. If more than three days have passed since the missed dose, the dose should be skipped, and the patient should take the next dose on the regularly scheduled day for administration.7 Albiglutide pens can be stored in the refrigerator until the expiration date or at room temperature for up to four weeks before use.7 Compared to other GLP-1 RAs, albiglutide is associated with less HbA1c reduction (–1% vs –1.5%) and weight loss (–1 kg vs –2 to –2.5 kg).11,12 This is likely due to the larger molecule size of albiglutide, which may not allow the agent to have full access to the satiety center and may lead to reduced effects on GI motility.4 As one would suspect, albiglutide is associated with fewer GI side effects compared to other GLP-1 RAs.11 Interestingly, among the agents in this class, albiglutide is associated with the most injection-site reactions, including localized redness and pruritus.11 A one-month supply of albiglutide costs approximately $400 without prescription insurance; however, the manufacturer does offer a patient assistance program.7,13 Although albiglutide may not provide as much HbA1c lowering as the other GLP-1 RAs, patients who have not tolerated other GLP-1 RAs because of the GI-related side effects may benefit from treatment with albiglutide. Dulaglutide, the newest GLP-1 RA on the market (approved in September 2014), is administered as a once-weekly subcutaneous injection. The starting dose of dulaglutide is 0.75 mg, which can be increased to 1.5 mg for further HbA1c reduction. Dulaglutide is formulated in unit-dose pens and does not require reconstitution. Dulaglutide pens can be stored in the refrigerator until the expiration date or at room temperature for up to 14 days before use. Dulaglutide should be stored in its original packaging, as it is sensitive to light.6 When injecting, a patient can use this medication immediately after removing it from the refrigerator or can wait for up to 30 minutes. Letting the medication reach room DrugTopics .c om continuing education temperature may lead to a more comfortable injection. The injection can be given in the subcutaneous tissue of the abdomen, thigh, or upper arm. A patient can repeatedly use the same body region to inject; however, the patient should rotate the exact injection site. This also applies if the patient is using insulin.6 To inject, the pen must be unlocked by pulling off the base cap. After the pen is placed at the injection site, the lock ring should be twisted. The patient should push the injection button, which will cause a loud click to be heard. The pen should be held in place frmly against the skin for fve to 10 seconds or until the patient hears another loud click. Proper disposal of the pen in a sharps container is required. If the patient misses a dose and more than 72 hours remain before the next dose, the patient should take the missed dose as soon as possible. If fewer than 72 hours remain until next dose, the patient should take the next dose on the regularly scheduled day for administration.6 Dulaglutide lowers HbA1c by approximately 1.5%, similar to extended-release exenatide and liraglutide, and has a similar adverse effect profle.12,14,15 However, in a head-to-head trial, dulaglutide was deemed signifcantly different in weight reduction (–2.90 vs –3.61 kg; P = 0.01) compared to liraglutide.14 As with albiglutide, the difference in weight reduction is likely due to the larger particle size of this agent. Unlike other GLP-1 RAs, dulaglutide may slightly increase heart rate [1.9 to 2.6 beats/min; standard error (SE) = 0.5].15 A month’s supply of dulaglutide costs approximately $1000 without insurance; however, the manufacturer offers a prescription assistance program.6,13 Dulaglutide is the only once-weekly GLP-1 RA pen that does not require reconstitution. Another recent addition to the GLP-1 RA class of drugs is the exenatide extendedrelease pen, which was approved in March pause&ponder in which patient(s) would you consider using an SgLt2 inhibitor? DrugTopics .c om magenta cyan yellow black 2014. This product is a once-weekly subcutaneous injection that is available as a 2-mg pen. before use, the pen should be stored in the refrigerator away from light.10 To use the pen, the patient should remove it from the refrigerator and keep it at room temperature for at least 15 minutes. Next, the patient should remove the pen and needle from the tray and twist the needle onto the pen. Holding the pen upright, the patient should twist the knob on the bottom of the pen until hearing the frst click and seeing the green label disappear. This begins reconstitution of the medication. With one hand, the patient should hold onto the end of the pen with the orange label and firmly tap the pen against the palm of the other hand approximately 80 times, rotating the pen every 10 taps to fully mix the contents. The patient should then look through the window in the pen to ensure that the medication appears uniformly cloudy. Holding the pen upright, the patient should again twist the knob until he or she hears another click, sees the orange label disappear, and fnds the injection button exposed.10 After mixing this medication, the patient needs to inject it immediately. Injection sites include the subcutaneous tissue of the thigh, abdomen, or upper arm. The patient can use the same body region for injections week to week but should rotate the exact injection site. To administer the medication, the patient should remove the needle cap, insert the needle into the injection site, press the injection button (the patient will hear a click), and hold in place for 10 seconds. After administration, proper disposal of the pen in a sharps container is required. If a patient misses a dose and more than 72 hours remain before the next dose, the patient should take the missed dose as soon as possible. If fewer than 72 hours remain until the next dose, the patient should take the next dose on the regularly scheduled day for administration.10 The patient should be mindful of potential injection site reactions such as nodules or pruritus, and he or she should immediately notify a healthcare provider if severe pain, edema, blisters, open wounds, or dark scabs occur at the injection site.10 The new pen dosage form is much simpler to use than the previous single-dose Pharmacists should be sure to review medication profles to prevent therapeutic duplication. tray, which required the patient to mix and draw up the dose from a vial.10 both systems are similar in price, costing approximately $450 per month without insurance; however, the manufacturer offers a patient assistance program.10,13 Pharmacists can play a key role in explaining the differences among the available GLP-1 RAs, including differences in safety and effcacy. Pharmacists can also provide specifc administration instructions for each medication. because GLP-1 RAs work very similarly to DPP-4 inhibitors, pharmacists should be sure to review medication profles to prevent therapeutic duplication. Pharmacists can also assist in recommending individualized therapy plans for patients with type 2 diabetes mellitus and titration of insulin regimens after the initiation of GLP-1 RAs, if needed. Inhaled Insulin. Insulin has been a mainstay in diabetes treatment for more than 90 years. Traditionally, insulin is administered subcutaneously because of poor bioavailability; however, this route is not ideal for patient satisfaction. In 2006, a short-acting dry insulin powder inhaler was approved for the treatment of types 1 and 2 diabetes mellitus. because of poor market uptake, diffculty with reimbursement, high cost, and a potential association with lung cancer, the manufacturer pulled this product from the market in 2007.16 In June 2014, the FDA approved Afrezza, an inhaled insulin regular formulation and inhaler system, for prandial glucose control in adults with diabetes.17This inhaled insulin product is available as a 4-unit (blue) and 8-unit (green) dry-powder cartridge to be used with the inhaler system. It is packaged in 3 × 5 blister packs with two packages per box (total of 30 cartridges). The medication should be stored in the Februar y 2015 Drug topics 43 ES567064_drtp0215_043.pgs 02.05.2015 20:30 ADV Continuing Education neW & eMeRging tHeRaPieS FoR diaBeteS tReatMent refrigerator; however, if a package is kept unopened at room temperature, it is good for 10 days. Once the package is open, the contents must be used within three days.18 The inhaler system can be stored at room temperature or refrigerated. After 15 days, the inhaler should be discarded and a new inhaler should be used. Units correspond to U-100 insulin regular, and the manufacturer provides instructions for transitioning to inhaled insulin from prandial insulins. To use this product, the patient should remove the inhaler and cartridge from the refrigerator and keep them at room temperature for at least 10 minutes before use. Holding the system level, the patient should then open the inhaler, place a cartridge inside the inhaler, and close the inhaler. Next, the patient should remove the mouthpiece, exhale, place the mouthpiece in his or her mouth while keeping his or her head level, tilt the device down, and seal his or her lips around the mouthpiece. The patient should then inhale deeply and hold his or her breath for as long as comfortable before exhaling and breathing normally. The used cartridge should be removed from the inhaler and thrown away in the household trash. This process may need to be repeated, using another cartridge, to reach the target dose. For example, if the patient requires 12 units, he or she will need to use one 8-unit cartridge and then repeat the process using one 4-unit cartridge.17 This inhaled insulin system exhibits its peak action in 15 to 30 minutes and has a duration of action of 180 minutes, making it ideal for prandial glucose control. because lung function is critical for proper absorption, this product is contraindicated in patients with chronic lung disease or in those who smoke. before initiation of inhaled insulin treatment, a patient will need to complete lung function tests, which should be repeated after 6 months and then annually, as studies have shown a slight decline in lung function with the use of inhaled insulin.17,18 If forced expiratory volume in one second decreases by more than 20%, inhaled insulin use may need to be discontinued. Concomitant albuterol use may increase lung absorption, so the dose of inhaled insulin may need to be reduced. During an acute lung illness such 44 magenta yellow black Drug topics Februar y 2015 as a cold, a patient can continue to use inhaled insulin but should monitor glucose levels frequently and follow the sick day management plan as discussed with his/ her provider.17 In a study of patients with type 2 diabetes mellitus, inhaled insulin decreased HbA1c by 0.4% after 24 weeks when it was added to oral therapies (baseline HbA1c = 8.26% [8.6%-10.1%]). Despite its rapid onset and short duration of action, inhaled insulin decreased fasting glucose levels (11.2 mg/dL, SE = 3.78) compared to placebo (3.78 mg/dL, SE = 3.86). After 24 weeks, patients in the inhaled insulin group gained 0.49 kg (SE = 0.333) compared to the placebo group, which lost 1.13 kg (SE = 0.347). In addition to hypoglycemia, the most common adverse event was nonproductive cough.19 In a study of patients with type 1 diabetes mellitus, inhaled insulin plus insulin glargine was compared with insulin aspart plus insulin glargine. After 24 weeks, HbA1c was reduced by 0.21% (SE = 0.06) in the inhaled insulin plus insulin glargine group and by 0.40% (SE = 0.06) in the insulin aspart plus insulin glargine group. Although inhaled insulin plus insulin glargine met the noninferiority margin, signifcantly more patients reached a target HbA1c of less than 7% in the insulin aspart plus insulin glargine group (18.3% vs 30.7%; P = 0.0158). In terms of safety, patients treated with inhaled insulin plus insulin glargine had a signifcantly lower incidence of severe hypoglycemia (18.4% vs 29.2%; P = 0.0156). The main adverse effect in patients treated with inhaled insulin plus insulin glargine was cough (31.6%).20 Inhaled insulin may be a useful option for patients requiring insulin at meals to lower postprandial glucose levels. This medication may be particularly benefcial for patients with frequent hypoglycemia or intolerance to needles and for cases in which adherence is decreased because of a high injection burden. While this new dosage form of insulin is promising for patients with type 2 diabetes mellitus, in practice, basal insulin is typically added to oral agents before prandial insulin. For patients with type 1 diabetes mellitus and high insulin sensitivity, this inhaled insulin product will not provide precise dosing schemes, as a foreseeable complication is the inability to titrate to a specifc target dose, given its available formulations, or deliver doses less than 4 units. Although this inhalation device is more portable than the previously approved device, it may be bothersome for patients to use multiple inhalations to achieve the target dose. Success on the market will likely depend on pricing, as well. (Although the product is approved, it was not available on the market as of December 2014.) A fnal concern with the use of inhaled insulin is long-term pulmonary safety. The two-year safety trials have demonstrated promising results; however, longer-term pulmonary outcomes are unclear and require additional investigation. A new drug class Sodium glucose cotransporter 2 inhibitors. The kidneys are a target for diabetes drug development because of their role in glucose homeostasis; they filter approximately 180 g of glucose each day. Sodium glucose cotransporter 2 (SGLT2) in healthy individuals reabsorbs ~90% of the fltered glucose.21 In patients with type 2 diabetes mellitus, expression of the SGLT2 transporter is up-regulated. In these patients, excretion of glucose occurs only at higher plasma glucose levels (>180 mg/dL), leading to prolongation of hyperglycemia.22 The SGLT2 inhibitors are a class of drugs that increase urinary glucose excretion by inhibiting reabsorption of glucose in the proximal tubule. Currently, there are three FDA-approved SGLT2 inhibitors: canagliflozin, dapaglifozin, and empaglifozin (Table 3).23-25 SGLT2 inhibitors are effective in lowering HbA1c, body weight, and blood pressure with a low risk of hypoglycemia.22 Canaglifozin was approved by the FDA in 2013 for use as monotherapy or in combination with other antidiabetic therapies.21 A product that combines canaglifozin and metformin is also available. The addition of canaglifozin to other antidiabetic therapies results in an increased reduction in HbA1c (approximately –0.15% additional) in patients with type 2 diabetes mellitus who have not achieved suffcient glucose control with metformin, sulfonylurea, metformin plus sulfonylurea, or metformin plus pioglitazone and insulin.22,26 Canaglifozin has been shown to be noninferior to sulfoDrugTopics .c om ES567069_drtp0215_044.pgs 02.05.2015 20:30 ADV continuing education TAbLE 3 Overview Of available SGlT2 inhibiTOrS Canaglifozin Dapaglifozin Empaglifozin Indication Adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus Tablet strengths 100 mg, 300 mg 5 mg, 10 mg 10 mg, 25 mg Dosing 100 mg by mouth once daily Before frst meal of the day Maximum 300 mg/day 5 mg by mouth once daily Every morning with or without food Maximum 10 mg/day 10 mg by mouth once daily Every morning with or without food Maximum 25 mg/day Renal impairment (eGFR) 45-60 mL/min/1.73 m2: Maximum 100 mg/day <45 mL/min/1.73 m2: Should not be initiated <60 mL/min/1.73 m2: Should not be initiated <45 mL/min/1.73 m2: Should not be initiated Hepatic impairment Avoid in severe impairment No adjustment necessary No adjustment necessary Contraindications Hypersensitivity reaction to drug, severe renal impairment, ESRD, dialysis, type 1 diabetes mellitus, diabetic ketoacidosis Precautions Hypotension, impaired renal function, hypoglycemia, urinary tract infection, increased LDL-C, hyperkalemia, genital mycotic infections Hypotension, impaired renal function, hypoglycemia, urinary tract infection, increased LDL-C, bladder cancer Hypotension, impaired renal function, hypoglycemia, urinary tract infection, increased LDL-C Hemoglobin A1c reduction (as monotherapy) –0.77% to –1.16% –0.66% to –0.84% –0.85% Weight change from baseline (as monotherapy) –2.8% (100 mg) –3.9% (300 mg) –2.6% (5 mg) –2.7% (10 mg) –2.8% (10 mg) –3.2% (25 mg) Adverse effects Urinary tract infection, female genital Hyperkalemia (dose related), female mycotic infection, nasopharyngitis genital mycotic infection, urinary tract infection, increased frequency of urination, renal insuffciency Hypoglycemia, increased frequency of urination, urinary tract infection, female genital mycotic infection Abbreviations: eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; LDL-C, low-density lipoprotein cholesterol Source: Refs 23-25 nylureas and DPP-4 inhibitors with respect to HbA1c reduction.22 When using canaglifozin, it is important to monitor the patient’s serum potassium levels after the initiation of therapy because of an increased risk of hyperkalemia. Magnesium and phosphate levels should also be monitored. Canaglifozin interacts with glucuronosyltransferase (UGT) enzyme inducers and digoxin. UGT enzyme inducers (rifampin, phenytoin, phenobarbital, ritonavir) may decrease canaglifozin exposure. Concomitant use of canaglifozin with digoxin can increase digoxin levels.23 Dapaglifozin was approved by the FDA in 2014.24 A combination of dapaglifozin and metformin is also available. Dapaglifozin is effective in reducing glucose levels not only as a monotherapy but also when added to metformin, glimepiride, pioglitazone, sitagliptin, and insulin.22 In a study that assessed the combination of metformin DrugTopics .c om magenta yellow black XR plus dapaglifozin versus metformin XR alone and dapaglifozin alone, combination therapy demonstrated a greater reduction in HbA1c than either monotherapy.27 Two year-long studies have demonstrated dapaglifozin’s long-term effcacy in controlling glycemia. One study found that when patients with inadequate glucose control despite high doses of insulin were given dapaglifozin, HbA1c and body weight were reduced without an increase in insulin dose.28 Unlike other SGLT2 inhibitors, the association of dapagliflozin and bladder cancer incidence is still unclear. Nevertheless, patients should be instructed to report any symptoms of macroscopic hematuria or other symptoms of bladder cancer to their prescriber.24 Empaglifozin is the newest addition to the SGLT2 inhibitor class.25 This agent has demonstrated effcacy as a monotherapy as well as in combination with other antidia- betic agents.22 In one study, the addition of empaglifozin to a combination of metformin and sulfonylurea resulted in a –0.59% reduction in HbA1c.22 Empaglifozin has the highest selectivity for SGLT2 over SGLT1 (>2500 fold) compared to dapagliflozin (>1200 fold) and canaglifozin (>250 fold). This is an important feature of empaglifozin, as SGLT1 is responsible for intestinal glucose absorption; inhibition of SGLT1 leads to diarrhea and severe dehydration. Higher selectivity for SGLT2 is associated with fewer GI side effects.29 Renal function must be assessed before and periodically after initiation of a SGLT2 inhibitor. It is also important to monitor LDL-C levels and to assess for the occurrence of hypotension and genital mycotic infection (ie, fungal and yeast infections) during treatment.23-25 Pharmacists should advise patients taking diuretics with any of the SGLT2 inhibitors that they are at Februar y 2015 Drug topics 45 ES567066_drtp0215_045.pgs 02.05.2015 20:30 ADV Continuing Education neW & eMeRging tHeRaPieS FoR diaBeteS tReatMent an increased risk of symptomatic hypotension. because SGLT2 inhibitors increase glycosuria, patients should be made aware of an increased risk of urinary and genital infections during SGLT2 inhibitor therapy.22 Additionally, SGLT2 inhibitors may lead to increased urination and thirst, constipation, and nausea. The importance of hydration should be emphasized to prevent any dehydration complications during therapy.23-25 SGLT2 inhibitors have the ability to reduce body weight, blood pressure, and HbA1c. It is hoped that because of these characteristics, SGLT2 inhibitors may also reduce a patient’s risk of developing cardiovascular disease; however, at this time, no evidence supports this speculation.22 Lastly, an important feature of SGLT2 inhibitors to note is the recent fnding of a potential nephron-protective effect, suggesting that SGLT2 inhibitors may slow the progression of diabetic nephropathy.22 Emerging therapies Glucagon-like protein-1 receptor agonists. In addition to several approved GLP-1 RAs, two new GLP-1 RAs may soon undergo new drug application (NDA) review by the FDA: lixisenatide and semaglutide. Lixisenatide is a once-daily injectable that is highly selective for GLP-1, thus leading to glucose-dependent insulin secretion and suppression of prandial glucagon production. Lixisenatide has a shorter duration of action compared to other GLP1 RAs. Its peak concentration occurs in one to two hours, with an elimination halflife of two to four hours. With its kinetic profle, this agent has been studied as a postprandial agent.30 A number of clinical trials with lixisenatide as monotherapy and in combination with oral antidiabetic medications and/ or insulin have been conducted.4 These studies have demonstrated a –0.73% to –1% decrease in HbA1c and a –0.2-kg to –2.96-kg weight reduction with lixisenatide as part of a diabetes medication regimen.4 One trial that compared lixisenatide with twice-daily exenatide found that lixisenatide was noninferior in reducing HbA1c.31 As with other short-acting GLP1 RAs, lixisenatide has been associated with nausea and vomiting.4 The risk of hypoglycemia with lixisenatide is low un- 46 magenta yellow black Drug topics Februar y 2015 less this agent is used in combination with sulfonylureas or basal insulin.4 Lixisenatide is approved for use in the European Union, Mexico, and Japan. The manufacturer of lixisenatide intends to resubmit its NDA with the FDA in 2015 after the completion of a cardiovascular outcome study.32 Semaglutide is a once-weekly subcutaneous injectable GLP-1 RA.33 Results of a safety and tolerability study supported its weekly use, with a half-life of 6.6 days, and demonstrated a favorable effect on fasting plasma glucose, fasting glucagon, and fasting insulin.34 Currently, little published information is available regarding the use of this agent. A number of clinical trials assessing semaglutide’s effcacy are ongoing.35 Results of these trials will indicate semaglutide’s potential for reducing HbA1c and weight along with its safety profle. Insulins Insulin glargine U300. Insulin glargine is currently available as a concentration of 100 units/mL.36 However, a new, more concentrated (300 units/mL) formulation of insulin glargine has recently been developed. After injecting the more concentrated insulin glargine U300, a small subcutaneous depot forms, which has a reduced dissolution rate compared to insulin glargine U100. Studies have indicated that insulin glargine U300 provides a flatter and more consistent and prolonged pharmacokinetic and pharmacodynamic profle compared to insulin glargine U100.37,38A number of phase 3 studies investigated the clinical effcacy and safety of insulin glargine U300. In the EDITION I study, patients with inadequately controlled type 2 diabetes mellitus who were taking greater than or equal to 42 units/ day of basal insulin and prandial insulin were randomized to treatment with insulin glargine U300 or U100 once daily with dose titration. The results demonstrated that insulin glargine U300 was noninferior to insulin glargine U100 with respect to HbA1c reduction at 6 months. Additionally, insulin glargine U300 was associated with a 21% reduction in confrmed severe or nocturnal hypoglycemia events compared with insulin glargine U100.39 The EDITION II study included patients with type 2 diabetes mellitus inadequately controlled with basal insulin and oral antidiabetic mediations. Patients were randomized to receive insulin glargine U300 or U100 once daily in combination with oral antidiabetic mediations for six months. The results demonstrated similar reductions in HbA1c with the two insulin glargine concentrations and a signifcant reduction in confrmed severe or nocturnal hypoglycemia events with insulin glargine U300.40 Unlike the previous EDITION studies, the EDITION III study compared daily administration of insulin glargine U300 to U100 in patients with type 2 diabetes mellitus inadequately controlled on oral antidiabetic mediations and naïve to insulin. Like the other EDITION studies, there were similar reductions in HbA1c in patients treated with both insulin glargine U300 and U100. However, there was not a signifcant difference between treatment groups in the incidence of confrmed severe or nocturnal hypoglycemia events.41 In all trials, there was no difference between insulin glargine U300 and the other study arm in the incidence of adverse events.39-42 With similar HbA1c-lowering potential, a lower incidence of severe and nocturnal hypoglycemia, and a reduction in injection volume when compared with insulin glargine U100, insulin glargine U300 may soon be a viable basal insulin option for patients with diabetes. An NDA for insulin glargine U300 was submitted to the FDA in July 2014.43 Interestingly, Lantus’s patent expires in early 2015.43 Insulin degludec. Insulin degludec may soon join the class of long-acting basal insulins. Insulin degludec is a novel basal insulin, as its mechanism of action is characterized by protraction. Insulin degludec is a soluble and stable dihexamer in its preparation; however, after its injection, multihexamer chains form to create a subcutaneous depot. Over time, the multihexamer chains disassemble, allowing insulin degludec to slowly and steadily enter the bloodstream.44 Given its design, insulin degludec has a half-life of more than 25 hours and a duration of action beyond 42 hours.45,46 In studies, steady state was achieved within two to three days, regardless of dose or type of diaDrugTopics .c om ES567072_drtp0215_046.pgs 02.05.2015 20:31 ADV continuing education betes, after once-daily administration of insulin degludec.46 Furthermore, insulin degludec has shown a predictable and flat glucose-lowering effect when used for the treatment of type 1 and type 2 diabetes mellitus.47 Conversely, in one study that compared insulin degludec with insulin glargine, insulin glargine had an increased glucose-lowering effect six to eight hours after the dose and peaked 14 to 26 hours after the dose.47Evaluating an insulin’s adverse event profle, particularly hypoglycemia and weight gain, is necessary. At the completion of the 52-week bEGIN basal-bolus Type 1 Diabetes trial, the rate of confrmed nocturnal hypoglycemia was 25% lower with insulin degludec than with insulin glargine (administered at any time, as long as consistent). Furthermore, this lower rate was observed as early as eight weeks into the study. The rates of confrmed diurnal and overall confrmed hypoglycemia were similar among patients treated with insulin degludec and those treated with insulin glargine.48 In the bEGIN basal-bolus Type 2 Diabetes trial, the rates of confrmed nocturnal, diurnal, and overall hypoglycemia were significantly lower with insulin degludec than with insulin glargine.49 In the bEGIN basal-bolus Type 1 Diabetes trial, weight gain was similar with insulin degludec and insulin glargine, with mean increases of +1.8 kg and +1.6 kg, respectively.48 In the bEGIN basal-bolus Type 2 Diabetes trial, weight gain was similar with insulin degludec and insulin glargine, with mean increases of +3.6 kg and +4.0 kg, respectively.49 Insulin degludec is formulated in two concentrations, 100 units/mL and 200 units/mL. One study demonstrated that the pharmacodynamics and pharmacokinetics of the 200-units/mL concentration are the same as the 100-units/mL concentration.50 With a more concentrated formulation, a lesser volume of insulin would need to be injected. After the injection of insulin degludec, a depot is formed and released over a long period of time; therefore, local tolerability was investigated. It was found that few participants withdrew from the study because of injection site intolerability.51 In another study that investigated the administration of insulin degludec in various subcutaneDrugTopics .c om black ous injection sites, there was no difference in glucose-lowering effect when this agent was injected into subcutaneous tissue in the abdomen, thigh, or upper arm.52 Several dosing schedules have been studied to determine whether varying dayto-day administration affects the effcacy and safety of insulin degludec. The schedules included daily injections, injections three times per week, and a fexible dosing regimen, defned as rotating morning and evening dosing to create intervals of 8 to 40 hours between insulin doses. A study comparing fxed daily dosing with fexible dosing in patients with type 2 diabetes found that the resulting HbA1c, fasting plasma glucose, and incidence of confrmed hypoglycemia were similar between groups.53 In another study, flexible insulin degludec dosing was compared with daily insulin glargine dosing. The reduction in HbA1c and incidence of adverse events were similar between the groups, meeting the noninferiority end point.54 The fexible dosing studies were not intended to mimic what would be done in clinical practice but rather to demonstrate that changes in the time of insulin degludec administration do not adversely affect glycemic control or the risk of hypoglycemia. This may be an appealing aspect for those wishing for greater autonomy in the administration time of insulin. Although this product is available in the European Union, Mexico, and Japan, it was rejected by the FDA in early 2013, despite a recommendation from the FDA’s advisory panel to approve the product. The FDA requested additional cardiovascular outcomes data from a dedicated trial, as some analyses suggested a possible increased risk of major adverse cardiovascular events associated with the product’s use.55 Insulin degludec has a number of favorable properties that address some limitations of currently available insulin therapies. With a long duration of action, effective reduction of HbA1c and fasting plasma glucose, lower risk for hypoglycemia compared to currently available agents, and potential for changing administration time, insulin degludec may soon provide another basal insulin option for the management of diabetes. PEGylated insulin lispro. In a new design of basal insulin, a polyethylene glycol chain has been added to rapid-acting insulin lispro at lysine b28. The addition of this chain increases the molecule’s hydrodynamic size, resulting in changes in the product’s pharmacokinetics, including altered tissue distribution, delayed absorption, and reduced renal clearance.56-58 Together, the changes increase the product’s half-life, which a phase 1 study found to be 24 to 48 hours, and duration of action, which was found to be at least 36 hours.57,59 Another study demonstrated that PEGylated insulin lispro (PEG-lispro) may have preferential transport to the liver rather than to the peripheral tissues compared with other exogenous insulins.60 This is noteworthy because increased uptake of insulin in peripheral tissues is associated with weight gain.61 When compared with insulin glargine in a study of patients with type 2 diabetes, once-daily PEG-lispro (morning administration) provided similar blood glucose levels with less variability. both agents were used in combination with metformin and/or a sulfonylurea. Patients treated with PEG-lispro lost weight (–0.58 kg) compared with those treated with insulin glargine (+0.31 kg). Furthermore, after adjustments were made for baseline differences, PEG-lispro demonstrated a statistically signifcant 48% rate reduction in nocturnal hypoglycemia.62 In a study of patients with type 1 diabetes mellitus, the overall hypoglycemia rate was 12% higher in those treated with PEG-lispro compared to those treated with insulin glargine; however, the nocturnal hypoglycemia rate was 25% lower in patients treated with PEG-lispro. Similar to the study in patients with type 2 diabetes mellitus, individuals treated with PEG-lispro lost weight (–1.2 kg) compared to those treated with insulin glargine (+0.69 kg).63 Using the data of the two trials, an exploratory analysis investigated the correlation between change in weight and other variables. No correlation was found between weight change and baseline body mass index or change in high-density lipoprotein cholesterol (HDL-C), and no consistent correlation was found between weight loss and other investigated variables.64 Februar y 2015 Drug topics 47 ES567073_drtp0215_047.pgs 02.05.2015 20:31 ADV Continuing Education neW & eMeRging tHeRaPieS FoR diaBeteS tReatMent In both studies, PEG-lispro was associated with an increase in alanine aminotransferase and aspartate aminotransferase levels, although mean values remained within normal limits.62,63 Additionally, PEGlispro was associated with lower HDL-C levels and higher LDL-C and triglyceride levels compared to insulin glargine.62,63 Studies are ongoing to evaluate the effcacy and safety of PEG-lispro. combination products Insulin degludec and insulin aspart. At this time, the coformulation of a long-acting basal insulin and a rapid-acting insulin is not available in the United States. The coformulation of insulin degludec and insulin aspart would be the frst of its kind, as insulin detemir and insulin glargine cannot be mixed with rapid-acting insulins.36,65 The coformulation of 70% insulin degludec and 30% insulin aspart would allow for basalbolus delivery, requiring fewer injections. This product is approved for use in the European Union, Japan, and other markets.66 One trial compared twice-daily coformulated insulin degludec and insulin aspart with twice-daily biphasic insulin aspart (30% rapid-acting insulin aspart/70% protamine-bound insulin aspart), both in combination with metformin, in insulinnaïve patients with type 2 diabetes mellitus. The coformulated insulin degludec and insulin aspart product resulted in lower fasting plasma glucose levels and fewer hypoglycemic events than biphasic insulin aspart.67 In another trial, daily administration of coformulated insulin degludec and insulin aspart compared with daily insulin glargine, both in combination with metformin, led to similar reductions in HbA1c and fasting plasma glucose levels with similar rates of hypoglycemia.68 The results of the studies suggest that the coformulation of insulin degludec and insulin aspart would provide glucose lowering with fewer daily injections. A NDA for the coformulation of insulin degludec and insulin aspart was submitted to the FDA at the same time as the single entity insulin degludec. The FDA rejected both insulin degludec-containing products, requiring additional cardiovascular data as described earlier.55 The manufacturer is gathering the required data and is planning NDA resubmission.66 48 magenta cyan yellow black Drug topics Februar y 2015 Insulin degludec and liraglutide. Position statements from the American Diabetes Association/European Association for the Study of Diabetes and the American Association of Clinical Endocrinologists support the use of incretin-based therapies as a possible alternative to insulin initiation after failure to achieve glycemic control with lifestyle changes and metformin.69,70 In the United States, exenatide immediate release is approved as add-on therapy to insulin glargine for patients with type 2 diabetes mellitus who are unable to achieve adequate glycemic control with a basal insulin alone.43 Additionally, the FDA has approved the use of insulin detemir, a basal insulin, in combination with liraglutide and metformin for patients with type 2 diabetes mellitus.71 Despite the approval of GLP-1 RA use with basal insulin, the products are not coformulated, and so multiple injections throughout the day are required for patients treated with these agents. The coformulation of insulin degludec and liraglutide would be the frst of its kind and would provide convenient administration of both products in a single, once-daily injection. This product contains a fxed ratio of 1 unit of insulin degludec and 0.036 mg of liraglutide per unit of drug.72 A 26-week trial in patients with type 2 diabetes mellitus inadequately controlled with metformin with or without pioglitazone compared daily coformulated insulin degludec and liraglutide with insulin degludec alone and liraglutide alone, all in addition to current metformin with or without pioglitazone. The reduction in HbA1c from baseline was significantly greater (P < 0.0001) with coformulated insulin degludec and liraglutide (–1.9%) compared to insulin degludec alone (–1.4%) and liraglutide alone (–1.3%). Additionally, the coformulated insulin degludec and liraglutide was associated with a signifcant reduction in fasting plasma glucose level and postprandial plasma glucose control. Although there was a signifcant reduction (P = 0.0023) in the risk of hypoglycemia with the coformulation compared to insulin degludec alone, there was a signifcant increase (P < 0.0001) in this risk with the coformulation versus liraglutide alone. The coformulation had fewer GI side effects compared to liraglutide alone.72 In a 26-week trial, patients with type 2 diabetes mellitus taking basal insulin and metformin with or without sulfonylureas or glinides were randomized to once-daily coformulated insulin degludec and liraglutide or insulin degludec alone, both in combination with metformin. both treatment groups were titrated to achieve a fasting plasma glucose level of 72 to 90 mg/dL. As in the previous study, signifcantly higher (P < 0.0001) HbA1c reduction was seen with the coformulation (–1.9%) compared with insulin degludec alone (–0.9%). The mean weight reduction was –2.7 kg with the coformulation compared to no weight change with insulin degludec alone. The incidence of hypoglycemia was comparable between the treatment groups. Nausea and vomiting occurred more frequently with the coformulated therapy, as expected.73 These study results indicate that combination therapy with a GLP-1 RA and a basal insulin would not only reduce the frequency of injections, but would also provide HbA1c reduction, plasma glucose lowering, and weight loss. Although GI side effects are likely, their incidence seems to be lower with combination therapy. conclusion As new diabetes medications become available, pharmacists must expand their medication knowledge base and evaluate how to best incorporate the new products into diabetes management. Currently available medications vary in a number of ways, including pathophysiologic function, HbA1c reduction, effect on weight, use with renal and/or hepatic impairment, and adverse effects. As an essential member of the multidisciplinary healthcare team, pharmacists should share their knowledge of the new medications’ characteristics to aid prescribers in developing patient care plans.• The references are available online at www.drugtopics.com/cpe. For immediate cpE credit, take the test now online at www.drugtopics.com/cpe once there, click on the link below Free cpE Activities DrugTopics .c om ES567067_drtp0215_048.pgs 02.05.2015 20:30 ADV TeST queSTiOnS 1. 2. Which GLP-1 RA is associated with the most injection site reactions? a. Albiglutide b. Dulaglutide c. Exenatide extended release d. Liraglutide c. Increase the dose to 300 mg once daily. d. Decrease the dose 100 mg every other day. 8. A patient’s eGFR is 59 mL/min/1.73 m2. The doctor calls your pharmacy to ask you which SGLT2 inhibitor you would recommend and at which dose. Which of the following regimens would you recommend? a. Canaglifozin 300 mg daily b. Dapaglifozin 5 mg daily c. Dapaglifozin 10 mg daily d. Empaglifozin 10 mg daily 9. Which of the following should be monitored while a patient is taking a SGLT2 inhibitor? a. Renal function b. Blood pressure c. Genital mycotic infection d. All of the above Which new GLP-1 RA is associated with the lowest occurrence of GI adverse events? a. Albiglutide b. Dulaglutide c. Exenatide extended release d. Lixisenatide 3. Which GLP-1 RA requires no waiting or mixing before use? a. Albiglutide b. Dulaglutide c. Exenatide extended release d. Liraglutide 4. Which patients are at higher risk for GI-related side effects with the use of GLP-1 RAs? a. Those also using metformin b. Those with renal dysfunction c. Those with hepatic dysfunction d. Those who slowly titrate their dose 5. Which patient is the best candidate for inhaled insulin regular? a. A patient with type 1 diabetes and asthma b. A patient with type 1 diabetes who actively smokes c. A patient with type 2 diabetes and an average fasting plasma glucose level of 200 mg/dL and an average prandial plasma glucose level of 120 mg/dL d. A patient with type 2 diabetes and an average fasting plasma glucose level of 120 mg/dL and an average prandial plasma glucose level of 200 mg/dL 11. Which of the following SLGT2 inhibitors is most specifc for the SGLT2 receptor? a. Canaglifozin b. Dapaglifozin c. Empaglifozin d. All are equally specifc In which scenario is the inhaled insulin regular still good to use? a. An opened package stored at room temperature for 2 weeks. b. An opened package that has been refrigerated for 2 weeks. c. An unopened package that has been refrigerated for 2 weeks. d. An unopened package stored at room temperature for 2 weeks. 13. While flling a prescription for ketoconazole, you notice that the patient is also taking alogliptin 12.5 mg daily. Which of the following should you do? a. Take no action. b. Call the doctor to discontinue alogliptin. c. Call the doctor to increase alogliptin to 25 mg daily. d. Call the doctor to decrease alogliptin to 6.25 mg daily. A patient is taking canaglifozin 100 mg daily and was recently prescribed phenytoin. Which of the following actions should be taken regarding canaglifozin use? a. Discontinue canaglifozin. b. No dose adjustment is necessary. 14. Which of the following insulin products uses protraction in its drug design? a. Insulin glargine U100 b. Insulin degludec c. Insulin glargine U300 d. PEGylated insulin lispro 6. 7. DrugTopics .c om magenta yellow black 10. Which of the following is/are contraindications to the use of SGLT2 inhibitors? a. Type 1 diabetes mellitus b. Diabetic ketoacidosis c. Hyperosmolar hyperglycemic state d. A and B 12. If a patient is on dialysis, what should the dose of alogliptin be? a. 6.25 mg daily b. 12.5 mg daily c. 25 mg daily d. Alogliptin is contraindicated in the setting of dialysis 15. Which of the following is NOT true of insulin degludec? a. It is formulated in 100-unit/mL and 300unit/mL concentrations. b. It has similar glucose lowering despite its site of administration. c. It is associated with a signifcantly lower rate of nocturnal hypoglycemia compared to insulin glargine. d. Its administration time does not adversely affect glycemic control. 16. The two studies discussed in the article demonstrated which of the following results for coformulated insulin degludec and liraglutide? a. Comparable weight loss b. Comparable GI side effects c. Signifcant decrease in HbA1c d. Signifcant reduction in risk of hypoglycemia 17. Which insulin product may be associated with an increase in aminotransferases? a. Insulin degludec b. Insulin glargine U100 c. Insulin glargine U300 d. PEGylated insulin lispro 18. Which of the following is not a beneft of using insulin glargine U300 versus insulin glargine U100? a. Greater HbA1c-lowering potential b. Lesser quantity of insulin to inject c. Lesser incidence of nocturnal hypoglycemia d. More consistent pharmacokinetic profle 19. Which of the following GLP-1 RAs is NOT approved by the FDA? a. Albiglutide b. Exenatide c. Liraglutide d. Lixisenatide 20. The combination of insulin degludec and insulin aspart was studied in which concentration? a. 30% insulin degludec/70% insulin aspart b. 70% insulin degludec/30% insulin aspart c. 0.036 unit insulin degludec/1 unit insulin aspart d. 1 unit insulin degludec/0.036 unit insulin aspart Februar y 2015 Drug topics 49 ES567071_drtp0215_049.pgs 02.05.2015 20:31 ADV Product Updates FEATURED THIS MONTH: ORAL CARE A batch of new products from Listerine includes Listerine Naturals Antiseptic Mouthwash, shred-resistant Ultraclean Floss, and the specially designed UltraClean Access Flosser. Some people fnd that Crest Sensi-Stop Strips are so effective that one application will diminish dental sensitivity for a month. OTC Put your money where your mouth is JULIANNE STEIN, CONTENT CHANNEL MANAGER T Care, Healthy White, and Ultraclean — and an Ultraclean Access Flosser with a long ergonomic handle and nonslip grip. (www.listerine.com) Listerine Arm & Hammer We begin with several new Listerine products from McNeil-PPC. Did you know that tooth-brushing misses 75% of your mouth? So says the Listerine product literature. But Listerine Naturals Antiseptic Mouthwash “cleans virtually 100%.” Active ingredients include essential oils from such plant sources as the eucalyptus tree, Brazilian cornmint, wintergreen, and ajowan. Corn-based alcohol helps the essential oils penetrate plaque bioflm to kill the bacteria that cause gingivitis. This mouthwash has the Good Housekeeping Seal of Approval. (www.listerine.com) Listerine has launched three other mouthwashes — that is, mouth rinses — in its Healthy White line: Vibrant Rinse, Gentle Rinse, and Restoring Rinse. All three products promise to whiten teeth, restore enamel, and kill the germs that cause bad breath. (www.listerine.com) Also new from Listerine are four flosses — Cool Mint, Gentle Gum Church & Dwight is offering several new Arm & Hammer dental-care products, starting with the Truly Radiant product line, which includes a toothpaste, whitener, and brush. Truly Radiant Toothpaste combines baking soda, calcium, fuoride, and peroxide to remove stains, restore gloss, and “strengthen, clean, and repair tooth enamel for a radiant smile in just 5 days.” The added peroxide of the Truly Radiant Whitening Booster is said to boost the whiteness factor of one’s teeth in just two days. And the battery-powered dualaction of the Truly Radiant Deep Clean Spin Brush is said to whiten teeth and remove 100% more plaque and fve times more hard-to-reach plaque than a manual toothbrush will do, all at a “fraction of the cost of competing branded rechargeable brushes.” (www.trulyradiant.com) Designed for the younger set is Arm & Hammer’s Spinbrush GloBrush, which comes in “three different fun handle designs,” with a timer that lights 50 magenta cyan yellow black DRUG TOPICS Februar y 2015 up to signal the designated brushing time. After two minutes, it turns itself off. (www.armandhammer.com) Finally, Arm & Hammer’s Complete Care Plus Enamel Strengthening Toothpaste flls in dental crevices and rebuilds and strengthens enamel with a liquid calcium fuoride formula that provides “unsurpassed enamel strengthening at half the cost,” while baking soda whitens teeth and goes after the harmful acids that can weaken them. (www.armandhammer.com) Crest Folks who cringe, shudder, or shriek when they thoughtlessly dive into a bowl of ice cream or take an incautious sip of hot coffee can try Crest’s new SensiStop Strips. One side of each strip is coated with dipotassium oxalate gel, a desensitizing agent. For some people, just one strip, applied for 10 minutes to the problem area, may result in a month’s worth of relief. Three treatments should do it for most. (www.crest.com) White Glo New to the States is the White Glo product line from Australia, featuring an array of whitening toothpastes, bleach- PRODUCT IMAGES COURTESY OF MCNEIL-PPC / PROCTER & GAMBLE his month the subject is oral care, and we’ve rounded up a real grab bag of products designed to keep those pearly whites in tiptop condition. DrugTopics .c om ES567051_drtp0215_050.pgs 02.05.2015 20:25 ADV FEATURED THIS MONTH: ORAL CARE PRODUCT IMAGES COURTESY OF BARROS LABORATORIES / DR. FRESH The White Glo line of tooth-whitening products from Australia, including toothpastes, bleaching systems, brushes, and mouthwash, is due to hit retailer’s shelves at the end of the month. ing systems, whitening toothbrushes (the bristles are “extra-condensed”), and whitening mouthwash. Toothpastes include special formulations for Smokers and Coffee and Tea Drinkers; a Night & Day formula; whiteners featuring AntiPlaque agents and Herbal ingredients, respectively; and a 2in1 Whitening Toothpaste with Mouthwash. Whitening systems include Extreme Teeth Whitening Pen with Whitening Strips; Express Teeth Whitening System (it has a superstrong bleaching gel); and a Dual System tooth-whitener and stain-lifter combo. Also available are dental flosser toothpicks and a traveler’s pack of necessary items. By the end of the month, these products will be found at numerous retail outlets, including Costco, IGA, Supervalu chains, Albertsens, Bartell Drugs, Pharmaca, and Vitamin World. (www.whiteglo.com) Oral Essentials Last October, Kourosh Maddahi, DDS, a best-selling author and celebrity dentist in Beverly Hills, launched Oral Essentials Mouthwash, the first in a projected line of oral care products made without artificial dyes, flavors, or sweeteners. Main ingredients include aloe vera and Dead Sea salt (the salt prevents production of harmful toxins that cause infection and disease). The mouthwash is flavored with xylitol, a plant sugar. In DrugTopics .c om Product Updates Dr. Fresh’s latest offerings for children include the Firefly Star Wars Ready Go Brush (choice of Vader or Yoda), and a 40th anniversary tribute to Hello Kitty, Hello Kitty Anticavity Mouth Rinse. development are a toothpaste, dental floss, breath mints, and chewing gum. (http://oralessentials.com/) Organix-South ing (green), to keep going (yellow), or to stop (red). Suction cups keep the toothbrushes upright when not in use. Too cute for words is the pink Hello Kitty Anticavity Mouth Rinse bottle topped by a dispenser in the form of a little Hello Kitty head. The sugar- and alcohol-free mouthwash contains fluoride to fight cavities and protect enamel. It comes in a kid-friendly “melon-kiss” flavor and features a convenient “nomess” measuring cup at the bottom of the bottle that slides away when not in use. (www.fireflytoothbrush.com) First to launch in a new line of oral care products from Organix-South is the XyliVita toothbrush, available in four colors, with medium, soft, or extra-soft nylon bristles and a handle made from 100% biodegradable recycled materials. Other products soon to launch include vitamininfused Xylitol toothpastes, a toothpaste for sensitive teeth, a Multi-Care Mouthwash, and Xylitol whitening chewing gums. Advertiser Index (www.xylivita.com) Dr. Fresh The latest products for kids from Dr. Fresh include three toothbrushes and a mouthwash. The Firefly Star Wars Ready Go Brush comes in Darth Vader black and Yoda green, while the Firefly Hello Kitty Toothbrush is, of course, very pink. All three toothbrushes feature a light-up timer that functions like a little traffic light to tell children to begin brush- Accu-CHEK Aviva Roche Diagnostics Corp. 23A* Corporate Auburn Pharmaceuticals 21 Corporate Mylan Inc. CV4 Florajen American Lifeline CV3 Granix Teva Oncology 17B-18B* Hyslinga - ER Purdue Pharma 16A-17A* Nasacort Sanofi Aventis 37A* Neulasta Amgen Inc. 37B* Nexefed Acura Pharmaceuticals Prescription Compounding Kits Cutispharma Inc Testosterone Perrigo Gel 1% Valsartan Tablets Camber *Indicates a demographic advertisement. 25 CV2 3-4 27 Products & Services SHOWCASE Go to: products.modernmedicine.com COM PLIANCE SERVICE S View our DEMO NOW! www.prspharmacyservices.com/compliancetrack Search for the company name you see in each of the ads in this section for FREE INFORMATION! 52 magenta cyan yellow black DRUG TOPICS Februar y 2015 DrugTopics .c om ES567311_drtp0215_052_CL.pgs 02.05.2015 22:02 ADV Go to: products.modernmedicine.com E D U C AT I O N Book Offer: Nuts & bolts help for independent pharmacy operations • 80+pagesbasedon 40+yearsexperience • Seereviewby MarySheehan,R.Ph.at www.amazon.com [email protected] (800) 282-2318 Products & Services SHOWCASE FINANCING EXPANSION REMODELING ACQUISITION REFINANCE MARKETPLACE ADVERTISING KEEPING INDEPENDENTS INDEPENDENT You need a bank that shares your entrepreneurial PRODUCTS AND SERVICES PATRICK CARMODY at 440-891-2621 [email protected] spirit, understands the independent pharmacy business and wants to see you thrive. You’ve found your bank. Live Oak Bank. ÄÃɶ¸ÉÄÊǡĶä»IJ¸ºÇÈfor additional information. Jimmy Neil 910.212.4951 RECRUITMENT JOANNA SHIPPOLI at Whitney Bouknight 910.798.1205 (800) 225-4569 x 2615 E-mail: [email protected] Mike Bollinger 910.212.4953 liveoakbank.com • 877.890.5867 ©2015 Live Oak Banking Company. All rights reserved. Member FDIC Search for the company name you see in each of the ads in this section for FREE INFORMATION! DrugTopics .c om magenta cyan yellow black Februar y 2015 DRUG TOPICS ES567308_drtp0215_053_CL.pgs 02.05.2015 22:01 53 ADV MARKETPLACE Products & Services Brokers SEE MORE BROKERS ON NEXT PAGE! 54 magenta cyan yellow black DRUG TOPICS Februar y 2015 DrugTopics .c om ES567314_drtp0215_054_CL.pgs 02.05.2015 22:02 ADV MARKETPLACE Products & Services Brokers Continuing Education GETAWAY SEMINARS, INC. 1-888-573-6462 www.getawayseminars.com “Voted Among The TOP Seminar Programs By Pharmacists.” ACPE accredited by St. John’s University School of Pharmacy, NYC EARN 5 LIVE CREDITS PER DAY Classes from 8AM -1PM • Key West - Feb 13-15 • New Orleans- March 13-15 • Las Vegas - May 15-17 • Turks & Caicos All Inclusive - Jun 19-21 • Atlantis- July 24-26 • Alaskan Cruise - Aug 14-21 • Las Vegas - Sept 18-20 • Atlantic City - Oct 23-25 • South Beach Miami - Nov 20-22 Education Need to Pass NAPLEX ? ¨ Do the NAPLEX 3 Step with 2 ® 1 3 NAPLEX® Review QUICKCARDS¨ with Memoronics¨ plus Posters, Audio CD, Math Practice, Telephone quizzing, and Patient Profiles. Using Memory Techniques of: Visual Auditory Repetition Self Testing THE STUDY SYSTEM IS THE SOLUTION For details, please visit our website. www.prontopass.com PLACE YOUR AD HERE! MARKETPLACE CAN WORK FOR YOU! DrugTopics .c om magenta cyan yellow black Februar y 2015 DRUG TOPICS ES567380_drtp0215_055_CL.pgs 02.06.2015 00:56 55 ADV MARKETPLACE Products & Services Pharmacy Consulting MARKETPLACE ADVERTISING Selling Your Pharmacy… Are You Prepared? In our free webinar, you will ´nd answers to your questions, straight from the experts, as we prepare you for the sale of your pharmacy in every way possible. Sign up today for this amazing free tool! www.stillwellrx.com/webinar (855) 880-4722 FOR PRODUCTS AND SERVICES ADVERTISING: PATRICK CARMODY at 440-891-2621 Email: [email protected] FOR RECRUITMENT ADVERTISING: Joanna Shippoli at (800) 225-4569 x 2615 E-mail: [email protected] Content Licensing for Every Marketing Strategy Marketing solutions fit for: Outdoor | Direct Mail | Print Advertising Tradeshow/POP Displays | Social Media | Radio & TV Leverage branded content from Drug Topics to create a more powerful and sophisticated statement about your product, service, or company in your next marketing campaign. Contact Wright’s Media to fnd out more about how we can customize your acknowledgements and recognitions to enhance your marketing strategies. For information, call Wright’s Media at 877.652.5295 or visit our website at www.wrightsmedia.com 56 magenta cyan yellow black DRUG TOPICS Februar y 2015 DrugTopics .c om ES567313_drtp0215_056_CL.pgs 02.05.2015 22:02 ADV WHAT’S NEW Product Updates RX & OTC New products JULIANNE STEIN, CONTENT CHANNEL MANAGER 3 1 2 RX CARE PHOTOS COURTESY OF ABBVIE, NOVARTIS, PROMIUS PHARMA New drugs FDA has approved carbidopa/levodopa enteral suspension [1] (Duopa), AbbVie’s combination treatment for advanced Parkinson’s disease. Duopa remains effective for 16 hours, while a small portable infusion pump delivers a continuous dose straight to the small intestine. Patients can call 844-386-4968 to reach the DuoConnect support program. Some needy patients may be able to obtain Duopa at no cost. (www.abbvie.com). FDA has approved a long-acting capsule form of carbidopa-levodopa (Rytary; Impax Laboratories) to treat Parkinson’s disease, Parkinsonism, and post-encephalitic Parkinsonism after fnding a manufacturing facility inadequate and turning it down twice before. (www.rytary.com) FDA also recently aproved a fixeddose combination of memantine hydrochloride extended-release, an NMDA receptor antagonist, and donepezil hydrochloride, an acetylcholinesterase inhibitor (Namzaric; Actavis/Adamas), a new treatment for moderate-to-severe dementia in Alzheimer’s patients. This product will launch in the second quarter of the year. (www.namzaric.com) Symplemed has announced FDA approval of perindopril arginine/amlodipine besylate tablets (Prestalia), licensed from the French company Servier, for the treatment of hypertension in patients for whom monotherapy is inadequate. This DrugTopics .c om magenta cyan yellow black is the frst fxed-dose product to combine an ACE inhibitor and a calcium channel blocker. Symplmed’s bpCareConnect program (www.bpcareconnect.com), “caps blood pressure medication costs, provides monitoring devices, offers online tracking tools, and ships directly to the patients.” (www.prestalia-us.com) FDA has given accelerated approval to Novartis’ Meningococcal Group B Vaccine [recombinant, adsorbed]) (Bexsero), for administration to young people between the ages of 10 and 25, to prevent meningitis B, the leading cause of bacterial meningitis in the United States. Bexsero is now licensed in 37 countries. Since its frst approval in Europe, over one million doses have been distributed worldwide. (www.bexsero-us.com). Novartis has also announced FDA approval of injectable secukinumab [2] (Cosentyx) for treatment of moderateto-severe plaque psoriasis. Cosentyx is the frst approved human monoclonal antibody to selectively bind to IL-17A and inhibit its interaction with the IL-17 receptor that triggers the infammatory response. Patients can call 844-267-3689 to reach the Personal Support Program. (www.cosentyx.com) New generics Camber has launched valsartan tablets, USP, generic for Novartis’ Diovan, in doses of 40, 80, 160, and 320 mg, used to treat high blood pressure and heart failure. (www.camberpharma.com) Camber also launched zolmitriptan 2.5-mg and 5-mg tablets, generic for IPR’s Zomig tablets, used to treat migraine headaches. (www.camberpharma.com) Also from Camber: pantoprazole sodium delayed-release tablets USP, the generic version of Pfzer’s Protonix, used to treat gastroesophageal refux disease (GERD). (www.camberpharma.com) FDA has approved Ivax/Teva’s esomeprazole, the frst generic version of AstraZeneca’s Nexium, for treatment of GERD. (www.tevapharm.com) Teva has launched linezolid injection, the AP-rated bioequivalent to Pfzer’s Zyvox Injection, used to treat pneumonia and bacterial and skin structure infections. (www.tevapharm.com) Teva also has launched its own valsartan tablets, generic for Novartis’ Diovan. (www.tevapharm.com) NEW APP Isotretinoin use requires strict guidelines. Between March 1, 2010, and Feb. 28, 2011, over 400,000 attempts to fll isotretinoin prescriptions were denied due to failure to meet those guidelines. Promius Pharma, maker of Zenatane, has launched The Promius Promise App [3], to help patients comply. For information about the free download, go to http://zenatane.com. Februar y 2015 DRUG TOPICS 57 ES567048_drtp0215_057.pgs 02.05.2015 20:25 ADV Final Word IN MY VIEW Oluwole Williams, BS Pharm, PharmD Pharmacy ethics and corporate economic objectives Integrity of character and ethical behavior are indispensable to the profession of pharmacy. Corporations spend signifcant amounts on manpower development because they recognize the potential harm to their business operations that may result from employee ignorance, negligence, or sabotage. Beyond the very stiff sanctions prescribed by U.S. federal and state laws against acts of omission/commission in the provision of pharmacy dispensing services, company leaders are also aware that inappropriate employee conduct in matters of ethics may ruin the public image of the organization, attract signifcant fnes, and damage business goals. Not just the money Pharmacy has never been a profession for “gold-diggers.” It is an occupation for people who have genuine compassion and concern for those who need pharmaceutical care in their quest for good health. Human resources recruitment is a service critical to the future of pharmacy and to the survival of corporations in this economic sector. Pharmacy recruiters must be dedicated to the well-being of the patients who ultimately will be served. It is important, therefore, that this area of activity receive some form of scrutiny or regulation by federal and state departments of health, to prevent the emergence of unscrupulous elements that might be after pecuniary gain or involved in clandestine businesses with criminal intent, which could pose real danger to the health of the populace and to the welfare of pharmacists and related personnel. All healthcare providers This message applies not only to pharmacy staff recruitment and training; it applies equally to other healthcare personnel, including nurses, physicians, 58 magenta cyan yellow black DRUG TOPICS Februar y 2015 dental surgeons, ophthalmologists, podiatrists, ENT surgeons, and physiotherapists. Across the board, there must be no clandestine, sinister, parochial motives in the employment of healthcare providers; similarly, only people of proven integrity should be permitted to serve in recruitment frms/agencies that are engaged in manpower recruiting for the health sector. Just as the importation of fake drugs into this country poses a danger to the health of its people, and just as the widespread use of unregulated internet pharmacies from unscrupulous sources poses a danger to naïve consumers, so unscrupulous individuals can compromise the delivery of healthcare services. The responsibility lies with concerned professionals — pharmacists, medical doctors, dentists, etc. — to creatively assess and protect Americans from any potential harm to their health. image, attracting more business. 4. Declining gross profts and unfavorable government sanctions/ fnes may be effectively prevented through careful attention to employee needs and recruitment. 5. Expensive budget allocations to corporate advertising may not translate into business profits if by their behavior employees are sabotaging the business objectives of the corporation. 6. Poor accessibility to skilled manpower will result in business losses if the existing procedures and practices hamper a smooth delivery of professional services. 7. It is more effcient and proftable to have a suffciency of skilled manpower available at a moderate cost overall than to have a small population of overpaid personnel who are stretched beyond effectiveness. Human values = business values In summary, it is important for corporations in the healthcare industry to recognize that: 1. Employee training, recruitment, and supervision are critical elements in the survival/proftability of an organization. 2. Employee demeanor or misdemeanor, knowing or unknowing, can adversely affect the business goals and objectives of the organization. 3. A diligent, dedicated, honest, and well-educated workforce will have a positive effect on the corporation’s Best practices Pharmacists by their professional training and orientation are well equipped to meet the public’s need for healthcare, particularly in the areas of prescription dispensing and drug information services. Their professional skills should be carefully adapted to the business operations of the corporate body without jeopardy to their professional ethics or harm to the economic objective of the organizations they serve. Oluwole Williams practices pharmacy in the Philadelphia area. Contact him at [email protected]. DrugTopics .c om ES567060_drtp0215_058.pgs 02.05.2015 20:29 ADV There are 15 billion good reasons to keep Florajen probiotics in your pharmacy refrigerator. (instead of on the shelf) W e’ve known for over twenty years that a probiotic’s efficacy boils down to the right strains in the right potency, maintained through refrigeration. As the only probiotic company founded and managed by bacteriologists, we understand that our highly complex microbiome— home to over 100 trillion microbes—requires a highly potent probiotic to make a significant impact. That is why Florajen3 contains over 15 billion live cultures per capsule—potency that can only be maintained through constant refrigeration. Recommend Florajen when you fill antibiotic prescriptions, so there’s no confusion for your patient trying to locate the best choice in probiotics both in affordability and efficacy. Within easy reach right there in the pharmacy refrigerator, Florajen probiotics provide significantly more cells per dollar spent, meaning fewer antibiotic side effects, better compliance, and better patient outcomes. For more information, call 800-257-5433 or visit www.florajen.com! The Most Effective and Affordable Probiotics Refrigerated Available† for Freshness & Maximum Potency Available in pharmacists’ refrigerators and store coolers nationwide High Potency Probiotics www.florajen.com † Florajen contains more live probiotic and bile tolerant cells per dollar spent than any competitor. Statements have not been evaluated by the Food and Drug Administration. This product is not medicinal and is not intended to diagnose, treat, cure or prevent any disease. magenta cyan yellow black ©2015 American Lifeline, Inc. All rights reserved. 0215 ES567459_DRTP0215_CV3_FP.pgs 02.06.2015 01:54 ADV NOW AVAILABLE! Two Points of Reference. The 2014/2015 GBR ® —Generic Brand Reference—Guide, which contains a comprehensive, cross-referenced listing of generic and brand pharmaceuticals, is now available in print and as an app for Android™,* Apple® † and BlackBerry ® ‡ devices. To order the FREE print edition, go to Mylan.com/mylan-resources/access-gbr. To download the FREE app, scan the appropriate code or visit the app store for your device. Android Apple BlackBerry Mylan.com *Trademark of Google Inc. † Registered trademark of Apple, Inc. ‡ Registered trademark of Research in Motion (RIM). Copyright 2014 Mylan Inc. NON-2014-0329 MYNMKT544 10/14 magenta cyan yellow black ES567463_DRTP0215_CV4_FP.pgs 02.06.2015 01:55 ADV
