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USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category C: There are no adequate and well-controlled studies inpregnant women. ULORIC should be used during pregnancy only if the potentialbenefit justifies the potential risk to the fetus.Febuxostat was not teratogenic in rats and rabbits at oral doses up to 48 mg per kg(40 and 51 times the human plasma exposure at 80 mg per day for equal bodysurface area, respectively) during organogenesis. However, increased neonatalmortality and a reduction in the neonatal body weight gain were observed whenpregnant rats were treated with oral doses up to 48 mg per kg (40 times thehuman plasma exposure at 80 mg per day) during organogenesis and throughlactation period.Nursing MothersFebuxostat is excreted in the milk of rats. It is not known whether this drug isexcreted in human milk. Because many drugs are excreted in human milk, cautionshould be exercised when ULORIC is administered to a nursing woman.Pediatric UseSafety and effectiveness in pediatric patients under 18 years of age have notbeen established.Geriatric UseNo dose adjustment is necessary in elderly patients. Of the total number of subjectsin clinical studies of ULORIC, 16 percent were 65 and over, while 4 percent were75 and over. Comparing subjects in different age groups, no clinically significantdifferences in safety or effectiveness were observed but greater sensitivity ofsome older individuals cannot be ruled out. The C max and AUC 24 of febuxostatfollowing multiple oral doses of ULORIC in geriatric subjects ( 65 years) weresimilar to those in younger subjects (18-40 years).Renal ImpairmentNo dose adjustment is necessary in patients with mild or moderate renalimpairment (Cl cr 30-89 mL per min). The recommended starting dose of ULORICis 40 mg once daily. For patients who do not achieve a sUA less than 6 mg perdL after 2 weeks with 40 mg, ULORIC 80 mg is recommended.There are insufficient data in patients with severe renal impairment (Cl cr lessthan 30 mL per min); therefore, caution should be exercised in these patients.Hepatic ImpairmentNo dose adjustment is necessary in patients with mild or moderate hepaticimpairment (Child-Pugh Class A or B). No studies have been conducted inpatients with severe hepatic impairment (Child-Pugh Class C); therefore, cautionshould be exercised in these patients.Secondary HyperuricemiaNo studies have been conducted in patients with secondary hyperuricemia (includingorgan transplant recipients); ULORIC is not recommended for use in patients whomthe rate of urate formation is greatly increased (e.g., malignant disease and itstreatment, Lesch-Nyhan syndrome). The concentration of xanthine in urinecould, in rare cases, rise sufficiently to allow deposition in the urinary tract.OVERDOSAGEULORIC was studied in healthy subjects in doses up to 300 mg daily for sevendays without evidence of dose-limiting toxicities. No overdose of ULORIC wasreported in clinical studies. Patients should be managed by symptomatic andsupportive care should there be an overdose.CLINICAL PHARMACOLOGYPharmacodynamicsEffect on Uric Acid and Xanthine Concentrations: In healthy subjects, ULORICresulted in a dose dependent decrease in 24-hour mean serum uric acidconcentrations, and an increase in 24-hour mean serum xanthine concentrations.In addition, there was a decrease in the total daily urinary uric acid excretion.Also, there was an increase in total daily urinary xanthine excretion. Percentreduction in 24-hour mean serum uric acid concentrations was between 40% to55% at the exposure levels of 40 mg and 80 mg daily doses.Effect on Cardiac Repolarization: The effect of ULORIC on cardiac repolarizationas assessed by the QTc interval was evaluated in normal healthy subjects and inpatients with gout. ULORIC in doses up to 300 mg daily, at steady state, did notdemonstrate an effect on the QTc interval.Special PopulationsRenal Impairment: Following multiple 80 mg doses of ULORIC in healthy subjectswith mild (Cl cr 50-80 mL per min), moderate (Cl cr 30-49 mL per min) or severerenal impairment (Cl cr 10-29 mL per min), the C max of febuxostat did not changerelative to subjects with normal renal function (Cl cr greater than 80 mL per min).AUC and half-life of febuxostat increased in subjects with renal impairment incomparison to subjects with normal renal function, but values were similaramong three renal impairment groups. Mean febuxostat AUC values were up to1.8 times higher in subjects with renal impairment compared to those withnormal renal function. Mean C max and AUC values for 3 active metabolitesincreased up to 2- and 4-fold, respectively. However, the percent decrease inserum uric acid concentration for subjects with renal impairment wascomparable to those with normal renal function (58% in normal renal functiongroup and 55% in the severe renal function group).No dose adjustment is necessary in patients with mild to moderate renalimpairment [see Dosage and Administration and Use in Specific Populations].The recommended starting dose of ULORIC is 40 mg once daily. For patientswho do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg,ULORIC 80 mg is recommended. There is insufficient data in patients withsevere renal impairment; caution should be exercised in those patients [see Usein Specific Populations.ULORIC has not been studied in end stage renal impairment patients who areon dialysis.Hepatic Impairment: Following multiple 80 mg doses of ULORIC in patientswith mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepaticimpairment, an average of 20-30% increase was observed for both C max andAUC 24 (total and unbound) in hepatic impairment groups compared to subjectswith normal hepatic function. In addition, the percent decrease in serum uricacid concentration was comparable between different hepatic groups (62% inhealthy group, 49% in mild hepatic impairment group, and 48% in moderatehepatic impairment group). No dose adjustment is necessary in patients withmild or moderate hepatic impairment. No studies have been conducted insubjects with severe hepatic impairment (Child-Pugh Class C); caution shouldbe exercised in those patients [see Use in Specific Populations.NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityCarcinogenesis: Two-year carcinogenicity studies were conducted in F344 ratsand B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinarybladder was observed at 24 mg per kg (25 times the human plasma exposureat maximum recommended human dose of 80 mg per day) and 18.75 mg perkg (12.5 times the human plasma exposure at 80 mg per day) in male rats andfemale mice, respectively. The urinary bladder neoplasms were secondary tocalculus formation in the kidney and urinary bladder.Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomalaberration assay in a Chinese hamster lung fibroblast cell line with and withoutmetabolic activation in vitro. Febuxostat was negative in the in vitro Ames assayand chromosomal aberration test in human peripheral lymphocytes, and L5178Ymouse lymphoma cell line, and in vivo tests in mouse micronucleus, ratunscheduled DNA synthesis and rat bone marrow cells.Impairment of Fertility: Febuxostat at oral doses up to 48 mg per kg per day(approximately 35 times the human plasma exposure at 80 mg per day) had noeffect on fertility and reproductive performance of male and female rats.Animal ToxicologyA 12-month toxicity study in beagle dogs showed deposition of xanthine crystalsand calculi in kidneys at 15 mg per kg (approximately 4 times the human plasmaexposure at 80 mg per day). A similar effect of calculus formation was noted inrats in a six-month study due to deposition of xanthine crystals at 48 mg per kg(approximately 35 times the human plasma exposure at 80 mg per day).PATIENT COUNSELING INFORMATION[see FDA-Approved Patient Labeling in the full prescribing information]General InformationPatients should be advised of the potential benefits and risks of ULORIC. Patientsshould be informed about the potential for gout flares, elevated liver enzymes andadverse cardiovascular events after initiation of ULORIC therapy.Concomitant prophylaxis with an NSAID or colchicine for gout flares shouldbe considered.Patients should be instructed to inform their healthcare professional if theydevelop a rash, chest pain, shortness of breath or neurologic symptomssuggesting a stroke. Patients should be instructed to inform their healthcareprofessional of any other medications they are currently taking with ULORIC,including over-the-counter medications.Distributed byTakeda Pharmaceuticals America, Inc.Deerfield, IL 60015U.S. Patent Nos. - 6,225,474; 7,361,676; 5,614,520.ULORIC ® is a registered trademark of Teijin Pharma Limited and used underlicense by Takeda Pharmaceuticals America, Inc.All other trademark names are the property of their respective owners©2009 Takeda Pharmaceuticals America, Inc.February 2009For more detailed information, see the full prescribing information forULORIC (febuxostat) tablets (PI1114 R1; February 2009) or contactTakeda Pharmaceuticals America, Inc. at 1.877.825.3327.PI1114 R1-Brf; February 2009L-TXF-0209-3

Straight TalkPharmacy Technicians:Truth and ConsequencesWith the flu season quicklyapproaching, imagine anabsolutely unbearable workdayin your pharmacy. Anticipating theworst, you call in extra pharmacists andpharmacy technicians to help fill whatare expected to be some of the busiestprescription days of the year. Sureenough, on a typical day during the fluoutbreak, a line starts early at the prescriptiondrop-off counter and continuesto build throughout the day. Carsare stacked up at the drive-through prescriptionwindow as though McDonald’swere giving out free Big Macs. As physicians’offices open, the pharmacy’sphones ring incessantly with new prescriptionorders and permissions to refillolder prescriptions. Everyone is workingto their fullest capacity, which necessitatesextra effort from all pharmacy personnel.Pharmacists’ and technicians’fingers are furiously tapping the computerkeyboards trying to input data asquickly as possible while making sure important informationis accurately recorded into patients’ medicalrecords. Medication stock bottles are being pulledfrom every shelf in the pharmacy, with their tabletsand capsules ready to be poured out into the smallerprescription containers and bottles lined up on theprescription counter, each awaiting a label withinstructions to be affixed to it. Once filled, the prescriptionswill be checked by a pharmacist beforebeing dispensed to the patient. The pharmacy counteris a mess and resembles the trading floor of the NewYork Stock Exchange after a busy day, with notes onscrap paper strewn everywhere. Pharmacy techniciansand pharmacists line up to fill the waiting prescriptionbottles and vials like a General Motors assembly line.And then it happens. . . a pharmacy technician preparesa prescription that contains a fatal dose of themedication. Because of the craziness in the pharmacy,the error gets passed over by a pharmacist who is supposedto check each and every prescriptionbefore it is dispensed.A doomsday scenario, you say, thatwould never happen in your pharmacy?Maybe, but the truth is, it does happen,and it is more than likely that thepharmacist, not the technician, will paythe consequences of any error. Dependingon its severity, the error could resultin a hefty fine and prison time for thepharmacist. While the above scenariomay be fictitious, a case reported byU.S. Pharmacist’s legal contributor, JesseC. Vivian, BS Pharm, JD, in thismonth’s Legal Considerations column(page 66), is unfortunately all too real.In that case of a fatal error, the technicianwas charged with negligenthomicide but was given a “get out ofjail free” card by the court, wasn’t evenfined, and actually went back to workin a retail pharmacy. The pharmacist,however, was found guilty of involuntarymanslaughter and faced up to 5years in prison and a $10,000 fine. His license wasrevoked, and he will probably never work again as apharmacist. All this because he did not check theaccuracy of a prescription filled by the technician.The column should be a wake-up call for everypharmacist who works closely with one or more pharmacytechnicians. While it is true that each case ofnegligence involving a technician will be judged onthe merits of the case, the message is clear. The truthis that if a pharmacist is not diligent about checking atechnician’s work, the consequences could be dire.Harold E. Cohen, RPhEditor-in-Chiefhcohen@jobson.com4U.S. Pharmacist • November 2009 • www.uspharmacist.com

U.S. PharmacistWhat’s NewsEditorial Board of AdvisorsJoseph Bova, RPhCommunity Pharmacy Owner,Cary’s Pharmacy,Dobbs Ferry, New York;Member, NYS Board of PharmacyCarmen Catizone, RPhExecutive Director, National Associationof Boards of PharmacyJohn M. Coster, PhD, RPhSenior VP of Government AffairsNational Community Pharmacists Assoc.Hewitt (Ted) W. Matthews, PhDDean, Southern School of Pharmacy,Mercer University, AtlantaDavid G. Miller, RPhPharmacy Affairs, Merck & Co., Inc.,West Point, PennsylvaniaMario F. Sylvestri, PharmD, PhDSenior Director, Medical Science Liaisons,Amylin PharmaceuticalsRay A. Wolf, PharmDMedical Education, Sanofi AventisMary Ann E. Zagaria,PharmD, MS, CGPSenior Care Consultant andPresident, MZ Associates, Inc.,Norwich, New YorkContributing EditorsLoyd V. Allen, Jr., PhDConnie Barnes, PharmDBruce Berger, PhDR. Keith Campbell, RPh, CDEPatrick N. Catania, PhD, RPhR. Rebecca Couris, PhD, RPhEd DeSimone, PhD, RPhRonald W. Maddox, PharmDSomnath Pal, BS (Pharm), MBA, PhDW. Steven Pray, PhD, DPhM. Saljoughian, PharmD, PhDJesse C. Vivian, BS Pharm, JDSend your comments viaEDITOR@USPHARMACIST.COMMail: 160 Chubb Avenue, Suite 306Lyndhurst, NJ 07071Telephone: (201) 623-0999Editorial Dept. Fax: (201) 623-0991Internet: www.uspharmacist.comFDA Approves Gardasil for Genital Warts in Men and BoysSilver Spring, MD — The FDA approved the vaccine Gardasil for theprevention of genital warts resulting from the human papillomavirus (HPV)types 6 and 11 in boys and men age 9 through 26 years. A randomized trial of4,055 males age 16 through 26 showed that Gardasil was 90% effective inpreventing genital warts, and studies measuring the immune response of malesage 9 through 15 were equally positive. Each year, about two out of every1,000 men in the United States are diagnosed with genital warts. Gardasilcurrently is approved for use in girls and women age 9 through 26 for theprevention of cervical, vulvar, and vaginal cancer caused by HPV types 16 and18; precancerous lesions caused by types 6, 11, 16, and 18; and genital wartscaused by types 6 and 11. Most genital warts are caused by HPV infection,which is the most common sexually transmitted infection in the U.S.IMS Predicts 4% to 6% Global Pharma Market Growth Next YearNorwalk, CT — IMS Health reported that the value of the globalpharmaceutical market in 2010 is expected to grow 4% to 6% on aconstant-dollar basis, exceeding $825 billion. The forecast predicts globalpharmaceutical market sales to grow at a 4% to 7% compound annual ratethrough 2013, and considers the impact of the global macroeconomy, thechanging mix of innovative and mature products, and the rising influence ofhealth care access and funding on market demand. The value of the globalpharmaceutical market is expected to expand to $975+ billion by 2013.“Overall, market growth is expected to remain at historically low levels, butstronger-than-expected demand in the U.S. is lifting both our short- andlong-term forecasts,” said Murray Aitken, senior vice president, HealthcareInsight, IMS Health.FDA Warns About Illegal H1N1 Vaccines on the WebSilver Spring, MD — The FDA warned consumers about purchasing anyproducts over the Internet that claim to diagnose, prevent, treat, or cure theH1N1 influenza virus. The warning comes after the FDA recently purchasedand analyzed several products represented online as Tamiflu (oseltamivir) thatmay pose risks to patients. One of the orders, which arrived in an unmarkedenvelope with a postmark from India, consisted of unlabeled white tabletstaped between two pieces of paper. When analyzed by the FDA, the tabletswere found to contain talc and acetaminophen, but none of the activeingredient oseltamivir. The Web site disappeared shortly after the FDA placedthe order.Smoking Bans Reduce Heart Attack RiskWashington, DC — A report from the Institute of Medicine says thatsmoking bans are effective at reducing the risk of heart attacks and heartdisease associated with secondhand smoke. The report also provides evidencethat breathing secondhand smoke boosts the risk for heart problems innonsmokers, adding that there is evidence that relatively brief exposures couldlead to a heart attack. About 43% of nonsmoking children and 37% ofnonsmoking adults are exposed to secondhand smoke in the U.S., accordingto public health data.5U.S. Pharmacist • November 2009 • www.uspharmacist.com

the cause of bipolar symptoms. Therapy for bipolar disorder often includes individual, group, and familytherapy to help patients and their friends and family understand the triggers, early signs, and treatmentof this condition.HEALTH SYSTEMS EDITIONVol. 34 No. 11TEAR ALONG PERFORATIONPATIENT TEACHING AIDBipolarDisorderNOVEMBER 2009The Journal for Pharmacists’ EducationU.S. Pharmacist is a Peer-Reviewed JournalDramatic High andLow Mood SwingsBipolar disorder, sometimes ca led manic depression,is a mental i lne s that is described as a fluctuationin mood extremes. Patients with bipolar disorder mayexperience high (mania) and low (depression) moodswings that are dramatic, seriously a fecting their livesand the lives of those around them. The cla sic picture of bipolar disorder includes swings from high tolow moods and back again, with each swing lasting from weeks to months and often with periods ofnormal mood in between the extremes. During mania, patients are often agitated, speeding throughtheir days with increased activity, little sleep, erratic behavior, and problems concentrating or stayingfocused. During depression, feelings of exhaustion, hopelessness, and futility are common, sometimeswith suicidal thoughts.The cause of bipolar disorder is most likely an imbalance in brain chemicals that a fect mood. Thisimbalance may be hereditary, since there is an increased risk of bipolar disorder and schizophreniawithin families. Diagnosis depends on a thorough history of mood and behavior in the past. Althoughabout 1% of the population has been diagnosed with bipolar disorder, the actual number of people isprobably much higher due to misdiagnosis.Without treatment, bipolar disorder is a debilitating condition that wi l not improve on its own.The goal of treatment is to stabilize the patient’s mood to avoid drastic and damaging mood swings.There are a variety of medications that act to even out the imbalance of brain chemicals thought to beCopyright Jobson Medical Information LLC, 2009 continuedIllustration: © 2009 Teri J. McDermott, MA, CMICOVER IMAGE:TeriMcDermott.comAs part of the reward pathway in alcoholuse, endorphins are released. Naltrexoneblocks the binding of endorphins to opioidreceptors, preventing dopamine release.CE CREDITSEmergency Contraception:An Update of Clinical andRegulatory Changes. See page 70THIS MONTHEditorial Focus: PsychotropicsNEXT MONTHEditorial Focus:Gastroenterologic DiseasesEarn additional CE credits online. Visit:www.uspharmacist.comCE PROGRAMS ON THEU.S. PHARMACIST WEB SITENew:Emergency Contraception: An Updateof Clinical and Regulatory ChangesRecent:Ovarian Cancer: One of theCommon Gynecologic MalignanciesPerimenopause: Managementof Common Symptoms Duringthe Menopausal TransitionAn Update on the CurrentTreatment of HIVIf you have any questions about ourCE programs, call (800) 825-4696,fax (212) 219-7849, or e-mailcecustomerservice@jobson.com.FEATURESSenior CareProgressive Supranuclear Palsy ...20Difficulty looking up without extending theneck or trouble using the stairs may be an initialsymptom of this condition.Mary Ann E. Zagaria, PharmD, MS, CGPSo Many Options, So LittleDifference in Efficacy: What Is theAppropriate Antidepressant? ...... 26These agents are equal in effectiveness, but itis hard to predict which one will work best fora given patient.Marjorie Rochette DeLucia, PharmD, MS,and Michael J. Schuh, PharmD, MBAMedications Used in OpioidMaintenance Treatment ............ 40It is important to keep abreast of currenttherapeutic options as increasingly morepatients are treated for dependence.Christie Choo, PharmD, BCPSHEALTH SYSTEMS EDITIONPTA0911 Bipolar 10_14scbo.indd 1 10/15/09 12:24 PMPATIENT TEACHING AIDBipolar Disorder. See page 17Pharmacologic Managementof Alcohol Dependence ............. 60Several medications are available that may helppatients achieve abstinence and avoid relapse.Krina H. Patel, PharmDPharmacy LawCriminalization ofMedication Errors ............ 66A recent case equating a pharmacist’s mistakewith manslaughter raises the question of pharmacytechnician responsibility.Jesse C. Vivian, BS Pharm, JD●2 CE CreditsEmergency Contraception:An Update of Clinical andRegulatory Changes ................ 70Current information about levonorgestrel-basedemergency birth control and strategies for educatingconsumers are discussed.Kathleen H. Besinque, PharmD, MSEdSchizophrenia: A Review of Pharmacologic andNonpharmacologic Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HS-2Pharmacists should play an active role in the management of this complicated form of mental illness.Stacy Eon, PharmD, and Jennifer Durham, PharmDProphylactic Therapies in Traumatic Brain Injury Management . . . . . HS-10Clear guidelines for the proper administration of drugs used to treat this condition are lacking.Jennifer Confer, PharmD, and Jon Wietholter, PharmDNewly Approved mTOR Inhibitors for the Treatment ofMetastatic Renal Cell Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . HS-20Temsirolimus and everolimus are now indicated as therapy for this type of cancer.Diana Hey Cauley, PharmD, BCOPIn-Service PrimersNutrition and Clinical Depression . . . . . . . . . . . . . . . . . . . . . . . . . . HS-28Manouchehr Saljoughian, PharmD, PhDU.S. PHARMACIST ® (ISSN 01484818; USPS No. 333-490) is published monthly by Jobson Medical Information LLC, 100 Avenue of the Americas, New York, NY 10013-1678. Periodicals postagepaid at New York, and additional mailing offices. Postmaster: Send address changes to U.S. PHARMACIST, P.O. Box 2027, Skokie, IL 60076-7927. Canada Post: Publications Mail Agreement #40612608.Canada Returns to be sent to Bleuchip International, P.O. Box 25542, London, ON N6C 6B2. Subscriptions: One-year subscription rate: USA $58.00; Faculty and Students at U.S. Colleges of Pharmacy$39.00; Canada $81.00 (U.S.); and air mail to all other countries $157.00. Single copies are $6.00 each. All subscriptions payable in U.S. dollars. Payment must accompany order. Send checks andsubscription requests to U.S. PHARMACIST, P.O. Box 2027, Skokie, IL 60076-7927 or call Customer Service:1-877-529-1746 (U.S. only) or 1-847-763-9630. Copyright 2009 by Jobson MedicalInformation LLC, 100 Avenue of the Americas, New York, NY 10013-1678. Reproduction of articles without permission from the publisher is expressly prohibited. Acceptance of advertising by U.S.PHARMACIST does not constitute endorsement of the advertiser, its products or services. The opinions, statements and views expressed by contributors to U.S. PHARMACIST are the authors’ and donot necessarily reflect those of the publisher, editor-in-chief, editors, editorial board of advisors, or the staff of U.S. PHARMACIST.6U.S. Pharmacist • November 2009 • www.uspharmacist.com

Q. Which Global Generic Company’s TransdermalPatches Were Most Dispensed in the U.S.Last Year?A. Mylan Pharmaceuticals.*With one of the most advanced transdermal development and manufacturing facilities in theUnited States—brand or generic—Mylan is well-recognized as an innovator in transdermaldrug delivery technology. In fact, last year 65% of all generic patches dispensed in the U.S.carried the Mylan name.*We have developed more generic transdermal patches than any company in the U.S. and allof our patches are designed with patient safety in mind. None have a bulky, liquid, gel-filledreservoir, which eliminates any concern about the dangers associated with leakage, andnone have aluminum or other metals in their backing, which may cause potential burns inMRI patients. So when you need generic transdermal patches…think Mylan.*IMS National Prescription Audit. 12 months ending December 2008.©2009 Mylan Pharmaceuticals Inc. MYNMKT308

U.S. PharmacistA Jobson PublicationSenior Vice President–Editor-in-ChiefHarold E. Cohen, RPhExecutive EditorRobert DavidsonSenior EditorBonnie OstrowskiSenior Associate EditorMarjorie BordenNOVEMBER 2009The Journal for Pharmacists’ EducationU.S. Pharmacist is a Peer-Reviewed JournalVol. 34 No. 11Projects EditorNancy Robertson, MSConsulting Clinical EditorMary Gurnee, PharmD, RPhSenior Vice President–PublisherHarold E. Cohen, RPh (201) 623-0982Associate PublisherJack McAleer (201) 623-0987East Coast Regional Sales ManagerMark Hildebrand (201) 623-0984Midwest/West Regional Sales ManagerMegan Conley (773) 450-7339Marketing ManagerDeborah Mortara (201) 623-0990Classified Advertising SalesHeather Brennan (800) 983-7737 x106Design DirectorSharyl Sand CarowProduction ManagerDina Romano (201) 623-0942Corporate Production DirectorJohn Anthony CaggianoDirector, Continuing Education ProcessingRegina Combs (800) 825-4696Vice President, Circulation DirectorEmelda BareaVice President,Creative Services and ProductionMonica TettamanziChief Executive OfficerJeff MacDonaldChief Financial OfficerDerek WinstonCEO, Information Services DivisionMarc FerraraSenior Vice President, OperationsJeff LevitzVice President, Human ResourcesLorraine OrlandoU.S. Pharmacist160 Chubb Avenue, Suite 306Lyndhurst, NJ 07071Tel: (201) 623-0999Fax: (201) 623-0991E-mail: editor@uspharmacist.comWeb: www.uspharmacist.comPrinted on paper containing anaverage of 96 percent post-consumerrecycled waste.DEPARTMENTSStraight TalkPharmacy Technicians:Truth and Consequences . . . . . . 4Harold E. Cohen, RPhWhat’s News. . . . . . . . . . . . . . 5TrendWatchAcute Negative FeelingsAmong Adults . . . . . . . . . . . . 10Nonpositive beliefs and emotions generallyoccur to a similar degree across age groups.Somnath Pal, BS (Pharm), MS, MBA, PhDWorthlessnessHelplessnessRestlessnessSadness“Everything isan effort”NervousnessPrevalence of Selected Acute Negative Feelings2.93.75.26.73.17.94.210.13.04.92.63.57.33.97.42.79.63.10 5 10 15 20 25 30 35 40Percentage of adults surveyed© JUPITERIMAGES7.97.98.47.57.418-44 years45-64 years65-74 years75+ years8.4Consult Your PharmacistFatigue and Drowsiness:Everyday Exhaustionand Beyond . . . . . . . . . . . . . . 12Prolonged tiredness and sleepiness are aconcern for many people.W. Steven Pray, PhD, DPhFDA Fast Facts . . . . . . . . . . . 24Generic Trends . . . . . . . . . . . 54ContemporaryCompoundingKetamine Hydrochloride10-mg Troches . . . . . . . . . . . 58In lozenge form, this analgesic andanesthetic agent can be prepared to suitthe patient’s individual flavor preference.Loyd V. Allen, Jr, PhDClassified Advertising . . . . . . 80Career and business opportunities, products,and services for the pharmacist.Product News . . . . . . . . . . . . 82New Products in This IssueAfinitor / Novartis Pharmaceuticals Corporation • Authorized Generics / Greenstone LLC •Embeda / King Pharmaceuticals • Kapidex / Takeda Pharmaceuticals • Onglyza / AstraZeneca •Uloric / Takeda Pharmaceuticals • Welchol / Daiichi-SankyoHealth Systems Edition: Distinctive Labeling / Baxter Healthcare • Injectables / Pfizer Injectables •Product Labeling / Teva Pharmaceuticals8U.S. Pharmacist • November 2009 • www.uspharmacist.com

If key productsare missing from yourmulti-source topical inventoryperhaps you shouldrely on the specialist.E. FOUGERA & CO.A division of Nycomed US Inc., Melville, NY 11747 • Toll free: 800-645-9833 • www.fougera.com © 2009 Fougera. All rights reserved. Iss. 9/09

TrendWatchAcute Negative FeelingsAmong AdultsThe 2007 NationalHealth InterviewSurvey for noninstitutionalizedadults provides anunderstanding ofthe prevalence ofacute feelings ofsadness, hopelessness,worthlessness,or nervousness orthat everything isan effort.Sadness, Hopelessness,Worthlessness,or EverythingFeeling Likean Effort: Tenpercent of respondentsexperiencedsadness; 6% felthopeless; 5% feltworthless; and 13% feltthat everything was aneffort. Twelve percent ofwomen felt sad, comparedwith 8% of men.More non-Hispanicblack respondents thannon-Hispanic whiterespondents felt thateverything is an effort.The highest percentageof respondents withthese feelings had lessthan a high-schooldiploma, and respondentsleast likely to haveSomnath Pal,BS (Pharm), MBA, PhDProfessor of PharmacyAdministration, College ofPharmacy & Allied HealthProfessions, St. John’s University,Jamaica, New YorkWorthlessnessHelplessnessRestlessnessSadness“Everything isan effort”NervousnessPrevalence of Selected Acute Negative Feelings2.93.75.26.73.17.94.210.13.04.92.63.57.33.97.42.79.6these feelings had atleast a bachelor’s degree.Adults in poor familieswere twice as likely asadults in families thatwere better off to feelsad, hopeless, worthless,or that everything is aneffort.Among respondentsunder age 65 years, 25%of those with Medicaidcoverage experiencedfeelings of sadness, comparedwith 15% of thosewho were uninsured and6% of those who hadprivate health insurance.Among individuals aged65 years and over, 19%of those with Medicaidand Medicare coverageexperienced feelings of3.10 5 10 15 20 25 30 35 40Percentage of adults surveyed© JUPITERIMAGES7.97.98.47.57.418-44 years45-64 years65-74 years75+ years8.4sadness, compared with11% of those with onlyMedicare coverage and8% of those with privatehealth insurance.Divorced respondentswere more likely thanother respondents to feelsad or that everything isan effort.Feelings of Nervousnessor Restlessness: Thirteenpercent of respondentsexperienced nervousness,and 15% reported restlessness.Sixteen percentof women felt nervous,versus 11% of men.Non-Hispanic whiterespondents had morefeelings of nervousnessthan non-Hispanic blackrespondents. Thehighest percentageof adults withthese feelings hadless than a highschooldiploma;those least likelyto have these feelingspossessed abachelor’s degreeor higher. Adultsin poor familieswere more likelyto feel nervousthan adults infamilies that werebetter off.Among individualsunder age 65years, 26% ofthose with Medicaidcoverage experiencedfeelings ofnervousness, comparedwith 15% of those whowere uninsured and 12%of those who had privatehealth insurance. Amongadults aged 65 years andover, 25% of those withMedicaid and Medicarecoverage experiencedfeelings of nervousness,versus 11% of those whohad only Medicare coverageand 11% of thosewith private healthinsurance. Adults whowere married were leastlikely to have feelings ofnervousness or restlessness,compared withadults who weredivorced or separated,never married, or livingwith a partner.10U.S. Pharmacist • November 2009 • www.uspharmacist.com

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Consult Your PharmacistFatigue and Drowsiness:Everyday Exhaustion and BeyondFatigue and drowsinessare a part ofeveryday life for millionsof people, and prolongedfatigue is a concern for10% to 25% of thosewho visit general practitioners.1 The high incidenceof fatigue is due tosuch issues as today’shectic lifestyle, lack ofleisure time, poor sleephabits, and certain medicalconditions. Pharmacistsare in an ideal positionto provide assistanceto patients complainingabout continual fatigueand daytime drowsiness.FatigueFatigue is commonlyexperienced and is thefeeling of tiredness orexhaustion that follows ahard day of work ormentally and physicallychallenging exercise. 2,3Patients may also complainthat they are weary,that their energy is gone,or that they feel lack ofmotivation to accomplishother tasks.Counseling PatientsWith Fatigue: Whencounseling patients withfatigue, the pharmacistW. Steven Pray, PhD, DPhBernhardt Professor, NonprescriptionProducts and DevicesCollege of Pharmacy, SouthwesternOklahoma State UniversityWeatherford, OklahomaCaffeine's stimulant effect is well known and is the primary reasonfor its ubiquitous use. The dose approved as safe and effective is100 to 200 mg, not more often than every 3 to 4 hours.© JUPITERIMAGESshould first attempt toascertain whether thefatigue is a normalresponse to overwork ora continual problem thatseems unrelated to theamount or extent ofeffort performed thatday, week, or month. Ifit is the former, theproblem is probably ashort-term, minor difficultythat will resolve onits own once the stressorshave subsided. However,if the patient is able tosleep normally but stillexperiences continualfatigue that seems unrelatedto ongoing mentalor physical stress, thefatigue may be secondaryto medications or a medicalcondition. 3 Forexample, patients withhypothyroidism complainthat they awakenrefreshed, but that activityresults in rapid onsetof fatigue. 3Causes of Fatigue:Fatigue can be caused bya wide variety of medicalconditions. 1,3,4 As manyas 40% of those reportingsymptoms of chronicfatigue were eventuallydiscovered to have a psychiatricor medical conditionthat had not yetbeen diagnosed but wasultimately treated successfully.4 Etiologiesinclude premenstrualsyndrome, premenstrualdysphoric disorder, allergicrhinitis, asthma, anemias,hypo- or hyperthyroidism,Addison’sdisease, fibromyalgia,arthritis, lupus, cancer,Parkinson’s disease, congestiveheart failure, diabetes,conditions causingpersistent pain, infections(e.g., AIDS, mononucleosis),renal disease,and hepatic disease. 4-8Depression and griefinduce fatigue. Sleep disorderscause fatigue,including insomnia, narcolepsy,and obstructivesleep apnea. Alcohol andother drugs of abuse(e.g., cocaine, narcotics)cause fatigue, and thepatient may find thatmaking healthier lifestylechoices will resolve theproblem. Malnutritionleads to fatigue, as doanorexia and other eatingdisorders. The wide spectrumof potential etiologiesmakes it critical forpharmacists to referpatients with unexplainedfatigue to a physicianfor a full medicalevaluation.Chronic FatigueSyndrome: Chronicfatigue syndrome (CFS)is a cause of chronictiredness that affects 1 to4 million Americans. 4 Itsramifications are profound,in that one-fourthof sufferers are notemployed and many arereceiving disability benefits.It differs from normalfatigue in its sever-12U.S. Pharmacist • November 2009 • www.uspharmacist.com

✁PATIENT INFORMATIONCombating Fatigue and DrowsinessEveryone has felt tired or sleepy during the day.Undue tiredness may be caused by a number ofserious medical conditions, so if simple advice orOTC products containing caffeine do not help, it iswise to see a physician.© JUPITERIMAGESSteps YouCan TakeBefore you take anymedications for fatigueand drowsiness, youmay wish to try somerelatively easy solutions.You should not go tobed and arise at oddtimes or at differenttimes each day. Thebest advice is to set atime for going to bedand also for arising andtry to stick to them asmuch as possible.Everyone has experiencedthe “fun” of stayingup till 4 AM or laterand then sleeping inuntil noon the next day.Even 8 hours of sleepcannot fool your bodyinto normalcy, and youwill feel the effects ofyour altered schedulethe next day. In addition,strive to get atleast 7 to 8 hours ofsleep a night. Trying toget through the nextday without adequatesleep leads to daytimedrowsiness that is amajor cause of fatalautomobile accidents.Avoid stimulants suchas caffeine or oral nasaldecongestants (e.g.,Sudafed) too close tobedtime, as the stimulanteffect may notallow you to drop off tosleep at the right time,leaving you fatigued thefollowing day.You should alwayseat a healthy, balanceddiet and drink sufficientwater to keep fullyhydrated. Avoid allalcohol, nicotine, anddrugs of abuse. If youhabitually drink caffeine-containingsoftdrinks, coffee, or tea,try to reduce theamount or eliminatethem completely todetermine whether theyare responsible for atired feeling. Youshould also be aware ofany medications you aretaking that may causedrowsiness, such asantihistamines, antihypertensives,corticosteroids,diuretics, andsleep aids.PHARMACY STAMPOne method toreduce fatigue is toreduce life stresses. Itmay be necessary tochange from a job thatcauses severe stress toone that allows a morerelaxing day of work.When you have sparetime, do not spend itplaying high-stress videogames that require splitsecondtiming and fastreflexes. Instead, go for awalk, read a book, orhave a pleasant conversationwith family andfriends. If you are caughtin a relationship that isfraught with problems,deal with them directlyor end the relationship.NonprescriptionMedicationsThe only pharmacyproduct proven safe andeffective in helpingfight fatigue and drowsinessis caffeine, foundin such OTC productsas Vivarin and NoDoz.Each caplet or tabletcontains 200 mg of caffeine.Take one dosenot more often thanevery 3 to 4 hours.These products are onlysafe for those aged 12years and above. Theyare not a substitute forhealthy sleep andshould never be used tokeep you awake allnight. They should notbe used if you are pregnantor breastfeedingwithout speaking toyour physician first.Energy DrinksAvoid the use of thepopular energy drinks.Virtually all containingredients of unknownsafety and effectiveness,such as herbs anddietary supplements.One contains suchunproven ingredients asginkgo, guarana, inositol,L-carnitine, ginseng,and milk thistle.Using products such asthese is a risky gamblewith your health, sincethey can have adverseeffects and are notproven to provide a safeboost of energy.Remember, if you have questions, Consult Your Pharmacist.13U.S. Pharmacist • November 2009 • www.uspharmacist.com

Consult Your Pharmacistity, in the incapacitatingfeeling that patientsexperience, and in thefact that bed rest doesnot relieve it. 1,9 Thedegree of fatigue limitsor halts social engagements,educationalefforts, work, and personalactivity. Studiesfrom the CDC revealthat the disabling effectsof CFS rival those ofsuch overwhelming conditionsas chronicobstructive pulmonarydisease (COPD), rheumatoidarthritis, lupus,multiple sclerosis, heartdisease, and end-stagerenal disease.The degree of disabilityvaries widely amongpatients and in the samepatient from episode toepisode. Some patientsexperience periods wherethey are relatively free ofsymptoms, followed by aperiod of extreme disability.1 This cyclical patternis often seen with CFS.To meet the formaldiagnosis of CFS,patients should haveexperienced symptomsfor 6 months or more. 1Further, the fatigue isnot caused by any underlyingmedical conditionsand is accompanied bysuch nonspecific ancillarysymptoms as sorethroat, joints that arepainful but lack erythemaor inflammation,unrelenting muscle pain,headaches that differfrom the norm in severityor symptoms, andlymph node tenderness(axillary or cervical). 1Patients do not feelrefreshed after sleep, andthey also notice thatphysical or mental exerciseproduces a malaisethat persists for morethan 24 hours. Theirability to concentrate ontasks is reduced, andtheir memory isimpaired. These arereferred to as the eightsymptoms that defineCFS.Treatment options forCFS are diverse and ofvariable use. The CDCurges practitioners toadapt treatment plans tothe individual patient’spresent symptoms. 10Sleep disturbances maybe initially treated withsimple sleep hygienemeasures, followed bynonprescription antihistaminesleep aids such asSominex and Unisom. Ifthese medications areneeded beyond 14 days,however, the patientshould be urged to seekcare from a physician.Muscle and joint painWhat’s in Red Bull?The popular product known as Red Bull claims to be an“energy drink.” The company Web site does not directlystate that the taurine (an amino acid) in the product providesenergy, but it does mention other beneficialeffects. 13 It says that “one can of Red Bull Energy Drinkcontains approximately the same amount of caffeine as acup of coffee,” a vague statement that should be clarifiedto disclose the exact amount. The drink also containsglucuronolactone, B vitamins, sucrose, and glucose.Patients should not assume that its formula is safer ormore effective than caffeine alone.and headache may beamenable to nonprescriptionacetaminophen, ibuprofen,or naproxen.The CDC alertspatients to the fallaciesof using nutritional andherbal supplements forCFS. 10 Although somepatients report relieffrom these products,they are not regulated bythe FDA, and thusobjective data to provetheir efficacy and safetyare often lacking. TheCDC warns patientsagainst such herbs ascomfrey, ephedra, kava,germander, chaparral,bitter orange, licoriceroot, and yohimbine dueto reports of toxicitycoupled with lack of efficacydata. 10The CDC also mentionsthe use of alternativetherapies such asacupuncture, aquatictherapy, gentle massage,meditation, deep breathing,biofeedback, yoga,and tai chi. 10 The agencyurges patients to discussthese options with ahealth care provider tomake sure that they havebeen proven safe andeffective.Medications That CauseFatigue: Medicationsthat are reported to causefatigue include antihistamines,antihypertensives,corticosteroids, diuretics,and sleep aids for insomnia.2 Some agents inducetoxic myopathy that canlead to fatigue. 11 If prescriptionmedications aresuspected to be the causeof fatigue or of CFS,patients should be askedto visit their prescriberfor a full evaluation andconsideration of alternativemedications.DrowsinessDrowsiness differs fromfatigue in that it is a subjectivefeeling that sleepis needed. A patient maynot be tired at all, butfalls prey to an overwhelmingneed for sleepat an inappropriate timeor in an inappropriatesituation. 12Counseling PatientsWith Drowsiness: It isnormal to experiencedrowsiness after inadequatesleep because thepatient has a “sleep debt.”However, some patientscomplain of abnormalsleepiness in spite of havingobtained sufficientsleep the night before.The pharmacist can questionthese patients abouttheir sleep patterns, howmuch they normally14U.S. Pharmacist • November 2009 • www.uspharmacist.com

Consult Your Pharmacistsleep, whether they snore,and whether their bedpartner complains thatthey have episodes ofbreathing cessation duringthe night (sleepapnea). If the answers tothese are unrevealing, thepatient should be urgedto visit a physician, whomay conduct sleep studiesto determine the rootcause of this abnormaldrowsiness. If thepatient’s habits seem todemonstrate poor sleep,interrupted sleep, orinadequate sleep, he orshe should be advised toadopt the principles ofsleep hygiene. Patientsmay be asked whetherthey are depressed, anxious,stressed, or sufferinggeneral life boredom. Atrial of antidepressantsmay help some of thesepatients.Causes of Drowsiness:Drowsiness may becaused by such widelyvarying etiologies asrotating shift work,sedating medications(e.g., antihistamines,antidepressants, painmedications), hypothyroidism,hypercalcemia,hyponatremia or hypernatremia,sleep apnea,and narcolepsy. 12NonprescriptionProductsIn addition to helpingpatients uncover thesources of fatigue ordrowsiness and referringthem when appropriate,pharmacists can also recommendnonprescriptiontreatment. The onlymedication found to besafe and effective for selfusewhen used as labeledis caffeine. 2 Caffeine’sstimulant effect is wellknownand is the primaryreason for its ubiquitousrecreational use.The stimulant doseapproved as safe andeffective is 100 to 200mg, not more often thanevery 3 to 4 hours. 2Products include Vivarinand NoDoz, both containing200 mg of caffeineper tablet/caplet.These products are notto be recommended foranyone under the age of12 years.Labels will warnpatients that these productscontain approximatelyas much caffeineas a cup of coffee andthat they should limit orstop caffeine use whiletaking them. Failure todo so could lead to nervousness,sleeplessness,irritability, and tachycardia.Of course, a cup ofcoffee can contain widelydivergent amounts ofcaffeine, so the FDAwarning is only an estimatefor consumer use.Labels warn patients thatthese products are foroccasional use only andthat they will not substitutefor sleep. Furthermore,if drowsiness orfatigue persists or recurs,patients should consulttheir physician. Theseproducts are not to beused if the patient ispregnant or breastfeeding.Their optimal use isfor patients who are performingboring, repetitivetasks that lead toinattention (e.g., assembly-linework). They mayalso be useful to maintainmaximal attentivenessduring driving.Some patients arealready consuming therecommended amount ofcaffeine in the form ofcoffee, tea, and softdrinks. Eight ounces ofbrewed coffee contains135 mg of caffeine, andthe same amount ofbrewed tea contains 50mg. 2 A 12-oz can ofCoca-Cola or Pepsi-Colacontains 34 to 38 mg ofcaffeine, where theamount in other softdrinks may be as high as55 mg/12 oz. A patientwho drinks several cansof caffeinated soft drinksdaily, along with a 20-ozcup of coffee from apopular coffee chain likeStarbucks (480 mg ofcaffeine) is already consuminga considerableamount of stimulant. 2The 200 mg in a singleNoDoz or Vivarin maynot be enough to provideany benefit beyond thealready high daily intakeand could lead tounwanted effects.ConclusionFatigue and drowsinessare common medicalconditions that can becaused by a host of seriousdisorders. Unless thecause is trivial and shortterm,the patient shouldbe referred to a physicianfor a full evaluation.REFERENCES1. Chronic fatigue syndrome.Symptoms. CDC. www.cdc.gov/cfs/cfssymptomsHCP.htm. AccessedSeptember 30, 2009.2. Pray WS. Nonprescription ProductTherapeutics. 2nd ed. Baltimore,MD: Lippincott Williams &Wilkins; 2006.3. Fatigue. National Library of Medicine.www.nlm.nih.gov/medlineplus/ency/article/003088.htm.Accessed September 30, 2009.4. Chronic fatigue syndrome. Background.CDC. www.cdc.gov/cfs/.Accessed September 30, 2009.5. Zanni GR. Diagnosing and treatingfibromyalgia. Consult Pharm.2009;24:572-589.6. Cuatrecasas G. Fibromyalgic syndromes:could growth hormone therapybe beneficial? Pediatr EndocrinolRev. 2009;6(suppl 4):529-533.7. Rapkin AJ, Winer SA. Premenstrualsyndrome and premenstrualdysphoric disorder: quality of lifeand burden of illness. Expert RevPharmacoecon Outcomes Res.2009;9:157-170.8. Lou JS. Physical and mentalfatigue in Parkinson’s disease:epidemiology, pathophysiology andtreatment. Drugs Aging.2009;26:195-208.9. Chronic fatigue syndrome.National Library of Medicine.www.nlm.nih.gov/medlineplus/chronicfatiguesyndrome.html.Accessed September 30, 2009.10. Chronic fatigue syndrome.Treatment options. CDC. www.cdc.gov/cfs/cfstreatmentHCP.htm.Accessed September 30, 2009.11. Dalakas MC. Toxic and druginducedmyopathies. J Neurol NeurosurgPsychiatry. 2009;80:832-838.12. Drowsiness. National Library ofMedicine. www.nlm.nih.gov/medlineplus/ency/article/003208.htm.Accessed September 30, 2009.13. Red Bull Energy Drink.Ingredients. www.redbull.com/cs/Satellite/en_INT/Products/Red-Bull-Energy-Drink-021242751115866?p=1242745950125. AccessedSeptember 30, 2009.15U.S. Pharmacist • November 2009 • www.uspharmacist.com

Use as directed.FOR YOURPATIENTS WITHHYPERTENSIONRECOMMEND COLD MEDICINEWITH A HEART.Tell your patients about the onlycold brand that won’t raise theirblood pressure: Coricidin ® HBP.Like many of your patients, S. Epatha Merkerson has hypertension. Since decongestants are contraindicated forhypertensive patients, they need to be careful when they get a cold. So assure your patients that Coricidin HBP is the smartchoice because it’s decongestant-free and specially made to relieve cold symptoms without raising blood pressure.Recommend the full line of products from Coricidin HBP. Powerful cold medicine with a heart.Schering-Plough, maker of Coricidin ® HBP,sponsors the AHA High Blood Pressure website.©2009 Schering-Plough HealthCare Products, Inc.

PATIENT TEACHING AIDBipolarDisorderTEAR ALONG PERFORATIONDramatic High andLow Mood SwingsBipolar disorder, sometimes called manic depression,is a mental illness that is described as a fluctuationin mood extremes. Patients with bipolar disorder mayexperience high (mania) and low (depression) moodswings that are dramatic, seriously affecting their livesand the lives of those around them. The classic picture of bipolar disorder includes swings from high tolow moods and back again, with each swing lasting from weeks to months and often with periods ofnormal mood in between the extremes. During mania, patients are often agitated, speeding throughtheir days with increased activity, little sleep, erratic behavior, and problems concentrating or stayingfocused. During depression, feelings of exhaustion, hopelessness, and futility are common, sometimeswith suicidal thoughts.The cause of bipolar disorder is most likely an imbalance in brain chemicals that affect mood. Thisimbalance may be hereditary, since there is an increased risk of bipolar disorder and schizophreniawithin families. Diagnosis depends on a thorough history of mood and behavior in the past. Althoughabout 1% of the population has been diagnosed with bipolar disorder, the actual number of people isprobably much higher due to misdiagnosis.Without treatment, bipolar disorder is a debilitating condition that will not improve on its own.The goal of treatment is to stabilize the patient’s mood to avoid drastic and damaging mood swings.There are a variety of medications that act to even out the imbalance of brain chemicals thought to bethe cause of bipolar symptoms. Therapy for bipolar disorder often includes individual, group, and familytherapy to help patients and their friends and family understand the triggers, early signs, and treatmentof this condition.Copyright Jobson Medical Information LLC, 2009continued

PATIENT TEACHING AIDMedications Can Level the Extremesand Restore a More Normal MoodBipolar disorder can occur in several symptom patterns. Theseinclude cyclothymia (mild mood swings), bipolar I (one periodof mania sometimes following a period of depression), and themost common form, bipolar II (at least one period of mild orhypomania and one period of depression). When mania anddepression occur together, it is called mixed-state bipolar disorder.Identifying Symptoms: Bipolar symptoms typically begin inthe late teens to early 30s and are first seen after a significantThe manic phase is characterizedby euphoria, racing thoughts, andimpulsiveness.stressful or traumatic event. The tendency to develop this disease may be hereditary in some cases,since many families have more than one member with this condition.Symptoms of mania include excitation, exhilaration, feelings of self-importance, confusion,racing thoughts, problems concentrating, little interest in food or rest, and impulsiveness. Thesesymptoms take a toll on the physical and mental health of the patient. Since thoughts arejumbled and the mood is euphoric, patients often make poor decisions that make little sense.Psychosis can also be a symptom. During a psychotic episode, patients see or hear things thatdo not exist (hallucinations), or believe things that are not in touch with reality (delusions).Symptoms of depression include feelings of hopelessness and despondency, with little interestin activities that were once pleasurable. During the depressive phase of bipolar disorder, manypatients have problems eating and sleeping, feel nervous and irritable, and consider suicide.Seeking Help: Most patients with bipolar disorder recognize that they have a problem, but notall seek help. This is for a variety of reasons. Bipolar disorder is considered a mental illness, whichmay evoke feelings of shame and inadequacy. Many patients also do not want to treat their moodswings with medications. However, the only reliable and effective treatment for bipolar disorder ismedication to level the extremes and restore a more normal mood. Without therapy, bipolar disorderwill only worsen with time. Untreated, it can lead to serious depression and suicide, problemswith functioning in life, and drug or alcohol addiction. That is why it is important for patients tofind support in family, friends, and therapists who can help them lead a productive, normal life.Therapy for bipolar disorder can include individual therapy to help patients understand thecondition and care for themselves, group therapy to help patients understand how others are sufferingfrom this condition, and family therapy to educate patients’ loved ones about the disorderand what to do when they observe the beginnings of mood swings that patients may or may notnotice themselves.Drug therapy for bipolar disorder includes medications that rebalance the chemicals in the brainthat affect mood, thereby equalizing mood. The medication cannot be discontinued during periodsof normal mood, since bipolar disorder is a chronic condition that requires treatment of symptomsas well as prevention of symptoms. Although younger patients may not accept the idea of a lifetimeof medication, eventually they begin to understand its importance after suffering serious relapseswhen they discontinue therapy.Drug therapy for bipolar disorder might start out with lithium, quetiapine, or an antiseizuremedicine such as valproic acid. These drugs help stabilize mood and avoid swings. Some patientsmay require additional medicine for psychosis (antipsychotics such as risperidone or olanzapine)or sleep aids. Many doctors find that a combination of medicines that work in different ways isthe most effective treatment. All drugs take a period of weeks to months to work best, and sometimesdoses need to be increased or decreased to work better while avoiding side effects. Once theright drug therapy is established, patients need to be aware of the importance of continuing theirmedicines to avoid future episodes of mania or depression.

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HEALTH SYSTEMS EDITIONSchizophreniaA Review ofPharmacologic andNonpharmacologicTreatments© JUPITERIMAGESPatients with mental illness constitute a populationthat can be challenging for any health care provider,but they offer great opportunities for a pharmacistto make a meaningful contribution. The pharmacist’srole might involve assisting in the selection of medicationregimens, managing adverse drug reactions, orfacilitating adherence. These interventions can be particularlyimportant for patients with schizophrenia.DIAGNOSIS AND CLINICAL PRESENTATIONSchizophrenia is a chronic, debilitating mental illnessthat affects approximately 1% of the population. 1 Owingto the 10% lifetime prevalence of suicide in patientswith the disorder, early recognition and appropriatetreatment are imperative. 2 Schizophrenia typically presentsin late adolescence and persists throughout thepatient’s life, and males typically experience symptoms5 to 7 years earlier than females. 1,3Symptoms of schizophrenia may be classified as positive,negative, or cognitive. Positive symptoms includedisorganized speech or behavior and psychotic characteristicssuch as delusions or hallucinations. Delusions,or fixed false beliefs, occur when a patient misinterpretsan experience, leading toerroneous beliefs involving paranoiaor persecution. Hallucinations involvemore vivid sensory disruptions, withauditory hallucinations being themost common. 1,3 Negative symptoms,including affective flattening, alogia,avolition, and reduced social driveStacy Eon, PharmDPGY2 Pharmacy Resident in PsychiatryUniversity of North Carolina HospitalsChapel Hill, North CarolinaJennifer Durham, PharmDClinical PharmacistMoses Cone Memorial HospitalGreensboro, North Carolina(see TABLE 1), involve the diminution or absence ofnormal functions; they often are refractory to treatment.3,4 Cognitive symptoms are highly prevalent andmay include difficulties with verbal fluency, attention,and working memory. 3 Antipsychotic medicationshave little effect on cognitive symptoms; as aresult, these symptoms affect a patient’s ability to obtainemployment, establish personal relationships, and functionin many social settings. 3According to Diagnostic and Statistical Manual ofMental Disorders-IV-TR criteria, a patient can bediagnosed with schizophrenia if he or she presents withat least two of the following symptoms in addition tosocial dysfunction for a significant amount of time duringa 1-month period, with some symptoms persistingfor at least 6 months: delusions, hallucinations, disorganizedspeech, grossly disorganized or catatonicbehavior, or negative symptoms. 4 The diagnosis canalso be made solely on the basis of bizarre delusionsor hallucinations involving voices. 4PATHOPHYSIOLOGYAlthough the neurochemistry behind schizophrenia isnot fully understood, the disorder isthought to be caused by increaseddopaminergic transmission. 1 Thisincrease in dopamine effect causes thebrain to be hypersensitive to stimuli,making it difficult for the patientto distinguish between reality and hisor her delusions or hallucinations. 1HS-2U.S. Pharmacist • November 2009 • www.uspharmacist.com

IN THE TREATMENT OF MRSA BACTEREMIA AND MRSA COMPLICATED SKIN INFECTIONSINSIDE.OUTSIDE.ON HIS SIDE.n Landmark clinical trial of CUBICIN 6 mg/kg once daily demonstratedefficacy in S. aureus bacteremia caused by MRSA and MSSAn Proven clinical success of CUBICIN 4 mg/kg once daily in S. aureuscomplicated skin infections —both MRSA and MSSAINDICATIONS AND IMPORTANT SAFETY INFORMATIONCUBICIN is indicated for the following infections:Complicated skin and skin structure infections caused by susceptibleisolates of the following Gram-positive microorganisms: S. aureus (includingmethicillin-resistant isolates), Streptococcus pyogenes, Streptococcusagalactiae, Streptococcus dysgalactiae subspecies equisimilis, andEnterococcus faecalis (vancomycin-susceptible isolates only). Combinationtherapy may be clinically indicated if the documented or presumedpathogens include Gram-negative or anaerobic organisms.S. aureus bloodstream infections (bacteremia), including those withright-sided infective endocarditis, caused by methicillin-susceptible andmethicillin-resistant isolates. Combination therapy may be clinically indicatedif the documented or presumed pathogens include Gram-negative oranaerobic organisms.The efficacy of CUBICIN in patients with left-sided infective endocarditis dueto S. aureus has not been demonstrated. The clinical trial of CUBICIN inpatients with S. aureus bloodstream infections included limited data frompatients with left-sided infective endocarditis; outcomes in these patientswere poor. CUBICIN has not been studied in patients with prosthetic valveendocarditis or meningitis.Patients with persisting or relapsing S. aureus infection or poor clinicalresponse should have repeat blood cultures. If a culture is positive forwww.cubicin.com©2007 Cubist Pharmaceuticals, Inc.3974071907 September 2007CUBICIN is a registered trademark of Cubist Pharmaceuticals,Inc.S. aureus, MIC susceptibility testing of the isolate should be performedusing a standardized procedure, as well as diagnostic evaluation to ruleout sequestered foci of infection. Appropriate surgical intervention (eg,debridement, removal of prosthetic devices, valve replacement surgery)and/or consideration of a change in antibiotic regimen may be required.CUBICIN is not indicated for the treatment of pneumonia.Clostridium difficile-associated diarrhea (CDAD) has been reported with theuse of nearly all antibacterial agents, including CUBICIN, and may range inseverity from mild diarrhea to fatal colitis. CDAD has been reported to occurover 2 months post-antibiotic treatment. If CDAD is suspected, antibiotictreatment may need to be suspended.Patients receiving CUBICIN should be monitored for the development ofmuscle pain or weakness, particularly of the distal extremities. In patientswho receive CUBICIN, creatine phosphokinase (CPK) levels should bemonitored weekly, and more frequently in patients who received recent prioror concomitant therapy with an HMG-CoA reductase inhibitor. In patientswith renal insufficiency, both renal function and CPK should be monitoredmore frequently. Patients who demonstrate unexplained elevations in CPKwhile receiving CUBICIN should be monitored more frequently.CUBICIN should be discontinued in patients with unexplained signs andsymptoms of myopathy in conjunction with CPK elevation >1000 U/L(~5X ULN), or in patients without reported symptoms who have markedelevations in CPK >2000 U/L (≥10X ULN).Most adverse events reported in CUBICIN clinical trials were mild to moderatein intensity. The most common CUBICIN adverse events were anemia,constipation, diarrhea, nausea,vomiting, injection-site reactions,and headache.Please see Brief Summaryof Prescribing Informationon adjacent page.

Brief summary of prescribing information.INDICATIONS AND USAGE CUBICIN (daptomycin for injection) is indicatedfor the following infections (see also DOSAGE AND ADMINISTRATION andCLINICAL STUDIES in full prescribing information): Complicated skinand skin structure infections (cSSSI) caused by susceptible isolatesof the following Gram-positive microorganisms: Staphylococcus aureus(including methicillin-resistant isolates), Streptococcus pyogenes, S. agalactiae,S. dysgalactiae subsp equisimilis, and Enterococcus faecalis (vancomycin-susceptibleisolates only). Combination therapy may be clinicallyindicated if the documented or presumed pathogens include Gram-negativeor anaerobic organisms. Staphylococcus aureus bloodstream infections(bacteremia), including those with right-sided infective endocarditis,caused by methicillin-susceptible and methicillin-resistant isolates. Combinationtherapy may be clinically indicated if the documented or presumedpathogens include Gram-negative or anaerobic organisms. The efficacy ofCUBICIN in patients with left-sided infective endocarditis due to S. aureushas not been demonstrated. The clinical trial of CUBICIN in patients withS. aureus bloodstream infections included limited data from patients withleft-sided infective endocarditis; outcomes in these patients were poor (seeCLINICAL STUDIES in full prescribing information). CUBICIN has not beenstudied in patients with prosthetic valve endocarditis or meningitis. Patientswith persisting or relapsing S. aureus infection or poor clinical responseshould have repeat blood cultures. If a culture is positive for S. aureus,MICsusceptibility testing of the isolate should be performed using a standardizedprocedure, as well as diagnostic evaluation to rule out sequestered fociof infection (see PRECAUTIONS). CUBICIN is not indicated for the treatmentof pneumonia. Appropriate specimens for microbiological examinationshould be obtained in order to isolate and identify the causative pathogensand to determine their susceptibility to daptomycin. Empiric therapy maybe initiated while awaiting test results. Antimicrobial therapy should beadjusted as needed based upon test results. To reduce the developmentof drug-resistant bacteria and maintain the effectiveness of CUBICIN andother antibacterial drugs, CUBICIN should be used only to treat or preventinfections that are proven or strongly suspected to be caused by susceptiblebacteria.When culture and susceptibility information are available, theyshould be considered in selecting or modifying antibacterial therapy. In theabsence of such data, local epidemiology and susceptibility patterns maycontribute to the empiric selection of therapy.CONTRAINDICATIONS CUBICIN is contraindicated in patients withknown hypersensitivity to daptomycin.WARNINGS Clostridium difficile–associated diarrhea (CDAD) has beenreported with use of nearly all antibacterial agents, including CUBICIN,and may range in severity from mild diarrhea to fatal colitis. Treatmentwith antibacterial agents alters the normal flora of the colon, leading toovergrowth of C. difficile. C. difficile produces toxins A and B, which contributeto the development of CDAD. Hypertoxin-producing strains of C.difficile cause increased morbidity and mortality, since these infectionscan be refractory to antimicrobial therapy and may require colectomy.CDAD must be considered in all patients who present with diarrhea followingantibiotic use. Careful medical history is necessary because CDADhas been reported to occur over 2 months after the administration ofantibacterial agents. If CDAD is suspected or confirmed, ongoing antibioticuse not directed against C. difficile may need to be discontinued.Appropriate fluid and electrolyte management, protein supplementation,antibiotic treatment of C. difficile, and surgical evaluation should be institutedas clinically indicated.PRECAUTIONS General The use of antibiotics may promote the selectionof non-susceptible organisms. Should superinfection occur during therapy,appropriate measures should be taken. Prescribing CUBICIN in the absenceof a proven or strongly suspected bacterial infection is unlikely to providebenefit to the patient and increases the risk of the development of drugresistantbacteria. Persisting or Relapsing S. aureus Infection Patientswith persisting or relapsing S. aureus infection or poor clinical responseshould have repeat blood cultures. If a culture is positive for S. aureus,MICsusceptibility testing of the isolate should be performed using a standardizedprocedure, as well as diagnostic evaluation to rule out sequestered fociof infection. Appropriate surgical intervention (eg, debridement, removal ofprosthetic devices, valve replacement surgery) and/or consideration of achange in antibiotic regimen may be required. Failure of treatment due topersisting or relapsing S. aureus infections was assessed by the AdjudicationCommittee in 19/120 (15.8%) CUBICIN-treated patients (12 withMRSA and 7 with MSSA) and 11/115 (9.6%) comparator-treated patients(9 with MRSA treated with vancomycin and 2 with MSSA treated with antistaphylococcalsemi-synthetic penicillin). Among all failures, 6 CUBICINtreatedpatients and 1 vancomycin-treated patient developed increasingMICs (reduced susceptibility) by central laboratory testing on or followingtherapy. Most patients who failed due to persisting or relapsing S. aureusinfection had deep-seated infection and did not receive necessary surgicalintervention (see CLINICAL STUDIES in full prescribing information).Skeletal Muscle In a Phase 1 study examining doses up to 12 mg/kgq24h of CUBICIN for 14 days, no skeletal muscle effects or CPK elevationswere observed. In Phase 3 cSSSI trials of CUBICIN at a dose of 4 mg/kg,elevations in CPK were reported as clinical adverse events in 15/534(2.8%) CUBICIN-treated patients, compared with 10/558 (1.8%) comparator-treatedpatients. In the S. aureus bacteremia/endocarditis trial, at adose of 6 mg/kg, elevations in CPK were reported as clinical adverseevents in 8/120 (6.7%) CUBICIN-treated patients compared with 1/116(500 U/L) at baseline, 2/19 (10.5%) treated with CUBICIN and 4/24(16.7%) treated with comparator developed further increases in CPK whileon therapy. In this same population, no patients developed myopathy.CUBICIN-treated patients with baseline CPK >500 U/L (N=19) did not experiencean increased incidence of CPK elevations or myopathy relative tothose treated with comparator (N=24). In the S. aureus bacteremia/endocarditisstudy, 3 (2.6%) CUBICIN-treated patients, including 1 with traumaassociated with a heroin overdose and 1 with spinal cord compression, hadan elevation in CPK >500 U/L with associated musculoskeletal symptoms.None of the patients in the comparator group had an elevation in CPK>500 U/L with associated musculoskeletal symptoms. CUBICIN should bediscontinued in patients with unexplained signs and symptoms of myopathyin conjunction with CPK elevation >1,000 U/L (~5x ULN), or in patientswithout reported symptoms who have marked elevations in CPK >2,000U/L (10x ULN). In addition, consideration should be given to temporarilysuspending agents associated with rhabdomyolysis, such as HMG-CoAreductase inhibitors, in patients receiving CUBICIN. In a Phase 1 study examiningdoses up to 12 mg/kg q24h of CUBICIN for 14 days, no evidenceof nerve conduction deficits or symptoms of peripheral neuropathy wasobserved. In a small number of patients in Phase 1 and Phase 2 studies atdoses up to 6 mg/kg, administration of CUBICIN was associated withdecreases in nerve conduction velocity and with adverse events (eg, paresthesias,Bell’s palsy) possibly reflective of peripheral or cranial neuropathy.Nerve conduction deficits were also detected in a similar number of comparatorsubjects in these studies. In Phase 3 cSSSI and communityacquiredpneumonia (CAP) studies, 7/989 (0.7%) CUBICIN-treated patientsand 7/1,018 (0.7%) comparator-treated patients experienced paresthesias.New or worsening peripheral neuropathy was not diagnosed in any ofthese patients. In the S. aureus bacteremia/endocarditis trial, a total of11/120 (9.2%) CUBICIN-treated patients had treatment-emergent adverseevents related to the peripheral nervous system. All of the events wereclassified as mild to moderate in severity; most were of short duration andresolved during continued treatment with CUBICIN or were likely due to analternative etiology. In animals, effects of CUBICIN on peripheral nerve wereobserved (see ANIMAL PHARMACOLOGY in full prescribing information).Therefore, physicians should be alert to the possibility of signs and symptomsof neuropathy in patients receiving CUBICIN. Drug InteractionsWarfarin Concomitant administration of CUBICIN (6 mg/kg q24h for 5days) and warfarin (25 mg single oral dose) had no significant effect on thepharmacokinetics of either drug, and the INR was not significantly altered.As experience with the concomitant administration of CUBICIN and warfarinis limited, anticoagulant activity in patients receiving CUBICIN and warfarinshould be monitored for the first several days after initiating therapy withCUBICIN (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions infull prescribing information). HMG-CoA Reductase Inhibitors Inhibitorsof HMG-CoA reductase may cause myopathy, which is manifested asmuscle pain or weakness associated with elevated levels of CPK. Therewere no reports of skeletal myopathy in a placebo-controlled Phase 1 trialin which 10 healthy subjects on stable simvastatin therapy were treatedconcurrently with CUBICIN (4 mg/kg q24h) for 14 days. In the Phase 3 S.aureus bacteremia/endocarditis trial, 5/22 CUBICIN-treated patients whoreceived prior or concomitant therapy with an HMG-CoA reductase inhibitordeveloped CPK elevations >500 U/L. Experience with co-administration ofHMG-CoA reductase inhibitors and CUBICIN in patients is limited; therefore,consideration should be given to temporarily suspending use of HMG-CoAreductase inhibitors in patients receiving CUBICIN (see ADVERSEREACTIONS, Post-Marketing Experience). Drug-Laboratory TestInteractions There are no reported drug-laboratory test interactions.Carcinogenesis, Mutagenesis, Impairment of Fertility Long-termcarcinogenicity studies in animals have not been conducted to evaluate thecarcinogenic potential of daptomycin. However, neither mutagenic norclastogenic potential was found in a battery of genotoxicity tests, includingthe Ames assay, a mammalian cell gene mutation assay, a test for chromosomalaberrations in Chinese hamster ovary cells, an in vivo micronucleusassay, an in vitro DNA repair assay, and an in vivo sister chromatid exchangeassay in Chinese hamsters. Daptomycin did not affect the fertility orreproductive performance of male and female rats when administeredintravenously at doses up to 150 mg/kg/day, which is approximately 9times the estimated human exposure level based upon AUCs. PregnancyTeratogenic Effects: Pregnancy Category B Reproductive and teratologystudies performed in rats and rabbits at doses of up to 75 mg/kg, 2 and4 times the 6 mg/kg human dose, respectively, on a body surface areabasis, have revealed no evidence of harm to the fetus due to daptomycin.There are, however, no adequate and well-controlled studies in pregnantwomen. Because animal reproduction studies are not always predictive ofhuman response, this drug should be used during pregnancy only if clearlyneeded. Nursing Mothers It is not known if daptomycin is excreted inhuman milk. Caution should be exercised when CUBICIN is administered tonursing women. Pediatric Use Safety and efficacy of CUBICIN in patientsunder the age of 18 have not been established. Geriatric Use Of the 534patients treated with CUBICIN in Phase 3 controlled clinical trials of cSSSI,27.0% were 65 years of age or older and 12.4% were 75 years of age orolder. Of the 120 patients treated with CUBICIN in the Phase 3 controlledclinical trial of S. aureus bacteremia/endocarditis, 25.0% were 65 years ofage or older and 15.8% were 75 years of age or older. In Phase 3 clinicalstudies of cSSSI and S. aureus bacteremia/endocarditis, lower clinical successrates were seen in patients 65 years of age compared with those

SCHIZOPHRENIA: A REVIEW OF TREATMENTSTable 1Glossary of SomeSchizophrenia SymptomsAffective flattening: restricted emotional expressionAkathisia: uncontrollable motor restlessnessAlogia: restricted speechAvolition: lack of goal-directed behaviorDystonia: abnormal muscle tone, e.g., rigidityPseudoparkinsonism: drug-induced syndromeresembling parkinsonismResearchers continue to explore the roles that neurotransmittersother than dopamine, such a serotonin andacetylcholine, might play in schizophrenia. 1TREATMENTOwing to the complex nature of schizophrenia, treatmenttypically involves both pharmacologic and nonpharmacologictherapies.Nonpharmacologic TherapiesAlthough nonpharmacologic interventions may be perceivedas treatment modalities that cannot change thebiochemistry of schizophrenia, they can help patientslearn how to cope with their illness. Fostering healthyrelationships, maintaining employment, learning fromothers who struggle with mental illness, and participatingin cognitive behavioral therapy can all beeffective components of a patient’s treatment. 5A 2-year randomized study compared the effect ofintegrated treatment versus standard treatment in547 newly diagnosed schizophrenia patients. Standardtreatmentpatients were offered access to a communitymental-health center and received minimal home visits;integrated-treatment patients received home visitsfrom an assigned assertive community-treatment teammember and were offered family treatment sessions andsocial-skills training. Both arms were offered antipsychoticmedications. Patients in the integrated-treatmentarm showed clinically significant improvementin positive and negative symptoms and substance abuse,but no improvement in depression or suicidal behavior.The integrated-treatment group had a statisticallysignificant decrease in hospital stays during the firstyear, but the difference was not significant at 2 years.Finally, the mean antipsychotic dose for patients in theintegrated-treatment arm was significantly lower. 6 Thistrial illustrates that psychiatric care has a positive impacton a patient’s life when pharmacotherapy is augmentedwith lifestyle coaching and family involvement.PharmacotherapyMost patients with schizophrenia require chronic treatmentwith medications to control symptoms and achieveremission. Once a patient attains a satisfactory clinicalresponse, the regimen should continue indefinitely.First-line medication options include first- and secondgenerationantipsychotics. 1First-Generation Antipsychotics (FGAs): FGAs, alsoknown as conventional or typical antipsychotics, workvia dopamine receptor antagonism. 1 TABLE 2 includesa list of FGAs. This class of antipsychotics is associatedwith movement disorders, including extrapyramidalsymptoms (EPS) and tardive dyskinesia (TD). Symptomsof EPS include akathisia, dystonia, andpseudoparkinsonism (see TABLE 1). Akathisia can betreated either by lowering the antipsychotic dosage orwith benzodiazepines or centrally acting beta-blockerssuch as propranolol; dystonia and pseudoparkinsonismcan be treated with anticholinergic agents suchas benztropine or diphenhydramine. 1 TD, which typicallypresents as abnormal orofacial movements, developsin 30% of patients on long-term FGAs. UnlikeEPS, TD cannot be treated with medications, and itmay be irreversible even after the offending antipsychoticis discontinued. 1Second-Generation Antipsychotics (SGAs): WhereasFGAs work primarily as dopamine-2 receptor antagonists,the mechanisms are much broader for SGAs (alsoknown as atypical antipsychotics). In addition to havingan antagonistic effect on dopamine, SGAs alsoantagonize norepinephrine and serotonin receptors(TABLE 2). Aripiprazole has a unique mechanism ofaction involving mixed dopaminergic agonism andantagonism in addition to antagonism of serotonergicreceptors. 1Owing to serotonergic antagonism, SGAs are notassociated with high rates of EPS, with the exceptionof aripiprazole, which causes akathisia in approximately10% of patients. 7 Although patients taking SGAsusually do not experience movement-disorder issues,SGAs come with new risks that may negatively affectpatient adherence. Clozapine and olanzapine areassociated with metabolic syndrome, specifically weightgain, diabetes, and dyslipidemia; other atypical antipsychotics,however, offer minimal to no risk of thesemetabolic effects. 8 Clozapine also carries a risk ofseizures, anticholinergic effects, hypersalivation, myocarditis,and agranulocytosis. 9 The incidence of agranulocytosisin patients taking clozapine is 0.39%, and theincidence of death from agranulocytosis is 0.012%. 10The FDA requires all providers prescribing clozapineto be registered with the Clozaril National Registry.Absolute neutrophil counts must be monitored weeklyfor 6 months when therapy is initiated or adjusted, andcontinuously throughout the course of therapy. 1 Risperidoneand paliperidone are associated with hyperprolactinemia,leading to acute adverse events such as galac-HEALTH SYSTEMS EDITIONHS-5U.S. Pharmacist • November 2009 • www.uspharmacist.com

SCHIZOPHRENIA: A REVIEW OF TREATMENTSHEALTH SYSTEMS EDITIONTable 2Dosing of Conventional and Atypical AntipsychoticsDrug Name Starting Daily Dose Target Daily Dose or Range ScheduleConventional Antipsychotics (FGAs)Chlorpromazine (Thorazine) 50-100 mg 300-1,000 mg 3 times daily aFluphenazine (Prolixin) 5 mg 5-20 mg 3 times daily aHaloperidol (Haldol) 2-5 mg 2-20 mg 1-3 times daily aPerphenazine (Trilafon) 4-8 mg 16-64 mg 3 times daily aThiothixene (Navane) 4-10 mg 15-20 mg 2-3 times daily aTrifluoperazine (Stelazine) 4-10 mg 5-20 mg Twice daily aAtypical Antipsychotics (SGAs)Aripiprazole (Abilify) 10-15 mg 10-15 mg Once dailyClozapine (Clozaril) 12.5-25 mg 300-450 mg 1-2 times dailyIloperidone (Fanapt) 2 mg 12-24 mg Twice daily aOlanzapine (Zyprexa) 5-10 mg 20 mg Once dailyPaliperidone (Invega) 6 mg 6 mg Once dailyRisperidone (Risperdal) 2 mg 2-8 mg 1-2 times daily aQuetiapine IR (Seroquel IR) 50 mg 300-400 mg 2-3 times dailyQuetiapine XR (Seroquel XR) 300 mg 400-800 mg Once dailyZiprasidone (Geodon) 40 mg 40-160 mg Twice daily, with foodLong-Acting Depot InjectionsFluphenazine decanoate 12.5-25 mg IM 6.25-50 mg IM Every 1-3 wk(Prolixin Decanoate) every 1-3 wk every 2-4 wkHaloperidol decanoate 25-50 mg IM 50-200 mg IM Every 3-4 wk(Haldol Decanoate) every 2-4 wk every 2-4 wkRisperidone (Risperdal Consta) 12.5 mg IM every 2 wk 25 mg IM every 2 wk Every 2 wkaThe total daily dose of most antipsychotics can be administered once daily if tolerated. Exceptions are clozapine, quetiapine, andziprasidone, which likely will require multiple daily doses to control symptoms.FGA: first-generation antipsychotic; IM: intramuscularly; SGA: second-generation antipsychotic.Source: Reference 22.torrhea (spontaneous flow of milk from nipple), amenorrhea(absence of menses), and sexual dysfunction.Osteoporosis may be a long-term effect of hyperprolactinemia.9,11Both conventional and atypical agents, particularlyhaloperidol, chlorpromazine, iloperidone, thioridazine,and ziprasidone, are associated with prolongation ofthe QTc interval, with the last two agents having thehighest incidence. 9,12,13 The incidence of QTc prolongationwith these agents is approximately twice thatof a healthy population not taking antipsychotics. 14Providers must always consider the side effects of antipsychoticsand discuss them with their patients prior toprescribing.There is very little literature supporting the idea thatSGAs are more effective than FGAs. A number of metaanalyseshave been published comparing the efficacyof the two classes, as have meta-analyses comparing variousSGAs with one another, but no conclusions havebeen made about the comparative efficacy of the variousagents. 9,15,16 Both CUtLASS (Cost Utility of theLatest Antipsychotic Drugs in Schizophrenia Study)and CATIE (Clinical Antipsychotic Trials of InterventionEffectiveness) showed that atypical antipsychoticsoffer no benefit over conventional antipsychotics; however,CATIE 2 concluded that clozapine may have anadvantage over other atypical antipsychotics in treatment-refractorypatients. 17-19 Clozapine’s benefit maybe a result of the increase in provider interaction dueto monitoring for agranulocytosis. 20HS-6U.S. Pharmacist • November 2009 • www.uspharmacist.com

SCHIZOPHRENIA: A REVIEW OF TREATMENTSHEALTH SYSTEMS EDITIONStage 1Stage 2Stage 3Stage 4Stage 5Stage 6• Atypical antipsychotic• Atypical or conventional antipsychotic• Not the same atypical from stage 1• Clozapine• May try earlier if history of recurrent suicidality, violence,or substance abuse• Clozapine plus• Conventional or atypical antipsychotic or ECT• Trial of single atypical or conventional agent not tried instages 1 and 2• Combination therapy, such as atypical plus conventional antipsychotic;combination of atypical and/or conventional antipsychotics plus ECT;or conventional or atypical antipsychotic plus mood stabilizerSource: Reference 29. Adapted with permission of the Texas Department of StateHealth Services.ECT: electroconvulsive therapy.Figure 1. Algorithm for the treatment of schizophrenia. A patient should progressto the next stage if he or she experiences a partial response or nonresponse tothe current stage.Improvements in sleep disturbance and agitationmay be seen in the first 2 days of antipsychotic therapy;however, the full effect may not be seen for 6 to8 weeks. If the patient reports no symptom relief in 2to 4 weeks, either the antipsychotic dose should beincreased or a new agent should be selected. 1,21Recommended doses of FGAs and SGAs are givenin TABLE 2. 22 These doses have been suggested by themanufacturers of the respective agents; however,practitioners often prescribe outside of the recommendedrange. While this often is unavoidable in treatment-resistantpatients, the practice may result in adverseevents and limited additional efficacy. Also, manypatients probably will not require the higher end ofthe dosing range for FGAs. Specifically, patientsexperiencing their first psychotic break will likely respondto much lower doses of antipsychotics and be moresensitive to adverse events than a patient in a moreadvanced stage of schizophrenia. 21 Additionally, it shouldbe noted that the total daily dose of most antipsychoticscan be administered once daily if tolerated, and thiswill improve adherence. Exceptions tothis are clozapine, quetiapine, andziprasidone, which probably will requiremultiple daily doses to control symptoms.Finally, treatment with multipleantipsychotics should be considered alast resort and avoided if at all possible,as it often provides no additionalefficacy and increases the risk of intolerableside effects.In general, FGAs are more affordablethan SGAs, with perphenazine andfluphenazine costing more than otherFGAs. Currently, the only generic SGAsare clozapine and risperidone. Costshould be a major consideration whenchoosing an antipsychotic, with a preferencefor FGAs if a patient can toleratethem.Other Medications: Whereas antipsychoticsremain the primary pharmacologictreatment for schizophrenia, anumber of other medications may beused to augment them. One such classis the mood stabilizers, which oftenare used in patients experiencing increasedagitation or aggression. Overall, patientswith schizophrenia are not violent;however, episodes in which positivesymptoms are exacerbated may lead toincreased agitation. 3 During suchinstances, mood stabilizers may be beneficial.In a meta-analysis of 11 studiescomparing antipsychotic monotherapywith lithium augmentation, more patients receivinglithium had a clinically significant response, with anumber needed to treat of 8. 23 Two small studies havecompared antipsychotic monotherapy with carbamazepineaugmentation; in these studies, patients oncarbamazepine showed clinically significant overallglobal improvement. 24 Similarly, there is only limitedevidence to support the use of augmentation therapywith valproate, including a single small study showingless agitation in the valproate augmentation groupversus the antipsychotic monotherapy group. 25 A metaanalysisof five studies evaluating the efficacy of antipsychoticaugmentation with lamotrigine showed that20% to 30% of clozapine-resistant patients withschizophrenia had a clinically significant improvementwhen lamotrigine was added. 26 In a randomized, double-blind,placebo-controlled study of patients withschizophrenia, the addition of topiramate resulted ina reduction of both positive and negative symptomscompared with patients on antipsychotic monotherapy.27 Mood stabilizers have great potential for theHS-8U.S. Pharmacist • November 2009 • www.uspharmacist.com

SCHIZOPHRENIA: A REVIEW OF TREATMENTStreatment of schizophrenia, but more research is needed.Benzodiazepines have been studied for their benefitsin augmenting antipsychotics. Although the studieshave been small, they have shown some advantageover antipsychotic monotherapy in treating agitationin schizophrenia. This effect is short-lived, however,with a return of symptoms within 1 hour of a benzodiazepinedose. 28One of the most straightforward algorithms forthe treatment of schizophrenia was published by theTexas Department of State Health Services (FIGURE 1).This algorithm is based on evidence when available,and expert consensus where no evidence exists. If apatient fails trials of two stages of this algorithm withno appreciable improvement in symptoms, the diagnosisof schizophrenia should be re-evaluated, andthe possibility of co-occurring substance abuse shouldbe considered. 29ADHERENCEA number of studies have been designed to measurepatient adherence to antipsychotics compared withother medications, but the results are difficult to interpret.This is primarily because each study defines andmeasures nonadherence differently. A meta-analysisof adherence studies reported that patients take an averageof 58% of their prescribed antipsychotic doses(range 24%-90%). The meta-analysis found that patientstake medications for physical ailments an average of76% of the time (range 60%-92%), implying thatadherence to antipsychotics may be lower than adherenceto other medications. 30 Some barriers to care inpatients with schizophrenia include stigma about mentalillness, lack of access to care, and fragmentation ofservices. 5 A pharmacist can help a patient overcomethese barriers through education and identification ofpatient-assistance programs when financial issues arise.Additionally, the pharmacist may recommend the useof long-acting depot antipsychotic injections to improveadherence to medication therapy. Recommended dosesof depot antipsychotics are given in TABLE 2.CONCLUSIONDespite the fact that there is no cure for schizophrenia,providing patients with guideline-based treatmentssupported by primary literature will afford the bestopportunity for controlling the symptoms of their illness.The process of choosing appropriate medicationsand monitoring for appropriate adverse reactions shouldbe facilitated by a pharmacist whenever possible.HEALTH SYSTEMS EDITIONREFERENCES1. Freedman R. Schizophrenia. N Engl J Med. 2003;349:1738-1749.2. Siris SG. Suicide and schizophrenia. J Psychopharmacol. 2001;15:127-135.3. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “just thefacts” 4. Clinical features and conceptualization. Schizophr Res.2009;110:1-23.4. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,Text Revision (DSM-IV-TR). Washington, DC: American PsychiatricAssociation; 2000.5. Keshavan MS, Roberts M, Wittmann D. Guidelines for clinical treatmentof early course schizophrenia. Curr Psych Rep. 2006;8:329-334.6. Petersen L, Jeppesen P, Thorup A, et al. A randomized multicentretrial of integrated versus standard treatment for patients with a firstepisode of psychotic illness. BMJ. 2005;331:602-608.7. Pae CU. A review of the safety and tolerability of aripiprazole. ExpertOpin Drug Saf. 2009;8:373-386.8. Newcomer JW. Second-generation (atypical) antipsychotics andmetabolic effects: a comprehensive literature review. CNS Drugs.2005;19(suppl 1):1-93.9. Leucht S, Corves C, Arbter D, et al. Second-generation versus firstgenerationantipsychotic drugs for schizophrenia: a meta-analysis. Lancet.2009;373:31-41.10. Honigfeld G, Arellano F, Sethi J, et al. Reducing clozapine-relatedmorbidity and mortality: 5 years of experience with the Clozaril NationalRegistry. J Clin Psychiatry. 1998;59(suppl 3):3-7.11. Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinemia:mechanisms, clinical features and management. Drugs. 2004;64:2291-2314.12. Cutler AJ, Kalali AH, Weiden PJ, et al. Four-week, double-blind,placebo- and ziprasidone-controlled trial of iloperidone in patients withacute exacerbations of schizophrenia. J Clin Psychopharmacol. 2008;28(2suppl 1):S20-S28.13. FDA Psychopharmacological Drugs Advisory Committee. Briefingdocument for Zeldox ® capsules (ziprasidone HCl). July 19, 2000.14. Glassman AH, Bigger JT Jr. Antipsychotic drugs: prolonged QTcinterval, torsade de pointes, and sudden death. Am J Psychiatry.2001;158:1774-1782.15. Leucht S, Komossa K, Rummel-Kluge C, et al. A meta-analysis ofhead-to-head comparisons of second-generation antipsychotics in thetreatment of schizophrenia. Am J Psychiatry. 2009;166:152-163.16. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generationantipsychotics. Arch Gen Psychiatry. 2003;60:553-564.17. Jones PB, Barnes TRE, Davies L, et al. Randomized controlled trialof the effect on quality of life of second- and first-generation antipsychoticdrugs on schizophrenia: Cost Utility of the Latest AntipsychoticDrugs in Schizophrenia Study (CUtLASS I). Arch Gen Psychiatry.2006;63:1079-1087.18. Lieberman JA, Stroup TS, McEvoy JP, et al, for the ClinicalAntipsychotic Trials of Intervention Effectiveness (CATIE) Investigators.Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.N Engl J Med. 2005;353:1209-1223.19. McEvoy JP, Lieberman JA, Stroup TS, et al, for the CATIE Investigators.Effectiveness of clozapine versus olanzapine, quetiapine, andrisperidone in patients with chronic schizophrenia who did not respondto prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163:600-610.20. Meltzer HY, Alphs L, Green AI, et al. Clozapine treatment for suicidalityin schizophrenia: International Suicide Prevention Trial (Inter-SePT). Arch Gen Psychiatry. 2003;60:82-91.21. APA Practice Guidelines. Lehman AF, Lieberman JA, Dixon LB, etal. Practice guideline for the treatment of patients with schizophrenia.2nd ed. www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=Schizophrenia2e_Inactivated_04-16-09. Accessed October 13,2009.22. Micromedex Healthcare Series [Intranet database]. Greenwood Village,CO: Thomson Healthcare. Accessed October 13, 2009.23. Leucht S, Kissling W, McGrath J. Lithium for schizophrenia.Cochrane Database Syst Rev. 2007;(3):CD003834.24. Leucht S, Kissling W, McGrath J. Carbamazepine for schizophrenia.Cochrane Database Syst Rev. 2007;(3):CD001258.25. Schwarz C, Volz A, Li C, Leucht S. Valproate for schizophrenia.Cochrane Database Syst Rev. 2008;(3):CD004028.26. Tiihonen J, Wahlbeck K, Kiviniemi V. The efficacy of lamotrigine inclozapine-resistant schizophrenia: a systematic review and meta-analysis.Schizophr Res. 2009;109:10-14.27. Afshar H, Roohafza H, Mousavi G, et al. Topiramate add-on treatmentin schizophrenia: a randomised, double-blind, placebo-controlledclinical trial. J Psychopharmacol. 2009;23:157-162.28. Volz A, Khorsand V, Gillies D, Leucht S. Benzodiazepines forschizophrenia. Cochrane Database Syst Rev. 2007;(1):CD006391.29. Moore TA, Buchanan RW, Buckley PF, et al. The Texas MedicationAlgorithm Project antipsychotic algorithm for schizophrenia: 2006update. J Clin Psychiatry. 2007;68:1751-1762.30. Cramer JA, Rosenheck R. Compliance with medication regimens formental and physical disorders. Psychiatr Serv. 1998;49:196-201.HS-9U.S. Pharmacist • November 2009 • www.uspharmacist.com

HEALTH SYSTEMS EDITION© JUPITERIMAGESProphylactic Therapies inTraumatic Brain InjuryManagementTraumatic brain injury (TBI), defined as a strongimpact to the head or a penetrating head injurythat alters the function of the brain, affects thelives of approximately 1.4 million people in the UnitedStates each year. 1 TBI currently accounts for an estimated1.1 million emergency department admissionsand 50,000 deaths annually. Individuals at highest riskfor TBI are young children 6 months to 4 years old,males between the ages of 15 and 30 years, elderly individuals(aged 75 years or older), and certain militarypersonnel. According to the CDC, the leading causesof TBI include falls (28%), motor vehicle crashes (20%),events in which a person is struck by or against anobject (19%), and assaults (11%). 1Types of InjuriesTo appropriately treat and provide care to patientswith TBI, it is important to understand the mechanismand pathophysiology behind the injury. Thereare three key mechanisms of injury—blunt, penetrating,and blast, which are furtherdivided into primary or secondaryinjuries. 2 Blunt injuries are the mostcommon cause of TBI and are frequentlythe result of motor vehicle(i.e., automobile, motorcycle, pedestrian)crashes, falls, sports-relatedinjuries, and assaults. Penetratinginjuries result when any sharp orblunt object penetrates the scalp orskull (e.g., gunshot wounds). Lastly,Jennifer Confer, PharmDCritical Care Clinical SpecialistCabell Huntington HospitalClinical Assistant Professor, West VirginiaUniversity School of PharmacyHuntington, West VirginiaJon Wietholter, PharmDInternal Medicine Clinical SpecialistCabell Huntington HospitalClinical Assistant Professor, West VirginiaUniversity School of PharmacyHuntington, West Virginiablast wounds are the result of a combination of bluntand penetrating injuries.In addition to identifying the mechanism ofinjury, TBI is also separated into either primary or secondaryinjury. 2 A primary injury occurs at the time ofinjury and directly damages neuronal tissue. Resultantlesions from a primary injury are either focal, wherethe injury is in a localized area of the brain, or diffuse,in which the injury is large and widespread. Thesecondary injury that occurs from TBI is not initiallyseen; instead it is the result of a normal physiologicalresponse to the primary injury, such as tissue hypoxia,that develops over a period of time from hours tomonths following the primary injury. 2For decades, the concentration of TBI managementwas on maintaining the control of intracranial pressure(ICP) and cerebral perfusion pressure. As will be discussed,the focus of TBI management no longer residesin one central area; instead, managing all aspects ofTBI are now important areas of therapeutic decisionmaking. Building upon the 2007Guidelines for the Management ofSevere Traumatic Brain Injury, thisarticle will focus on prophylactictherapies currently being used andrecommended in patients with TBI(TABLE 1).Prophylactic SteroidsBeneficial effects of corticosteroidsin TBI were originally discovered inHS-10U.S. Pharmacist • November 2009 • www.uspharmacist.com

Fentanyl transdermal system shouldONLY be used in patients who are alreadyreceiving opioid therapy, who havedemonstrated opioid tolerance, andwho require a total daily dose at leastequivalent to fentanyl transdermal system25 mcg/hr. Patients who are consideredopioid-tolerant are those who have beentaking, for a week or longer, at least 60 mgof morphine daily, or at least 30 mg of oraloxycodone daily, or at least 8 mg of oralhydromorphone daily or an equianalgesicdose of another opioid.Because serious or life-threateninghypoventilation could occur, fentanyltransdermal system is contraindicated:• in patients who are not opioid-tolerant• in the management of acute pain or inpatients who require opioid analgesiafor a short period of time• in the management of postoperativepain, including use after out patientor day surgeries (e.g., tonsillectomies)• in the management of mild pain• in the management of intermittentpain [e.g., use on an as needed basis(prn)]The safety of fentanyl transdermal systemhas not been established in children under2 years of age. Fentanyl transdermalsystem should be administered to childrenonly if they are opioid-tolerant and 2 yearsof age or older (see PRECAUTIONS:Pediatric Use).Patients using fentanyl transdermal systemshould avoid exposure to external heatsources, such as heating pads, hot tubs,long hot baths, and sunbathing. An increasein body temperature may result in a suddenand possible dangerous rise in their bodyfentanyl level. Fentanyl transdermalsystem may cause death from overdosage;therefore, it is important for healthcareprofessionals, patients and caregivers toknow the signs of fentanyl overdose, whichcan include trouble breathing and extremesleepiness. Fentanyl transdermal systemshould be stored in a safe place andkept out of the reach of children. Used,unneeded or defective fentanyl patchesshould be safely disposed of by foldingthe sticky side of the patch together(until it sticks to itself) and flushing itdown the toilet.The most common adverse events reportedin clinical trials were fever, nausea, vomiting,constipation, dry mouth, somnolence,confusion, asthenia, and sweating.Please see adjacent Brief Summaryof Prescribing Information, includingBOXED WARNING.In the management of persistent, moderate to severe chronic pain that requirescontinuous, around-the-clock opioid administration foran extended period of time and cannot be managed by other means*Why Take A Chance WithOther Fentanyl Patches?One patch can cause burns.This matrix patch contains aluminum in its backing, which canoverheat during a magnetic resonance imaging (MRI) scan andburn the patient who is wearing it.Other patches can leak.They contain a reservoir of fentanyl gel that can leak and causepotentially life-threatening complications.Mylan FENTANYL is the first marketedfentanyl patch designed to avoid therisks associated with burns and leaks.The Mylan FENTANYL TRANSDERMALSYSTEM C II has no aluminum or othermetals in its backing. Also importantto patient safety, Mylan Fentanyl has aproprietary matrix design without aliquid, gel-filled reservoir that can leak.It is an innovative solution in transdermaldrug delivery.*Other means include non-steroidal analgesics, opioid combination products, or immediate-release opioids.©2009 Mylan Pharmaceuticals Inc. MYNFEN031No metal. No burns. No leaks.

FENTANYL TRANSDERMAL SYSTEMBRIEF SUMMARY: Please see package insert for full prescribing information.FOR USE IN OPIOID-TOLERANT PATIENTS ONLYFentanyl transdermal system contains a high concentration of a potent Schedule II opioid agonist, fentanyl.Schedule II opioid substances which include fentanyl, hydromorphone, methadone, morphine, oxycodone, andoxymorphone have the highest potential for abuse and associated risk of fatal overdose due to respiratorydepression. Fentanyl can be abused and is subject to criminal diversion. The high content of fentanyl in thepatches (fentanyl transdermal system) may be a particular target for abuse and diversion.Fentanyl transdermal system is indicated for management of persistent, moderate to severe chronic pain that:• requires continuous, around-the-clock opioid administration for an extended period of time, and• cannot be managed by other means such as non-steroidal analgesics, opioid combination products, orimmediate-release opioidsFentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, whohave demonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermalsystem 25 mcg/hr. Patients who are considered opioid-tolerant are those who have been taking, for aweek or longer, at least 60 mg of morphine daily, or at least 30 mg of oral oxycodone daily, or at least 8 mg oforal hydromorphone daily or an equianalgesic dose of another opioid.Because serious or life-threatening hypoventilation could occur, fentanyl transdermal system is contraindicated:• in patients who are not opioid-tolerant• in the management of acute pain or in patients who require opioid analgesia for a short period of time• in the management of postoperative pain, including use after out patient or day surgeries (e.g., tonsillectomies)• in the management of mild pain• in the management of intermittent pain [e.g., use on an as needed basis (prn)](See CONTRAINDICATIONS for further information.)Since the peak fentanyl levels occur between 24 and 72 hours of treatment, prescribers should be aware thatserious or life-threatening hypoventilation may occur, even in opioid-tolerant patients, during the initial applicationperiod.The concomitant use of fentanyl transdermal system with all cytochrome P450 3A4 inhibitors (such asritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazodone, amiodarone,amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil)may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drugeffects and may cause potentially fatal respiratory depression. Patients receiving fentanyl transdermalsystem and any CYP3A4 inhibitor should be carefully monitored for an extended period of time and dosageadjustments should be made if warranted (see CLINICAL PHARMACOLOGY: Drug Interactions, WARNINGS,PRECAUTIONS and DOSAGE AND ADMINISTRATION in full prescribing information for further information). Thesafety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyltransdermal system should be administered to children only if they are opioid-tolerant and 2 years of age orolder (see PRECAUTIONS: Pediatric Use in full prescribing information).Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy of comparablepotency. Use in non-opioid-tolerant patients may lead to fatal respiratory depression. Overestimating thefentanyl transdermal system dose when converting patients from another opioid medication can result in fataloverdose with the first dose. Due to the mean elimination half-life of 17 hours of fentanyl transdermal system,patients who are thought to have had a serious adverse event, including overdose, will require monitoring andtreatment for at least 24 hours.Fentanyl transdermal system can be abused in a manner similar to other opioid agonists, legal or illicit. Thisrisk should be considered when administering, prescribing, or dispensing fentanyl transdermal system insituations where the healthcare professional is concerned about increased risk of misuse, abuse or diversion.Persons at increased risk for opioid abuse include those with a personal or family history of substance abuse(including drug or alcohol abuse or addiction) or mental illness (e.g., major depression). Patients should beassessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids. All patientsreceiving opioids should be routinely monitored for signs of misuse, abuse and addiction. Patients atincreased risk of opioid abuse may still be appropriately treated with modified-release opioid formulations;however, these patients will require intensive monitoring for signs of misuse, abuse, or addiction.Fentanyl transdermal system patches are intended for transdermal use (on intact skin) only. Do not use afentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.Avoid exposing the fentanyl transdermal system application site and surrounding area to direct external heatsources, such as heating pads or electric blankets, heat or tanning lamps, saunas, hot tubs, and heated waterbeds, while wearing the system. Avoid taking hot baths or sunbathing. There is a potential for temperaturedependentincreases in fentanyl released from the system resulting in possible overdose and death. Patientswearing fentanyl transdermal systems who develop fever or increased core body temperature due tostrenuous exertion should be monitored for opioid side effects and the fentanyl transdermal system doseshould be adjusted if necessary.INDICATIONS AND USAGE: Fentanyl transdermal system is indicated for management of persistent, moderate to severechronic pain that:• requires continuous, around-the-clock opioid administration for an extended period of time, and• cannot be managed by other means such as non-steroidal analgesics, opioid combination products, orimmediate-release opioidsFentanyl transdermal system should ONLY be used in patients who are already receiving opioid therapy, who havedemonstrated opioid tolerance, and who require a total daily dose at least equivalent to fentanyl transdermal system25 mcg/hr (see DOSAGE AND ADMINISTRATION in full prescribing information). Patients who are consideredopioid-tolerant are those who have been taking, for a week or longer, at least 60 mg of morphine daily, or at least30 mg of oral oxycodone daily, or at least 8 mg of oral hydromorphone daily, or an equianalgesic dose of another opioid.Because serious or life-threatening hypoventilation could result, fentanyl transdermal system is contraindicatedfor use on an as needed basis (i.e., prn), for the management of postoperative or acute pain, or in patients who are notopioid-tolerant or who require opioid analgesia for a short period of time (see BOX WARNING and CONTRAINDICATIONS).An evaluation of the appropriateness and adequacy of treating with immediate-release opioids is advisable priorto initiating therapy with any modified-release opioid. Prescribers should individualize treatment in every case,initiating therapy at the appropriate point along a progression from non-opioid analgesics, such as non-steroidalanti-inflammatory drugs and acetaminophen, to opioids, in a plan of pain management such as outlined by the WorldHealth Organization, the Agency for Health Research and Quality, the Federation of State Medical Boards Model Policy,or the American Pain Society.Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids.Patients receiving opioids should be routinely monitored for signs of misuse, abuse, and addiction. Persons atincreased risk for opioid abuse include those with a personal or family history of substance abuse (including drug oralcohol abuse or addiction) or mental illness (e.g., major depression). Patients at increased risk may still beappropriately treated with modified-release opioid formulations; however these patients will require intensivemonitoring for signs of misuse, abuse, or addiction.CONTRAINDICATIONS: Because serious or life-threatening hypoventilation could occur, fentanyl transdermalsystem is contraindicated:• in patients who are not opioid-tolerant• in the management of acute pain or in patients who require opioid analgesia for a short period of time• in the management of postoperative pain, including use after out-patient or day surgeries (e.g., tonsillectomies)• in the management of mild pain• in the management of intermittent pain [e.g., use on an as needed basis (prn)]• in situations of significant respiratory depression, especially in unmonitored settings where there is a lackof resuscitative equipment• in patients who have acute or severe bronchial asthmaFentanyl transdermal system is contraindicated in patients who have or are suspected of having paralytic ileus.Fentanyl transdermal system is contraindicated in patients with known hypersensitivity to fentanyl or anycomponents of this product.WARNINGS:Fentanyl transdermal systems are intended for transdermal use (on intact skin) only. Do not use a fentanyltransdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.The safety of fentanyl transdermal system has not been established in children under 2 years of age. Fentanyltransdermal system should be administered to children only if they are opioid-tolerant and 2 years of age or older(see PRECAUTIONS: Pediatric Use in full prescribing information).Fentanyl transdermal system is ONLY for use in patients who are already tolerant to opioid therapy ofcomparable potency. Use in non-opioid-tolerant patients may lead to fatal respiratory depression.Overestimating the fentanyl transdermal system dose when converting patients from another opioid medicationcan result in fatal overdose with the first dose. The mean elimination half-life of fentanyl transdermal systemis 17 hours. Therefore, patients who have experienced serious adverse events, including overdose, will requiremonitoring for at least 24 hours after fentanyl transdermal system removal since serum fentanyl concentrationsdecline gradually and reach an approximate 50% reduction in serum concentrations 17 hours after system removal.Fentanyl transdermal system should be prescribed only by persons knowledgeable in the continuousadministration of potent opioids, in the management of patients receiving potent opioids for treatment of pain, andin the detection and management of hypoventilation including the use of opioid antagonists.All patients and their caregivers should be advised to avoid exposing the fentanyl transdermal systemapplication site and surrounding area to direct external heat sources, such as heating pads or electric blankets,heat or tanning lamps, saunas, hot tubs, and heated water beds, etc., while wearing the system. Patients shouldbe advised against taking hot baths or sunbathing. There is a potential for temperature-dependent increases infentanyl released from the system resulting in possible overdose and death.Based on a pharmacokinetic model, serum fentanyl concentrations could theoretically increase by approximatelyone-third for patients with a body temperature of 40°C (104°F) due to temperature-dependent increases in fentanylreleased from the system and increased skin permeability. Patients wearing fentanyl transdermal systems whodevelop fever or increased core body temperature due to strenuous exertion should be monitored for opioid sideeffects and the fentanyl transdermal system dose should be adjusted if necessary.Death and other serious medical problems have occurred when people were accidentally exposed to fentanyltransdermal system. Examples of accidental exposure include transfer of a fentanyl transdermal system from anadult’s body to a child while hugging, accidental sitting on a patch and possible accidental exposure of a caregiver’sskin to the medication in the patch while the caregiver was applying or removing the patch.Placing fentanyl transdermal system in the mouth, chewing it, swallowing it, or using it in ways other thanindicated may cause choking or overdose that could result in death.Misuse, Abuse and Diversion of OpioidsFentanyl is an opioid agonist of the morphine-type. Such drugs are sought by drug abusers and people withaddiction disorders and are subject to criminal diversion.Fentanyl can be abused in a manner similar to other opioids, legal or illicit. This should be considered whenprescribing or dispensing fentanyl transdermal system in situations where the physician or pharmacist is concernedabout an increased risk of misuse, abuse or diversion.Fentanyl transdermal system has been reported as being abused by other methods and routes of administration.These practices will result in uncontrolled delivery of the opioid and pose a significant risk to the abuser that couldresult in overdose and deaths (see WARNINGS and DRUG ABUSE AND ADDICTION).Concerns about abuse, addiction and diversion should not prevent the proper management of pain. However,all patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioidanalgesic products carries the risk of addiction even under appropriate medical use.Healthcare professionals should contact their state professional licensing board or state controlled substancesauthority for information on how to prevent and detect abuse or diversion of this product.Hypoventilation (Respiratory Depression): Serious or life-threatening hypoventilation may occur at any time duringthe use of fentanyl transdermal system especially during the initial 24 to 72 hours following initiation of therapy andfollowing increases in dose.Because significant amounts of fentanyl are absorbed from the skin for 17 hours or more after the patch isremoved, hypoventilation may persist beyond the removal of fentanyl transdermal system. Consequently, patientswith hypoventilation should be carefully observed for degree of sedation and their respiratory rate monitored untilrespiration has stabilized.The use of concomitant CNS active drugs requires special patient care and observation.Respiratory depression is the chief hazard of opioid agonists, including fentanyl the active ingredient in fentanyltransdermal system. Respiratory depression is more likely to occur in elderly or debilitated patients, usually followinglarge initial doses in non-tolerant patients, or when opioids are given in conjunction with other drugs that depressrespiration.Respiratory depression from opioids is manifested by a reduced urge to breathe and a decreased rate of respiration,often associated with the “sighing” pattern of breathing (deep breaths separated by abnormally long pauses).Carbon dioxide retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.This makes overdoses involving drugs with sedative properties and opioids especially dangerous.Fentanyl transdermal system should be used with extreme caution in patients with significant chronic obstructivepulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia,hypercapnia, or preexisting respiratory depression. In such patients, even usual therapeutic doses of fentanyltransdermal system may decrease respiratory drive to the point of apnea. In these patients, alternative non-opioidanalgesics should be considered, and opioids should be employed only under careful medical supervision at thelowest effective dose.Chronic Pulmonary Disease: Because potent opioids can cause serious or life-threatening hypoventilation, fentanyltransdermal system should be administered with caution to patients with preexisting medical conditions predisposingthem to hypoventilation. In such patients, normal analgesic doses of opioids may further decrease respiratory drive tothe point of respiratory failure.Head Injuries and Increased Intracranial Pressure: Fentanyl transdermal system should not be used in patients whomay be particularly susceptible to the intracranial effects of CO 2 retention such as those with evidence of increasedintracranial pressure, impaired consciousness, or coma. Opioids may obscure the clinical course of patients with headinjury. Fentanyl transdermal system should be used with caution in patients with brain tumors.Interactions with other CNS Depressants: The concomitant use of fentanyl transdermal system with other centralnervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g.,benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may causerespiratory depression, hypotension, and profound sedation or potentially result in coma. When such combinedtherapy is contemplated, the dose of one or both agents should be significantly reduced.Interactions with Alcohol and Drugs of Abuse: Fentanyl may be expected to have additive CNS depressant effectswhen used in conjunction with alcohol, other opioids, or illicit drugs that cause central nervous system depression.Interactions with CYP3A4 Inhibitors: The concomitant use of transdermal fentanyl with all CYP3A4 inhibitors (suchas ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, nefazadone, amiodarone,amprenavir, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, and verapamil) mayresult in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects andmay cause potentially fatal respiratory depression. Patients receiving fentanyl transdermal system and any CYP3A4inhibitor should be carefully monitored for an extended period of time, and dosage adjustments should be madeif warranted (see BOX WARNING, CLINICAL PHARMACOLOGY: Drug Interactions in full prescribing information,PRECAUTIONS, and DOSAGE AND ADMINISTRATION in full prescribing information for further information).PRECAUTIONS: General: Fentanyl transdermal system should not be used to initiate opioid therapy in patients whoare not opioid-tolerant. Children converting to fentanyl transdermal system should be opioid-tolerant and 2 years ofage or older (see BOX WARNING).Page 1 of 3

Patients, family members and caregivers should be instructed to keep patches (new and used) out of the reachof children and others for whom fentanyl transdermal system was not prescribed. A considerable amount of activefentanyl remains in fentanyl transdermal system even after use as directed. Accidental or deliberate application oringestion by a child or adolescent will cause respiratory depression that could result in death.Cardiac Disease: Fentanyl may produce bradycardia. Fentanyl should be administered with caution to patients withbradyarrhythmias.Hepatic or Renal Disease: Insufficient information exists to make recommendations regarding the use of fentanyltransdermal system in patients with impaired renal or hepatic function. If the drug is used in these patients, it shouldbe used with caution because of the hepatic metabolism and renal excretion of fentanyl.Use in Pancreatic/Biliary Tract Disease: Fentanyl transdermal system may cause spasm of the sphincter of Oddi andshould be used with caution in patients with biliary tract disease, including acute pancreatitis. Opioids like fentanyltransdermal system may cause increases in the serum amylase concentration.Tolerance: Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminutionof one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects ofdrugs, and may develop at different rates for different effects.Physical Dependence: Physical dependence is a state of adaptation that is manifested by an opioid specificwithdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of thedrug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by someor all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia,mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia,vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate. In general, opioids should not beabruptly discontinued (see DOSAGE AND ADMINISTRATION: Discontinuation of Fentanyl Transdermal System in fullprescribing information).Ambulatory Patients: Strong opioid analgesics impair the mental or physical abilities required for the performance ofpotentially dangerous tasks, such as driving a car or operating machinery. Patients who have been given fentanyltransdermal system should not drive or operate dangerous machinery unless they are tolerant to the effects of the drug.Information for Patients: Patients and their caregivers should be provided with a Medication Guide each timefentanyl transdermal system is dispensed because new information may be available.Patients receiving fentanyl transdermal system should be given the following instructions by the physician:1. Patients should be advised that fentanyl transdermal systems contain fentanyl, an opioid pain medicinesimilar to morphine, hydromorphone, methadone, oxycodone, and oxymorphone.2. Patients should be advised that each fentanyl transdermal system may be worn continuously for 72 hours, andthat each patch should be applied to a different skin site after removal of the previous transdermal patch.3. Patients should be advised that fentanyl transdermal system should be applied to intact, nonirritated, andnonirradiated skin on a flat surface such as the chest, back, flank, or upper arm. Additionally, patients shouldbe advised of the following:• In young children or persons with cognitive impairment, the patch should be put on the upper back to lowerthe chances that the patch will be removed and placed in the mouth.• Hair at the application site should be clipped (not shaved) prior to patch application.• If the site of fentanyl transdermal system application must be cleansed prior to application of the patch,do so with clear water.• Do not use soaps, oils, lotions, alcohol, or any other agents that might irritate the skin or alter itscharacteristics.• Allow the skin to dry completely prior to patch application.4. Patients should be advised that fentanyl transdermal system should be applied immediately upon removal from thesealed package and after removal of the protective liner. Additionally the patient should be advised of the following:• The fentanyl transdermal system should not be used if the seal is broken or the patch is cut, damaged, orchanged in any way.• The transdermal patch should be pressed firmly in place with the palm of the hand for 30 seconds,making sure the contact is complete, especially around the edges.• The patch should not be folded so that only part of the patch is exposed.5. Patients should be advised that the dose of fentanyl transdermal system or the number of patches applied tothe skin should NEVER be adjusted without the prescribing healthcare professional’s instruction.6. Patients should be advised that while wearing the patch, they should avoid exposing the fentanyl transdermalsystem application site and surrounding area to direct external heat sources, such as:• heating pads,• electric blankets,• sunbathing,• heat or tanning lamps,• saunas,• hot tubs or hot baths, and• heated water beds, etc.7. Patients should also be advised of a potential for temperature-dependent increases in fentanyl release from thepatch that could result in an overdose of fentanyl; therefore, patients who develop a high fever or increased bodytemperature due to strenuous exertion while wearing the patch should contact their physician.8. Patients should be advised that if they experience problems with adhesion of the fentanyl transdermal system,they may tape the edges of the patch with first aid tape. If problems with adhesion persist, patients mayoverlay the patch with a transparent adhesive film dressing (e.g., Bioclusive ® or Askina ® Derm).9. Patients should be advised that if the patch falls off before 72 hours a new patch may be applied to adifferent skin site.10. Patients should be advised to fold (so that the adhesive side adheres to itself) and immediately flush downthe toilet used fentanyl transdermal systems after removal from the skin.11. Patients should be advised that fentanyl transdermal system may impair mental and/or physical abilityrequired for the performance of potentially hazardous tasks (e.g., driving, operating machinery).12. Patients should be advised to refrain from any potentially dangerous activity when starting on fentanyltransdermal system or when their dose is being adjusted, until it is established that they have not beenadversely affected.13. Patients should be advised that fentanyl transdermal system should not be combined with alcohol or other CNSdepressants (e.g., sleep medications, tranquilizers) because dangerous additive effects may occur, resultingin serious injury or death.14. Patients should be advised to consult their physician or pharmacist if other medications are being or will beused with fentanyl transdermal system.15. Patients should be advised of the potential for severe constipation.16. Patients should be advised that if they have been receiving treatment with fentanyl transdermal system andcessation of therapy is indicated, it may be appropriate to taper the fentanyl transdermal system dose, ratherthan abruptly discontinue it, due to the risk of precipitating withdrawal symptoms.17. Patients should be advised that fentanyl transdermal system contains fentanyl, a drug with high potentialfor abuse.18. Patients, family members and caregivers should be advised to protect fentanyl transdermal system from theftor misuse in the work or home environment.19. Patients should be instructed to keep fentanyl transdermal system in a secure place out of the reach ofchildren due to the high risk of fatal respiratory depression.20. Patients should be advised that fentanyl transdermal system should never be given to anyone other than theindividual for whom it was prescribed because of the risk of death or other serious medical problems to thatperson for whom it was not intended.21. Patients should be informed that, if the patch dislodges and accidentally sticks to the skin of another person,they should immediately take the patch off, wash the exposed area with water and seek medical attention forthe accidentally exposed individual.22. When fentanyl transdermal system is no longer needed, the unused patches should be removed from theirpouches, folded so that the adhesive side of the patch adheres to itself, and flushed down the toilet.23. Women of childbearing potential who become, or are planning to become pregnant, should be advised toconsult a physician prior to initiating or continuing therapy with fentanyl transdermal system.24. Patients should be informed that accidental exposure or misuse may lead to death or other serious medicalproblems.Drug Interactions: Agents Affecting Cytochrome P450 3A4 Isoenzyme System: Fentanyl is metabolized mainlyvia the human cytochrome P450 3A4 isoenzyme system (CYP3A4), therefore potential interactions may occur whenfentanyl transdermal system is given concurrently with agents that affect CYP3A4 activity. Coadministration withagents that induce CYP3A4 activity may reduce the efficacy of fentanyl transdermal system. The concomitant useof transdermal fentanyl with all CYP3A4 inhibitors (such as ritonavir, ketoconazole, itraconazole, troleandomycin,clarithromycin, nelfanivir, nefazadone, amiodarone, amprenavir, aprepitant, diltiazem, erythromycin, fluconazole,fasamprenavir, grapefruit juice, and verapamil) may result in an increase in fentanyl plasma concentrations, whichcould increase or prolong adverse drug effects and may cause fatal respiratory depression. Patients receivingfentanyl transdermal system and any CYP3A4 inhibitor should be carefully monitored for an extended period of time,and dosage adjustments should be made if warranted (see BOX WARNING, CLINICAL PHARMACOLOGY: DrugInteractions in full prescribing information, WARNINGS, and DOSAGE AND ADMINISTRATION in full prescribinginformation for further information).Central Nervous System Depressants: The concomitant use of fentanyl transdermal system with other centralnervous system depressants, including but not limited to other opioids, sedatives, hypnotics, tranquilizers (e.g.,benzodiazepines), general anesthetics, phenothiazines, skeletal muscle relaxants, and alcohol, may cause respiratorydepression, hypotension, and profound sedation, or potentially result in coma or death. When such combined therapyis contemplated, the dose of one or both agents should be significantly reduced.MAO Inhibitors: Fentanyl transdermal system is not recommended for use in patients who have received MAOI within14 days because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.Carcinogenesis, Mutagenesis, and Impairment of Fertility: Studies in animals to evaluate the carcinogenicpotential of fentanyl HCl have not been conducted. There was no evidence of mutagenicity in the Ames Salmonellamutagenicity assay, the primary rat hepatocyte unscheduled DNA synthesis assay, the BALB/c 3T3 transformationtest, and the human lymphocyte and CHO chromosomal aberration in vitro assays.The potential effects of fentanyl on male and female fertility were examined in the rat model via two separateexperiments. In the male fertility study, male rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) viacontinuous intravenous infusion for 28 days prior to mating; female rats were not treated. In the female fertility study,female rats were treated with fentanyl (0, 0.025, 0.1 or 0.4 mg/kg/day) via continuous intravenous infusion for14 days prior to mating until day 16 of pregnancy; male rats were not treated. Analysis of fertility parameters in bothstudies indicated that an intravenous dose of fentanyl up to 0.4 mg/kg/day to either the male or the female aloneproduced no effects on fertility (this dose is approximately 1.6 times the daily human dose administered by a 100 mcg/hrpatch on a mg/m 2 basis). In a separate study, a single daily bolus dose of fentanyl was shown to impair fertility inrats when given in intravenous doses of 0.3 times the human dose for a period of 12 days.Pregnancy: Teratogenic Effects: Pregnancy Category C: No epidemiological studies of congenital anomalies ininfants born to women treated with fentanyl during pregnancy have been reported.The potential effects of fentanyl on embryo-fetal development were studied in the rat, mouse, and rabbit models.Published literature reports that administration of fentanyl (0, 10, 100, or 500 mcg/kg/day) to pregnant femaleSprague-Dawley rats from day 7 to 21 via implanted microosmotic minipumps did not produce any evidence ofteratogenicity (the high dose is approximately 2 times the daily human dose administered by a 100 mcg/hr patch ona mg/m 2 basis). In contrast, the intravenous administration of fentanyl (0, 0.01, or 0.03 mg/kg) to bred female ratsfrom gestation day 6 to 18 suggested evidence of embryotoxicity and a slight increase in mean delivery time in the0.03 mg/kg/day group. There was no clear evidence of teratogenicity noted.Pregnant female New Zealand White rabbits were treated with fentanyl (0, 0.025, 0.1, 0.4 mg/kg) via intravenousinfusion from day 6 to day 18 of pregnancy. Fentanyl produced a slight decrease in the body weight of the live fetusesat the high dose, which may be attributed to maternal toxicity. Under the conditions of the assay, there was noevidence for fentanyl induced adverse effects on embryo-fetal development at doses up to 0.4 mg/kg (approximately3 times the daily human dose administered by a 100 mcg/hr patch on a mg/m 2 basis).There are no adequate and well controlled studies in pregnant women. Fentanyl transdermal system should beused during pregnancy only if the potential benefit justifies the potential risk to the fetus.Nonteratogenic Effects: Chronic maternal treatment with fentanyl during pregnancy has been associated withtransient respiratory depression, behavioral changes, or seizures characteristic of neonatal abstinence syndrome innewborn infants. Symptoms of neonatal respiratory or neurological depression were no more frequent than expectedin most studies of infants born to women treated acutely during labor with intravenous or epidural fentanyl. Transientneonatal muscular rigidity has been observed in infants whose mothers were treated with intravenous fentanyl.The potential effects of fentanyl on prenatal and postnatal development were examined in the rat model. FemaleWistar rats were treated with 0, 0.025, 0.1, or 0.4 mg/kg/day fentanyl via intravenous infusion from day 6 ofpregnancy through 3 weeks of lactation. Fentanyl treatment (0.4 mg/kg/day) significantly decreased body weight in maleand female pups and also decreased survival in pups at day 4. Both the mid-dose and high-dose of fentanyl animalsdemonstrated alterations in some physical landmarks of development (delayed incisor eruption and eye opening) andtransient behavioral development (decreased locomotor activity at day 28 which recovered by day 50). The mid-doseand the high-dose are 0.4 and 1.6 times the daily human dose administered by a 100 mcg/hr patch on a mg/m 2 basis.Labor and Delivery: Fentanyl readily passes across the placenta to the fetus; therefore, fentanyl transdermal systemis not recommended for analgesia during labor and delivery.Nursing Mothers: Fentanyl is excreted in human milk; therefore, fentanyl transdermal system is not recommended foruse in nursing women because of the possibility of effects in their infants.Pediatric Use: The safety of fentanyl transdermal system was evaluated in three open-label trials in 291 pediatricpatients with chronic pain, 2 years of age through 18 years of age. Starting doses of 25 mcg/hr and higher were usedby 181 patients who had been on prior daily opioid doses of at least 45 mg/day of oral morphine or an equianalgesicdose of another opioid. Initiation of fentanyl transdermal system therapy in pediatric patients taking less than60 mg/day of oral morphine or an equianalgesic dose of another opioid has not been evaluated in controlled clinicaltrials. Approximately 90% of the total daily opioid requirement (fentanyl transdermal system plus rescue medication)was provided by fentanyl transdermal system.Fentanyl transdermal system was not studied in children under 2 years of age.Fentanyl transdermal system should be administered to children only if they are opioid-tolerant and 2 years of ageor older (see DOSAGE AND ADMINISTRATION in full prescribing information and BOX WARNING).To guard against accidental ingestion by children, use caution when choosing the application site for fentanyltransdermal system (see DOSAGE AND ADMINISTRATION in full prescribing information) and monitor adhesion of thesystem closely.Geriatric Use: Information from a pilot study of the pharmacokinetics of IV fentanyl in geriatric patients (N = 4)indicates that the clearance of fentanyl may be greatly decreased in the population above the age of 60. The relevanceof these findings to fentanyl transdermal system is unknown at this time.Respiratory depression is the chief hazard in elderly or debilitated patients, usually following large initial doses innontolerant patients, or when opioids are given in conjunction with other agents that depress respiration.Fentanyl transdermal system should be used with caution in elderly, cachectic, or debilitated patients as theymay have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance (see DOSAGE ANDADMINISTRATION in full prescribing information).ADVERSE REACTIONS: In post-marketing experience, deaths from hypoventilation due to inappropriate use offentanyl transdermal system have been reported (see BOX WARNING and CONTRAINDICATIONS).Premarketing Clinical Trial Experience: Although fentanyl transdermal system use in postoperative or acute painand in patients who are not opioid-tolerant is CONTRAINDICATED, the safety of fentanyl transdermal system wasoriginally evaluated in 357 postoperative adult patients for 1 to 3 days and 153 cancer patients for a total of 510patients. The duration of fentanyl transdermal system use varied in cancer patients; 56% of patients used fentanyltransdermal system for over 30 days, 28% continued treatment for more than 4 months, and 10% used fentanyltransdermal system for more than 1 year.Hypoventilation was the most serious adverse reaction observed in 13 (4%) postoperative patients and in 3 (2%) ofthe cancer patients. Hypotension and hypertension were observed in 11 (3%) and 4 (1%) of the opioid-naive patients.Various adverse events were reported; a causal relationship to fentanyl transdermal system was not alwaysdetermined. The frequencies presented here reflect the actual frequency of each adverse effect in patients whoreceived fentanyl transdermal system. There has been no attempt to correct for a placebo effect, concomitant use ofPage 2 of 3

other opioids, or to subtract the frequencies reported by placebo-treated patients in controlled trials.Adverse reactions reported in 153 cancer patients at a frequency of 1% or greater are presented in Table 1;similar reactions were seen in the 357 postoperative patients.In the pediatric population, the safety of fentanyl transdermal system has been evaluated in 291 patients withchronic pain 2 to 18 years of age. The duration of fentanyl transdermal system use varied; 20% of pediatric patientswere treated for 15 days; 46% for 16 to 30 days; 16% for 31 to 60 days; and 17% for at least 61 days. Twenty-fivepatients were treated with fentanyl transdermal system for at least 4 months and 9 patients for more than 9 months.There was no apparent pediatric-specific risk associated with fentanyl transdermal system use in children as youngas 2 years old when used as directed. The most common adverse events were fever (35%), vomiting (33%), andnausea (24%).Adverse events reported in pediatric patients at a rate of 1% are presented in Table 1.TABLE 1: ADVERSE EVENTS (at rate of ≥ 1%)Adults (N = 380) and Pediatric (N = 291) Clinical Trial ExperienceBody System Adults PediatricsBody as a Whole Abdominal pain*, headache*, fatigue*, Pain*, headache*, fever,back pain, fever, influenza-like symptoms*, syncope, abdominal pain,accidental injury, rigorsallergic reaction, flushingCardiovascular Arrhythmia, chest pain Hypertension, tachycardiaDigestive Nausea**, vomiting**, constipation**, Nausea**, vomiting**,dry mouth**, anorexia*, diarrhea*,constipation*, dry mouth,dyspepsia*, flatulencediarrheaNervous Somnolence**, insomnia, confusion**, Somnolence*, nervousness*,asthenia**, dizziness*, nervousness*,insomnia*, asthenia*,hallucinations*, anxiety*, depression*, euphoria*, hallucinations, anxiety,tremor, abnormal coordination, speech disorder, depression, convulsions,abnormal thinking, abnormal gait,dizziness, tremor, speechabnormal dreams, agitation, paresthesia, disorder, agitation, stupor,amnesia, syncope, paranoid reactionconfusion, paranoid reactionRespiratory Dyspnea*, hypoventilation*, apnea*, Dyspnea, respiratoryhemoptysis, pharyngitis*, hiccups,depression, rhinitis, coughingbronchitis, rhinitis, sinusitis,upper respiratory tract infection*Skin and Appendages Sweating**, pruritus*, rash, application site Pruritus*, application sitereaction – erythema, papules,reaction*, sweating increased,itching, edemarash, rash erythematous, skinreaction localizedUrogenital Urinary retention*, micturition disorder Urinary retention*Reactions occurring in 3% to 10% of fentanyl transdermal system patients**Reactions occurring in 10% or more of fentanyl transdermal system patientsThe following adverse effects have been reported in less than 1% of the 510 adult postoperative and cancerpatients studied:Cardiovascular: bradycardiaDigestive: abdominal distentionNervous: aphasia, hypertonia, vertigo, stupor, hypotonia, depersonalization, hostilityRespiratory: stertorous breathing, asthma, respiratory disorderSkin and Appendages, General: exfoliative dermatitis, pustulesSpecial Senses: amblyopiaUrogenital: bladder pain, oliguria, urinary frequencyPost-Marketing Experience: Adults: The following adverse reactions have been reported in association with theuse of fentanyl transdermal system and not reported in the premarketing adverse reactions section above:Body as a Whole: edemaCardiovascular: tachycardiaMetabolic and Nutritional: weight lossSpecial Senses: blurred visionUrogenital: decreased libido, anorgasmia, ejaculatory difficultyDRUG ABUSE AND ADDICTION: Fentanyl transdermal system contains a high concentration of fentanyl, a potentSchedule II opioid agonist. Schedule II opioid substances, which include hydromorphone, methadone, morphine,oxycodone, and oxymorphone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression.Fentanyl, like morphine and other opioids used in analgesia, can be abused and is subject to criminal diversion.The high content of fentanyl in the patches (fentanyl transdermal system) may be a particular target for abuseand diversion.Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factorsinfluencing its development and manifestations. It is characterized by behaviors that include one or more of thefollowing: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addictionis a treatable disease, utilizing a multidisciplinary approach, but relapse is common.“Drug seeking” behavior is very common in addicts and drug abusers. Drug-seeking tactics include emergencycalls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated“loss” of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contactinformation for other treating physician(s). “Doctor shopping” to obtain additional prescriptions is common amongdrug abusers and people suffering from untreated addiction.Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should beaware that addiction may be accompanied by concurrent tolerance and symptoms of physical dependence. In addition,abuse of opioids can occur in the absence of true addiction and is characterized by misuse for nonmedicalpurposes, often in combination with other psychoactive substances. Since fentanyl transdermal system may bediverted for nonmedical use, careful record keeping of prescribing information, including quantity, frequency, andrenewal requests is strongly advised.Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and properdispensing and storage are appropriate measures that help to limit abuse of opioid drugs.Fentanyl transdermal systems are intended for transdermal use (to be applied on the skin) only. Do not use afentanyl transdermal system if the seal is broken or the patch is cut, damaged, or changed in any way.OVERDOSAGE: Clinical Presentation: The manifestations of fentanyl overdosage are an extension of itspharmacologic actions with the most serious significant effect being hypoventilation.Treatment: For the management of hypoventilation, immediate countermeasures include removing the fentanyltransdermal system and physically or verbally stimulating the patient. These actions can be followed byadministration of a specific narcotic antagonist such as naloxone. The duration of hypoventilation following anoverdose may be longer than the effects of the narcotic antagonist’s action (the half-life of naloxone ranges from30 to 81 minutes). The interval between IV antagonist doses should be carefully chosen because of the possibilityof renarcotization after system removal; repeated administration of naloxone may be necessary. Reversal of thenarcotic effect may result in acute onset of pain and the release of catecholamines.Always ensure a patent airway is established and maintained, administer oxygen and assist or controlrespiration as indicated and use an oropharyngeal airway or endotracheal tube if necessary. Adequate bodytemperature and fluid intake should be maintained.If severe or persistent hypotension occurs, the possibility of hypovolemia should be considered and managedwith appropriate parenteral fluid therapy.READER INPUT FORMU.S. PHARMACISTJobson Medical Information LLC •160 Chubb Avenue • Suite 306 •Lyndhurst, NJ 07071 • Fax 201-623-0921Which two articles in this issue didyou like the most?1.2.Which two articles in this issue didyou like the least?1.2.Which areas of pharmacy would youlike us to address in the future?Would you be interested in writing areview article? If so, please indicate yourareas of expertise.Other comments or suggestions?If you would like to help us occasionally with aproject, please attach your business card here andmail, or photocopy and fax, to us. We value yourinput. Thanks!Page 3 of 3MYLAN ®Mylan Pharmaceuticals Inc.Morgantown, WV 26505REVISED JUNE 2008BS:FTS:R16HS-14U.S. Pharmacist • November 2009 • www.uspharmacist.com

TRAUMATIC BRAIN INJURYTable 1Current Dose Recommendations for Prophylaxis Based on2007 Guidelines for the Management of Severe Traumatic Brain InjuryProphylaxisCategory 2007 Guideline Recommendations Recommended Dosages for ProphylaxisSteroid Steroids do not improve outcome or lower ICP Steroid prophylaxis should not be given to patientsin severe TBI and are not recommended for TBI who present with severe TBIInfection There is no support for the use of prolonged Infection prophylaxis should not be routinelyantibiotics for systemic infection prophylaxis in prescribed for patients with severe TBI. If the patientintubated TBI patientsdoes require antibiotics for an infection that presents,choice of medication and dosage should be made appropriatelybased on local susceptibility and resistance patternsVenous The use of compression stockings for VTE Heparin: 5,000 units SQ every 8 hthrombo- prophylaxis should be placed for patients with Dalteparin: 5,000 units SQ once dailyembolism severe TBI, unless lower extremity injuries Enoxaparin: 30 mg SQ twice daily (or 40 mg SQ once daily)prevent their use. Pharmacologic therapies with Fondaparinux: 2.5 mg SQ once daily (for patients ≥50 kg)either LMWH or UFH should also be initiated LMWH should not be given to patients within patients with no contraindicationsCrCl

TRAUMATIC BRAIN INJURYHEALTH SYSTEMS EDITIONconcerning what the appropriate prophylactic measuresshould contain for patients with TBI. Most studies citedby the 2007 guidelines evaluating prophylactic antibioticusage in patients with external ventricular drainagehave shown no difference in infection rates. Additionally,one study showed that patients receiving bacitracinflushes experienced a significantly higher infectionrate than those without prophylactic measures. 7Prophylactic antibiotic use in patients with TBI haveshown no meaningful reduction in nosocomial infections.7 In addition, an increase in serious gram-negativeinfections was noted in this population. The guidelinesalso cite data showing an increase in resistant orgram-negative nosocomial pneumonias. This was seenwhen prophylactic antibiotics were given for longer than48 hours in general trauma patients. In contrast, onestudy showed a decrease in pneumonias when prophylacticantibiotics were given to patients with TBI. Nodifference in mortality was noted, so it is difficult toassess the usefulness of this therapeutic avenue. 7Since publication of the 2007 guidelines, one furtherstudy in patients with TBI has been completed. 8This study retrospectively evaluated the use of antibioticprophylaxis in patients with ICP monitor implantation.Of the 155 patients included in the analysis,only two developed CNS infections, and these wereboth in the group that received prophylactic antibiotics.Additionally, both complications from infectionsand multidrug resistant infections were significantlyincreased in the group that received antibiotics.In summary, there are currently no convincingdata to support infection prophylaxis in patients withTBI, especially in light of data suggesting that prophylaxismight predispose patients to more severe infectionswhen infections would arise. 7,8 To be fair, thereis a relative lack of data to give any definitive statementon the use of prophylactic antibiotics, but at thistime this practice cannot be supported.Venous Thromboembolism ProphylaxisVenous thromboembolism (VTE) is a topic that is verypertinent to patients with TBI, as they are at an increasedrisk of developing blood clots due to their typicallypersistent immobile state. The development of deepvein thrombosis (DVT) in patients with TBI who donot receive prophylaxis is as high as 25%. 9 However,there remains some uncertainty about the appropriatenessof VTE prophylaxis due to the questionable safetyof anticoagulation in patients who have TBI. Mechanicalmeans of VTE prophylaxis such as sequential compressiondevices seem to carry less risk in patients withTBI, but concomitant lower limb injuries can preventtheir use in some patients. Per the 2007 guidelines,mechanical VTE prophylaxis is recommended in allsevere patients with TBI who have no contraindicationsto usage, such as an intracranial bleed. 10Concerning pharmacologic options, the guidelinessuggest that low-molecular-weight heparin (LMWH)or low-dose unfractionated heparin (UFH) should beused in addition to mechanical means of VTE prophylaxiswhen no contraindications to LMWH or UFHexist. It is important to note, however, that the guidelinesdo not elicit a preferred agent, dosage, or timingof pharmacologic prophylaxis and also warn of theincreased risk of intracranial hemorrhage expansion. 10Three studies have been published since the guidelineson pharmacologic VTE prophylaxis in patientswith TBI. 11-13 A 2007 prospective study evaluated theuse of dalteparin in trauma patients in which 23%were patients with TBI. 11 These patients received prophylacticdalteparin (5,000 units SQ once daily) ifthere was no active or progressing bleed on CT scan.No patients developed or had increased intracranialbleeding after initiation of dalteparin, while only 3.9%of patients had evidence of DVT and 0.8% had evidenceof pulmonary embolism. A second prospectivestudy published in 2008 evaluated the use ofenoxaparin (30 mg SQ twice daily) in patients withTBI. 12 Progressive hemorrhagic injury was seen in3.4% of the TBI population, with 67% of those patientshaving clinically insignificant hemorrhagic changes.In addition, one patient died from a potential sideeffect from enoxaparin usage. The authors of thesetwo studies concluded that enoxaparin and dalteparinare safe options in patients with TBI and that bothagents have a relatively low risk of significant bleedingcomplications. 11,12A retrospective study published in 2009 looked ata comparison of the risk of DVT in patients withand without TBI utilizing either LMWH or UFH(doses not specified). 13 This study showed a three- tofourfold increase in DVTs in patients with TBI usingrelative risks with 95% confidence intervals. The highestrate was noted when prophylaxis was started greaterthan 48 hours after insult.In summary, it is currently acceptable to recommendmechanical and pharmacologic VTE prophylaxisin patients with TBI that have no contraindicationsto usage. 10-13 The evidence is shifting in favorof quick initiation of prophylactic agents regardless ofproduct selection. However, the breakpoint for decidingbetween mechanical and pharmacologic choicesor agents is still unknown and should be a course offuture study.Seizure ProphylaxisPosttraumatic seizure (PTS) is a common occurrencein patients with TBI. These seizures are broken intotwo groups: early (within 7 days of injury) and late(after 7 days). Certain risk factors have been shownto place patients with TBI at increased risk for PTS.These risk factors include: Glasgow Coma Score (aHS-16U.S. Pharmacist • November 2009 • www.uspharmacist.com

TRAUMATIC BRAIN INJURYneurological scale used to assess level of consciousness)less than 10; cortical contusion; depressed skull fracture;subdural, intracerebral, and epidural hematoma;penetrating head wound; or seizure within 24 hoursafter injury. 14Phenytoin and valproate sodium have been studiedin the prevention of early and late PTS. Onestudy cited by the 2007 guidelines showed a significantreduction in early PTS without showing any significanteffect on late PTS or survival with the use ofphenytoin. 14 In contrast, a randomized, double-blindstudy showed no early or late PTS benefit by usingphenytoin. Valproate sodium has shown a similar rateof early PTS reduction when compared to phenytoin.However, a trend toward higher mortality in the valproatesodium group was noted and could be cause forconcern. 14Since the publication of the guidelines, there havebeen two pertinent studies completed regarding seizureprophylaxis. 15-16 The first, a study from 2008, comparedthe incidence of seizures in patients with TBIwhen randomized to either phenytoin or levetiracetam. 15Results indicated that there was no significant differencein seizure incidence. However, patients receivinglevetiracetam showed increased incidence of electroencephalogram(EEG) abnormalities. An EEG was indicatedif patients displayed persistent coma, decreasedmental status, or clinical signs of seizures.The second study evaluated the incidence of latePTS in patients with TBI who did or did not receiveantiseizure prophylaxis upon initial presentation. 16This study was carried out in Italy, with phenobarbitalbeing one of the main agents used in antiseizureprophylaxis. Interestingly, in the retrospective portionof the study, 29% of patients who received antiseizureprophylaxis developed late PTS, while only 13% ofpatients who did not receive prophylaxis developedlate PTS. While the retrospective data were not statisticallysignificant, the prospective data were evenmore striking. A significant difference was noted inthe prospective group, where 39% of patients treatedwith antiseizure prophylaxis developed late PTS, whilenone of the patients who were not treated with antiseizureprophylaxis developed late PTS. However, phenobarbitalis not commonly used in the U.S. in thisregard because of its adverse-effect profile and multipledrug interactions, and because more appropriateantiepileptic selections are available; therefore,results must not be generalized too drastically.In summary, current literature including the 2007guidelines indicates that the incidence of early PTSappears to be reduced with the addition of prophylacticantiseizure medications. 14 However, there is currentlyno evidence to indicate that prophylactic antiseizuremedications alter mortality or incidence oflate PTS, and it is still unknown whether or not thiscourse of therapeutic prophylaxis is currently benefittingpatients.ConclusionTraumatic brain injury can be overwhelming and distressingto both patients and their family members. Inaddition to the emotional and social impacts that accompanyTBI, it is important to identify and deliver promptattention to the physical needs of the patient. Prophylacticmedications play an important role in patientswith TBI, yet as of now many categories lack definitivedata to direct appropriate therapeutic choices. Futurestudies are needed to clarify this important issue inthe management of patients with this condition.HEALTH SYSTEMS EDITIONREFERENCES1. Langlois JA, Rutland-Brown W, Thomas KE. Traumatic Brain Injury inthe United States: Emergency Department Visits, Hospitalizations, and Deaths.Atlanta, GA: Centers for Disease Control and Prevention, National Centerfor Injury Prevention and Control; 2006.2. Nolan S. Traumatic brain injury: a review. Crit Care Nurs Q.2005;28:188-194.3. Faupel G, Reulen HJ, Muller D, et al. Double-blind study on the effectsof steroids on severe closed head injury. In: Pappius HM, Feindel W, eds.Dynamics of Brain Edema. New York, NY: Springer-Verlag; 1976:337-343.4. Gobiet W, Bock WJ, Liesgang J, et al. Treatment of acute cerebral edemawith high dose of dexamethasone. In: Beks JW, Bosch DA, Brock M, eds.Intracranial Pressure III. New York, NY: Springer-Verlag; 1976:231-235.5. Brain Trauma Foundation, American Association of NeurologicalSurgeons, Congress of Neurological Surgeons, et al. Guidelines for themanagement of severe traumatic brain injury. XV. Steroids. J Neurotrauma.2007;24(suppl 1):S91-S95.6. Roberts I, Yates D, Sandercock P, et al. Effect of intravenous corticosteroidson death within 14 days in 10,008 adults with clinically significanthead injury (MRC CRASH trial): randomised placebo-controlled trial.Lancet. 2004;364:1321-1328.7. Brain Trauma Foundation, American Association of NeurologicalSurgeons, Congress of Neurological Surgeons, et al. Guidelines for themanagement of severe traumatic brain injury. IV. Infection prophylaxis.J Neurotrauma. 2007;24(suppl 1):S26-S31.8. Stoikes NF, Magnotti LJ, Hodges TM, et al. Impact of intracranial pressuremonitor prophylaxis on central nervous system infections and bacterialmulti-drug resistance. Surg Infect (Larchmt). 2008;9:503-508.9. Denson K, Morgan D, Cunningham R, et al. Incidence of venousthromboembolism in patients with traumatic brain injury. Am J Surg.2007;193:380-384.10. Brain Trauma Foundation, American Association of Neurological Surgeons,Congress of Neurological Surgeons, et al. Guidelines for the managementof severe traumatic brain injury. V. Deep vein thrombosis prophylaxis.J Neurotrauma. 2007;24(suppl 1):S32-S36.11. Cothren CC, Smith WR, Moore EE, Morgan SJ. Utility of once-dailydose of low-molecular-weight heparin to prevent venous thromboembolismin multisystem trauma patients. World J Surg. 2007;31:98-104.12. Norwood SH, Berne JD, Rowe SA, et al. Early venous thromboembolismprophylaxis with enoxaparin in patients with blunt traumatic braininjury. J Trauma. 2008;65:1021-1027.13. Reiff DA, Haricharan RN, Bullington NM, et al. Traumatic brain injuryis associated with the development of deep vein thrombosis independent ofpharmacological prophylaxis. J Trauma. 2009;66:1436-1440.14. Brain Trauma Foundation, American Association of NeurologicalSurgeons, Congress of Neurological Surgeons, et al. Guidelines for themanagement of severe traumatic brain injury. XIII. Antiseizure prophylaxis.J Neurotrauma. 2007;24(suppl 1):S83-S86.15. Jones KE, Puccio AM, Harshman KJ, et al. Levetiracetam versus phenytoinfor seizure prophylaxis in severe traumatic brain injury. Neurosurg Focus.2008;25:E3.16. Formisano R, Barba C, Buzzi MG, et al. The impact of prophylactictreatment on post-traumatic epilepsy after severe traumatic brain injury.Brain Injury. 2007;21:499-504.HS-19U.S. Pharmacist • November 2009 • www.uspharmacist.com

HEALTH SYSTEMS EDITIONNewly Approved mTORInhibitors for the Treatment ofMetastatic Renal Cell Carcinoma© JUPITERIMAGESThe American Cancer Society has estimated that57,760 new cases of kidney cancer and 12,980deaths due to kidney cancer will occur in theUnited States in 2009. Included in these statistics arerenal cell carcinoma (RCC) and transitional cell carcinomaof the renal pelvis. Kidney cancer is one of the 10 mostcommon types of cancer in men and women, with menat higher risk than women. The overall lifetime risk ofdeveloping kidney cancer is approximately 1 in 75 (1.34%). 1RCC constitutes 90% of kidney cancers, and the peakincidence is in the sixth decade of life. The histology isprimarily clear cell carcinoma (85%); the remaining 15%comprises papillary, chromophobe, and collecting-ductcarcinomas. The incidence of RCC is increasing, andabout 30% of patients present with metastatic disease.Risk factors include smoking, hypertension, obesity,cystic kidney disease, and genetic abnormalities. Onegenetic abnormality is the mutation of the von Hippel-Lindau tumor-suppressor gene often seen in clear-cellcarcinomas. 2Patients with metastatic RCC have an estimated 10%survival rate at 5 years. A prognostic model to predictsurvival was developed to stratify patients into low-risk(no risk factors), intermediate-risk (1-2 risk factors), andpoor-risk categories (>2 risk factors). 2 See TABLE 1 forpredictors of short survival. 3Current Treatment OptionsSurgery is an important option forpatients with RCC. Localized diseasecan be cured with surgery; unfortunately,Diana Hey Cauley, PharmD, BCOPClinical Pharmacy Specialist,Genitourinary Medical OncologyDivision of Pharmacy, University of TexasM.D. Anderson Cancer CenterHouston, Texasabout 30% of these patients will have disease recurrence.Surgery is a good choice for patients with advanceddisease, benefiting quality of life by reducing pain orbleeding, and sometimes even improving survival. 4For many years, immunotherapy with the biologicresponse modifiers interleukin-2 (IL-2) and interferonalpha(IFN-A) has been the mainstay of systemic treatmentfor metastatic disease. Treatment with these agentsalone or in combination yields a median survival of 12to 17.5 months. 3 High-dose IL-2, which was FDAapprovedin 1992 for advanced RCC, provides durablecomplete response in a small fraction of patients. Conventionalchemotherapy yields response rates of less than10% and often is used in a palliative context. High-dosenonmyeloablative chemotherapy followed by allogeneicstem-cell transplantation remains experimental. 2,4Targeted therapies have been developed to interferewith intracellular signaling, tumor-cell proliferation,differentiation, and angiogenesis. The small-moleculetyrosine kinase (TK) inhibitors bind to receptor TKs(RTKs) located on cell-surface growth factor receptors(GFRs), thereby inhibiting tumor growth. 2 Sorafenib,which was approved in 2005 for advanced RCC, inhibitsmultiple intracellular and cell-surface kinases, includingRaf; vascular endothelial GFR types 1 to 3 (VEGFR1-3); platelet-derived GFR (PDGFR)-beta; the stem cell factor receptor (c-kit);Fms-like TK-3 (Flt3); and glial cellline–derived neurotrophic factor receptor(RET). 4,5 Sunitinib, approved foradvanced RCC in 2006, also inhibitsHS-20U.S. Pharmacist • November 2009 • www.uspharmacist.com

Introducing Teva’s New andImproved Product LabelingNDC#s are prominentlyplaced in top left cornerLot number isimprinted foreasier trackingTALLman lettering,used when appropriate,helps reducedispensing errorsBar Coded with ascannable StandardRSS bar codeStrength is highlighted incolor for better visibility.Products with multiplestrengths are distinguishedby different colors.Manufacturinglocation of productExpirationDateFor up-to-date information on all of our products,including many latex-free and preservative-freeinjectables, visit www.tevausa.com©2009, Teva Pharmaceuticals USA 8430 A19 Hughes • Irvine, California 92618800.729.9991 • www.tevausa.com

HEALTH SYSTEMS EDITIONMTOR INHIBITORS FOR METASTATIC RENAL CELL CARCINOMAFigure 1. mTOR signaling pathway.mTOR: mammalian target of rapamycin; PI3K:phosphoinositide 3-kinase.multiple kinases, including VEGFR 1–3, PDGFR-alphaand -beta, c-kit, Flt3, colony-stimulating factor receptortype 1, and RET. 4,6Bevacizumab is a monoclonal recombinant humanizedantibody that binds to and neutralizes circulating VEGFligand, which prevents activation of the kinase VEGFR. 2It was FDA-approved in July 2009 in combination withIFN-A for patients with metastatic RCC. Clinical trialsalso demonstrate activity as single-agent therapy. 4Mammalian Target of Rapamycin (mTOR) PathwayThree primary signaling pathways associated with RTKsare currently identified in cancer cells. One of them isthe phosphoinositide 3-kinase (PI3K)/Akt/mTOR proteincascade (FIGURE 1); the other two are the protein kinaseC family and the Ras/mitogen-activated protein kinasecascades. Activation of RTK leads to stepwise activationof PI3K, then Akt, and then mTOR, directly promotingtumor growth. The mutation and overexpression of RTK,as well as growth receptors, are common in RCC. 7Table 1Predictors of Short SurvivalRisk FactorsLDH levelHBCorrected serum calcium levelInterval from original diagnosisto start of systemic treatmentKarnofsky performance scoreNumber of metastatic sitesDescription>1.5 × ULN10 mg/dL

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HEALTH SYSTEMS EDITIONMTOR INHIBITORS FOR METASTATIC RENAL CELL CARCINOMATable 2Temsirolimus Phase III Study ResultsOutcome Temsirolimus Temsirolimus IFN-AMeasure Arm + IFN-A Arm ArmMedian OS 10.9 mo 8.4 mo 7.3 moMedian PFS 5.5 mo 4.7 mo 3.1 moClinical benefit a 32.1% 28.1% 15.5%aProportion of patients with objective response or stable disease for ≥24 wk.IFN-A: interferon-alpha; OS: overall survival; PFS: progression-free survival.Source: Reference 3.with strong inducers and inhibitors, so these medicationsshould be avoided. If coadministration is unavoidable,the dose of temsirolimus should be increased to 50 mgwhen given with a strong CYP450 3A4 inducer andreduced to 12.5 mg when given with a strong inhibitor. 2Grapefruit juice should be avoided because it may increasesirolimus levels. Use temsirolimus with caution in patientswith hypersensitivity to polysorbate 80. 10Phase I and II clinical trials determined that temsirolimus25 mg IV could be given safely on a weekly basisand had promising activity in RCC. Researchers alsofound that patients with treatment-refractory, poorprognosisRCC who were receiving temsirolimus had amedian overall survival of 8.2 months versus 4.9 monthsfor IFN-A. 7 Subsequently, Hudes and colleagues conducteda phase III trial comparing three treatment arms in 626patients with metastatic RCC: temsirolimus 25 mg IVweekly; temsirolimus 15 mg IV weekly with IFN-A at3 to 6 MU subcutaneously (SC) three times weekly; andIFN-A 3 to 18 MU SC three times weekly. Patients hadto be treatment-naïve and have at least three predictorsof short survival. 3 See TABLE 2 for results. 3Dose reductions and delays were least common in thetemsirolimus single-agent arm. 3 The FDA approvedtemsirolimus for metastatic RCC in May 2007. As aresult of the phase II and III trials, temsirolimus is nowfavored as first-line treatment for patients with poorprognosismetastatic RCC. 9EverolimusEverolimus, also known as RAD001, is an orally administeredmTOR kinase inhibitor. It forms a complex withthe intracellular protein FKBP-12 and inhibits the mTORkinase. Everolimus reduces cell proliferation, cell growth,angiogenesis, and glucose uptake, and it inhibits HIF-1expression and reduces VEGF expression. 7,8,11Everolimus is administered once daily as a 10-mgtablet, at the same time every day, with or without food.It is metabolized hepatically via CYP450 3A4. Druginteractions with CYP450 3A4 inducers and inhibitorsshould be avoided. If treatment with a strong CYP450inducer cannot be avoided, the dose of everolimus maybe increased from 10 mg to 20 mg in 5-mg increments.The dose of everolimus may also be reducedto 5 mg in the presence of moderate hepaticimpairment or severe adverse events. Themean half-life is about 30 hours. Thereare six main metabolites of everolimus;they are 100 times less potent than theparent compound. Grapefruit juice shouldbe avoided. 11Phase I and II studies established thesafety and efficacy of everolimus administeredon a daily oral dosing schedule.They also demonstrated disease stabilizationor tumor reduction in metastaticRCC. 4,7,9,12 Responding to the need for active cancermedications after traditional agents have failed, a phaseIII study investigated the role of everolimus in second- orthird-line dosing. 12Motzer and colleagues conducted a phase III trial in410 patients with metastatic clear cell RCC assigned ina 2-to-1 ratio to two treatment arms: oral everolimus 10mg daily plus best supportive care or placebo plus bestsupportive care. 12 Patients had to have progressed by orwithin 6 months of stopping sunitinib, sorafenib, or bothdrugs; previous therapy with bevacizumab, IL-2, or IFN-Awas allowed. At progression, placebo patients couldtransition to active open-label everolimus treatment forethical reasons. At the second interim safety analysis, thestudy was halted early because the prolongation in progression-freesurvival (PFS) was greater than expected.See TABLE 3 for results. 12,13 The crossover from placeboto everolimus at disease progression would likely confoundthe median overall survival data for the everolimus group;therefore, the endpoint was not reached. 12In a follow-up to the phase III everolimus study,researchers collected 4.5 months of additional blindeddata for a total of 416 patients. The results of this studydemonstrated persistence of PFS prolongation. 13In March 2009, the FDA approved everolimus forthe treatment of advanced RCC after failure of treatmentwith sunitinib or sorafenib. 11 The drug also is FDAapprovedas a medical device as a component of theeverolimus-eluting coronary stent system for coronaryartery disease. 14 Everolimus is approved in Europe as animmunosuppressant for the prevention of solid organtransplant rejection. 9Adverse EventsThe primary adverse-events profile of the mTOR inhibitorsincludes hyperglycemia, hypercholesterolemia, andhyperlipidemia. This reflects the blockade of mTOR, theprimary signaling conduit for insulin and insulin growthfactor. Other common adverse events for temsirolimusand everolimus include fatigue, stomatitis, diarrhea,hypophosphatemia, low red blood cells and platelets, andperipheral edema. These adverse events are commonlyreversible upon treatment discontinuation. Less commonHS-24U.S. Pharmacist • November 2009 • www.uspharmacist.com

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HEALTH SYSTEMS EDITIONMTOR INHIBITORS FOR METASTATIC RENAL CELL CARCINOMATable 3Everolimus Phase III Study Results aOutcome Everolimus + Best Placebo + BestMeasure Supportive Care Supportive CareMedian PFS 4.9 mo 1.9 moMedian OS Not reached 8.8 moPatients with PR 1% 0%Patients with stable disease 63% 32%Patients with progressive disease 19% 46%aIncluding 4.5-mo follow-up.OS: overall survival; PFS: progression-free survival; PR: partial response.Source: References 12, 13.symptoms are renal insufficiency, interstitial pneumonitis,and low white blood cells. 8Fatigue is experienced by more than 50% of patientstaking mTOR inhibitors. About 10% have dose-limitingfatigue to the degree of warranting dose reduction. 9Hyperglycemia is experienced by more than 50% oftreated patients. Owing to the rising incidence of obesityand metabolic syndrome, it is important to identify theseadverse events quickly. Up to 10% of patients developsevere symptoms and require medical intervention withan oral hypoglycemic agent or SC insulin. Regular monitoringof triglycerides is recommended, with early dietaryinterventions for minor elevations and initiation of alipid-lowering agent for levels exceeding 500 mg/dL.Severe hypertriglyceridemia is associated with acutepancreatitis. 9Impairment of renal function and interstitial pulmonaryfibrosis are rare but important events. Serum creatinineshould be monitored regularly. The pulmonaryfibrosis is often steroid-responsive and frequently fullyreversible. If symptoms of progressive dyspnea or lunginfiltrates are present, the dose may be reduced or thetreatment discontinued. 9Both temsirolimus and everolimus are classified aspregnancy category D. Men and women receivingtemsirolimus should use contraception while receivingactive treatment and for 3 months afterthe final dose. Women taking everolimusshould use contraception while receivingactive treatment and for 8 weeks afterthe final dose. 10,11Patients being treated with mTORinhibitors should not receive live vaccines.Patients should also avoid close contactwith individuals who have received livevaccines. 10,11Investigational Combination StudiesThe goal of combining different therapiesis to achieve greater efficacy. Strategiesoften involve combining agents withdifferent mechanisms of action and sideeffectprofiles. Investigational combinations in phase Iand II studies include bevacizumab with either everolimusor temsirolimus; other studies are examiningtemsirolimus with sorafenib or IFN-A. 4,8 Certain combinationsrequire up-front dose reductions, such astemsirolimus with sorafenib, or are not safe, such astemsirolimus with sunitinib. 15CostThe average wholesale price (AWP) of the temsirolimusinjection kit 25 mg IV weekly is $1,499, or $5,996 permonth. The respective monthly AWPs of everolimus 5mg and 10 mg orally daily are $6,400 and $6,700. Themanufacturers offer assistance programs for eligiblepatients. Prior authorization often is required for thesehigh-cost medications.SummaryThere are two recently approved novel mTOR inhibitorswith activity in metastatic RCC. Temsirolimus is FDAapprovedfor first-line treatment of metastatic RCC andis favored for poor-prognosis patients. Everolimus isFDA-approved for second-line treatment of metastaticRCC after sunitinib or sorafenib failure. These agentsprovide a valuable choice for providers and patients withlimited treatment options.REFERENCES1. American Cancer Society. Detailed Guide: Kidney Cancer.What are the key statistics for kidney cancer?www.cancer.org/docroot/CRI/content/CRI_2_4_1X_What_are_the_key_statistics_for_kidney_cancer_22.asp?sitearea=.Accessed July 25, 2009.2. Reeves DJ, Liu CY. Treatment of metastatic renal cell carcinoma.Cancer Chemother Pharmacol. 2009;64:11-25.3. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus,interferon alfa, or both for advanced renal-cell carcinoma. NEngl J Med. 2007;356:2271-2281.4. Basso M, Cassano A, Barone C. A survey of therapy foradvanced renal cell carcinoma. Urol Oncol. Epub July 6,2009. www.urologiconcology.org/article/S1078-1439(09)00142-2/abstract [registration required]. AccessedJuly 20, 2009.5. Nexavar (sorafenib) package insert. Wayne, NJ: BayerHealthCare Pharmaceuticals, Inc; February 2009.6. Sutent (sunitinib) package insert. New York, NY: PfizerLabs; July 2009.7. Wysocki P. mTOR in renal cell cancer: modulator oftumor biology and therapeutic target. Expert Rev Mol Diagn.2009;9:231-241.8. Hudes GR. Targeting mTOR in renal cell carcinoma.Cancer. 2009;115(suppl 10):2313-2320.9. Dasanu CA, Clark BA III, Alexandrescu DT. mTORblockingagents in advanced renal cancer: an emerging therapeuticoption. Expert Opin Investig Drugs. 2009;18(2):175-187.10. Torisel (temsirolimus) injection package insert. Philadelphia,PA: Wyeth Pharmaceuticals Inc; September 2008.11. Afinitor (everolimus) package insert. East Hanover, NJ:Novartis Pharmaceuticals Corp; March 2009.12. Motzer RJ, Escudier B, Oudard S, et al. Efficacy ofeverolimus in advanced renal cell carcinoma: a double-blind,randomised, placebo-controlled phase III trial. Lancet.2008;372:449-456.13. Kay A, Motzer R, Figlin R, et al. Updated data from aphase III randomized trial of everolimus (RAD001) versusPBO in metastatic renal cell carcinoma (mRCC). Proc AmSoc Clin Oncol. 2009. Abstract 278 [presented at 2009ASCO Genitourinary Cancers Symposium].14. FDA. XIENCE V everolimus eluting coronary stenton the over-the-wire (OTW) or rapid exchange (RX) stentdelivery systems–P070015.www.fda.gov/medicaldevices/productsandmedicalprocedures/deviceapprovalsandclearances/recently-approveddevices/ucm074025.htm. Accessed July 15, 2009.15. Sosman J, Puzanov I. Combination targeted therapy inadvanced renal cell carcinoma. Cancer. 2009;115(suppl10):2368-2375.HS-26U.S. Pharmacist • November 2009 • www.uspharmacist.com

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HEALTH SYSTEMS EDITIONIn-Service PrimersResearch results inthe emerging areaof nutritionalneuroscience pointto a link betweenwhat people eat andthe quality of theirmental state.Manouchehr Saljoughian, PharmD, PhD,Alta Bates Summit Medical Center,Department of Pharmacy,Berkeley, CaliforniaNutrition andClinical DepressionOVERVIEWWhile the connectionbetween nutritionaldeficiencies and physicalillness is more obvious, fewpeople see the connectionbetween nutrition and depression.This is because depression ismore typically thought of aseither biochemicaly based oremotionally rooted. It is nowproven that nutrition can play akey role in the onset, as well asseverity and duration, of depression.Nutritional neuroscience isan emerging discipline that isshedding light on the linkbetween nutritional factors andhuman cognition, behavior, andemotions. 1There are two types of depression.Behavioral depression or“the blues” results from variouscauses, and most people experienceit at some point in theirlives. Clinical depression, on theother hand, is much more serious.It is usually caused by achemical imbalance in the brainand requires medical attention. 2Nutrition plays an importantrole in every aspect of well-being,and improper nutrition can leadto poor bodily function. Thereare many reports that people withclinical depression also sufferfrom malnutrition. The dietaryhabits of the general populationin the United States and manyAsian countries reveal that peopleare often deficient in many nutrients,especially essential aminoacids, vitamins, minerals, andomega-3 fatty acids. People whoare depressed often lose all senseof self and stop eating and caring.Food alone cannot preventdepression, but poor nutritionmakes the body incapable ofhealing itself. Supplements containingamino acids have beenfound to reduce symptoms ofdepression, as they are convertedto neurotransmitters, which inturn alleviate depression andother mental health problems. 3Since most antidepressant prescriptiondrugs have side effects,it is possible that some patientswho are not being observed bypsychiatrists will skip taking theirmedications. Such noncompliancecan put patients at a higherrisk for committing suicide orbeing hospitalized. An alternateand effective way for psychiatriststo circumvent noncompliance isto familiarize themselves withalternative or complementarynutritional therapies. Psychiatristscan recommend doses of dietarysupplements based on efficaciousstudies and adjust the doses basedon the results obtained by closelyobserving the changes in thepatient. 4If a person with depressionsuffers from loss of sleep, clinicianswill either increase theamount of amino acids in theirdiet or add iron for loss ofappetite. There are foods thatshould be included in the diet ofa person with clinical depression.Meat and amino acids such asphenylalanine, tryptophan,choline, and tyrosine—whichhelp the nervous system functionproperly—should be added to theHS-28U.S. Pharmacist • November 2009 • www.uspharmacist.com

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NUTRITION AND CLINICAL DEPRESSIONHEALTH SYSTEMS EDITIONdiet. Choline and tryptophan canbe found in many freshwater fish,and tyrosine can be found incheese. 5 Foods that should beavoided are alcohol and caffeine.Alcohol acts as a central nervoussystem depressant, which makesthe situation worse, and caffeineinterferes with sleep and promotesnervousness.Signs andSymptoms of DepressionMany people attribute the feelingsinduced by depression toother causes such as inability tohandle stress, social stigma, andalcoholism. However, depressionis not difficult to spot, and specificsigns and symptoms exhibitedby a person are helpful inidentifying its presence (seeTABLE 1). 6Brain Biochemical ImbalanceNeurotransmitters are the naturalbiochemicals that facilitate communicationbetween brain cells.These substances control ouremotions, memory, moods,behavior, sleep, and learning abilities.Neurotransmitters are manufacturedin the brain from theamino acid precursors we receivefrom food. Without adequateamino acid conversion, sufficientamounts of neurotransmitters arenot produced. 7 Alcohol destroysthese essential precursor aminoacids, which is probably whyalcoholics seem so emotionallydown and depressed.The two major neurotransmittersinvolved in preventingdepression are serotonin (fromthe amino acid L-tryptophan)and norepinephrine (from theamino acids L-phenylalanine andL-tyrosine). It is interesting thatthe depressive symptoms exhibitedindicate which amino acidsare lacking: If the symptoms aresleeplessness, anxiety, or irritability,then L-tryptophan is low; ifthe symptoms are lethargy,Table 1Signs of Depression• Indecisiveness• Continual fatigue and lethargy• Loss of appetite or binge eating• Withdrawal from daily activities• Inability to concentrate• Lack of motivation andunresponsiveness to people• Feeling helpless, immobilized• Sleeping too much; using sleepto escape reality• Insomnia, particularly earlymorninginsomnia• Lack of response to good news• Ongoing anxiety• An “I don’t care” attitude• Easily upset or angered• Listening to mood musicpersistently• Self-destructive behaviorSource: Reference 6.fatigue, sleeping too much, orfeelings of immobility, L-tyrosineor L-phenylalanine is lacking. 7Conversion of AminoAcids to NeurotransmittersThe amino acid tyrosine, foundin large amounts in cheese, hasan amazing effect on depression.Tyrosine is a nonessential aminoacid that is synthesized in thebody from phenylalanine. As abuilding block for several importantbrain chemicals, tyrosine isneeded to make epinephrine,norepinephrine, serotonin, anddopamine, all of which work toregulate mood. Tyrosine also aidsin the production of melanin(the pigment responsible for hairand skin color) and in the functionof organs responsible formaking and regulating hormones,including the adrenal,thyroid, and pituitary glands.Tyrosine is also involved in thesynthesis of enkephalins, substancesthat have pain-relievingeffects in the body. 8Low levels of tyrosine havebeen associated with low bloodpressure, low body temperature,and an underactive thyroid.Because tyrosine binds to freeradicals, it is considered a mildantioxidant. Thus, tyrosine maybe useful for individuals whohave been exposed to harmfulchemicals (such as from smoking)and radiation. The usualdose is 3 to 6 g per day, taken onan empty stomach. Vitamins B 6and C need to be taken to facilitatethe conversion of tyrosine tonorepinephrine. 8An alternative to tyrosine isthe amino acid L-phenylalanine,which can also be converted intonorepinephrine. L-phenylalanineis converted to a substance called2-phenylethylamine (2-PEA). Lowbrain levels of 2-PEA are alsoresponsible for some depression.2-PEA is converted to tyrosine,which then converts to norepinephrine.L-phenylalanine is abetter start than tyrosine, but if itcauses the brain to race due tothe formation of 2-PEA, thepatient should start with tyrosine.A disadvantage to taking L-phenylalanine is its slight potentialfor raising blood pressure.There is also some evidencethat excess L-phenylalanine cancause headaches, insomnia, andirritability. For these reasons, it isimportant to start with a lowdose. L-phenylalanine doses canrange from 500 mg to 1,500 mgdaily and should be taken on anempty stomach. 8The FDA prohibited the manufactureand sale of tryptophanin the United States in the fall of1980. Although the FDA continuesto enunciate its concernabout the use of L-tryptophan asa single product and related compoundssuch as L-5-hydroxytryptophan,the agency does not prohibitthe marketing of dietarysupplements that contain lowerHS-30U.S. Pharmacist • November 2009 • www.uspharmacist.com

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NUTRITION AND CLINICAL DEPRESSIONHEALTH SYSTEMS EDITIONdoses of L-tryptophan. 5-hydroxytryptophan(a direct precursor toserotonin) has been offered as analternative. The amino acid tryptophanis the precursor for serotoninand it is found in largeamounts in milk and turkey (seeTABLE 2). Serotonin controlsmood, sleep, sexual ability,appetite, and pain threshold.Increasing serotonin can liftdepression and end insomnia. 8Prostaglandin E1and DepressionAnother biochemical cause ofdepression is a genetic inability tomanufacture enoughprostaglandin E1 (PGE1), animportant brain metabolitederived from essential fatty acids(EFAs). The problem is the resultof an inborn deficiency in omega-6 essential fatty acids. Alcoholstimulates temporary productionof PGE1 and lifts the depression.When drinking is stopped, PGE1levels fall again and depressionreturns. To banish it, the patientsturn again to alcohol. Thus, adownward spiral toward alcoholismbegins.During the past 15 years,researchers have found that ifthey restore the PGE1 levels tonormal range in patients sufferingfrom alcoholism, they caneliminate both the depressionand the need to drink for relief.Research showsthat nutritionaldeficiencies inbrain chemistrycan result indepression, anger,hopelessness, andparanoia.This can be achieved with a substancecalled gamma-linolenicacid, which can be easily convertedto PGE1. 9The Effect of NutritionResearch shows that nutritionaldeficiencies in brain chemistrycan result in depression, anger,hopelessness, and paranoia. Thisis because the connectionTable 2Important Points About Tryptophan• Tryptophan alone will not be converted to serotonin. To ensure that it isproperly used, you must also take vitamins C and B 6.• Tryptophan is converted to niacin before its final conversion into serotonin.If your body is deficient in niacin, the tryptophan you take will supply youwith niacin, not serotonin. For this reason, it is a good idea to take a B-complex vitamin daily. This will give you both vitamin B 6and niacin andallow the tryptophan to be converted to serotonin.• Unlike serotonin, tryptophan (or more accurately, its breakdown product 5-hydroxytryptophan, or 5-HTP) can pass through the blood–brain barrier.Thus, supplementation of tryptophan would appear to be a simple and naturalalternative to selective serotonin reuptake inhibitor drugs.• Since it is not stored in the body, tryptophan cannot accumulate to toxiclevels. Taking high doses of supplements containing tryptophan, however,can produce some side effects such, as drowsiness, increased blood pressure,and bad dreams.between depression and vitaminand mineral deficiencies is oftenmissed. A closer look at the dietof patients suffering fromdepression indicates that theirnutrition is far from adequate.They make poor food choicesand frequently select foods thatcontribute to depression. 10The B-complex vitamins areessential to mental and emotionalwell-being. They cannot be storedin our bodies, so we dependentirely on our daily diet to supplythem. B vitamins aredestroyed by alcohol, refined sugars,nicotine, and caffeine. Continuedvitamin C deficiencycauses chronic depression,fatigue, and vague ill health, andinsufficient amounts of mineralsalso cause mental problems. Therelationship between vitamins Band C and minerals and depressionis shown in TABLE 3.CarbohydratesCarbohydrates, or polysaccharides,play an important role in thestructure and function of anorganism. In humans, they havebeen found to affect mood andbehavior. Food rich in carbohydratestriggers the release ofinsulin in the body. Insulin facilitatesthe release of blood sugarinto the cells, where it can be usedfor energy, and simultaneouslytriggers the entry of tryptophan tothe brain. Tryptophan in the brainaffects neurotransmitter levels.Consumption of diets low incarbohydrates tends to precipitatedepression, since the production ofthe brain chemicals serotonin andtryptophan, which promote thefeeling of well-being, is reduced. Itis suggested that low glycemicindex (GI) foods such as somefruits and vegetables, whole grains,and pasta are more likely to providea moderate but lasting effecton brain chemistry, mood, andenergy level than the high GIfoods. 10HS-32U.S. Pharmacist • November 2009 • www.uspharmacist.com

NUTRITION AND CLINICAL DEPRESSIONTable 3Effects of Vitamins and Minerals on DepressionVitamin Bs• Vitamin B 1(thiamine): Deficiencies trigger depression and irritability andcan cause neurologic and cardiac disorders among alcoholics.• Vitamin B 2(riboflavin): Adequate riboflavin may be required for cognitivefunction. Riboflavin has been reported to improve depression scores inpatients taking TCA drugs.• Vitamin B 3(niacin): Depletion causes anxiety, depression, apprehension,and fatigue.• Vitamin B 5(pantothenic acid): Symptoms of deficiency are fatigue, chronicstress, and depression. Vitamin B 5is needed for hormone formation andfor the uptake of amino acids and the brain chemical acetylcholine, whichcombine to prevent certain types of depression.• Vitamin B 6(pyridoxine): Deficiency can disrupt formation of neurotransmitters.Vitamin B 6is a coenzyme needed for conversion of tryptophan toserotonin and of phenylalanine and tyrosine to norepinephrine.• Folic acid (B 9): Folate and MTHF work best together by helping to regulatethe neurotransmitters that affect depression.• Vitamin B 12: This vitamin controls blood levels of the amino acid homocysteine.Elevated levels of this substance appear to be linked with heart diseaseand, possibly, depression and Alzheimer’s disease.Vitamin CContinued vitamin C deficiency causes chronic depression, fatigue, and vagueill health.MineralsDeficiencies in a number of minerals can also cause mental problems.• Calcium: Depletion affects the central nervous system. Low levels of calciumcause nervousness, apprehension, irritability, and numbness.• Zinc: Deficiencies result in lack of appetite and lethargy. When zinc is low,copper in the body can increase to toxic levels, resulting in paranoia andfearfulness. Zinc also protects the brain cells against the potential damagecaused by free radicals.• Iron: Depression is often a symptom of chronic iron deficiency. Othersymptoms include general weakness, exhaustion, lack of appetite, andheadaches.• Manganese: This metal is needed for proper use of the B-complex vitaminsand vitamin C. Since it also plays a role in amino acid formation, a deficiencymay contribute to depression resulting from low levels of the neurotransmittersserotonin and norepinephrine. Manganese also helps stabilizeblood sugar and prevent hypoglycemic mood swings.• Potassium: Depletion is frequently associated with depression, tearfulness,weakness, and fatigue. A 1981 study found that depressed patients weremore likely than controls to have decreased intracellular potassium.Decreased brain levels of potassium have also been found on autopsy ofsuicides. Potassium levels can be boosted by using one teaspoon of Morton’sLite-Salt every day.• Magnesium: Symptoms of deficiency include confusion, apathy, loss ofappetite, weakness, and insomnia.• Selenium: Low selenium intake is associated with lowered mood status.Intervention studies with selenium with other patient populations revealthat selenium improves mood and diminishes anxiety.MTHF: methyltetrahydrofolate; TCA: tricyclic antidepressant.Source: References 11-14.Proteins and Amino AcidsMany of the neurotransmitters inthe brain are made from aminoacids. Proteins are made up ofamino acids and are importantbuilding blocks of life. As manyas 12 amino acids are manufacturedin the body and theremaining eight (essential aminoacids) must be supplied throughdiet. A high-quality protein dietcontains all of the essential aminoacids. Foods rich in high-qualityprotein include meat, milk andother dairy products, and eggs.Plant proteins in beans, peas, andgrains may be low in one or twoessential amino acids.Protein intake and in turn theindividual amino acids can affectthe brain function and mentalhealth. The neurotransmitterdopamine is made from theamino acid tyrosine, and the neurotransmitterserotonin is madefrom tryptophan. If there is alack of either of these aminoacids, there will lack of neurotransmittersynthesis, which isassociated with low mood andaggression in patients. The excessivebuildup of amino acids mayalso lead to brain damage andmental retardation. For example,excessive amounts of phenylalaninein individuals with the diseasecalled phenylketonuria cancause brain damage and mentalretardation. 10Omega-3 Fatty AcidsThe brain is one of the organswith the highest level of lipids(fats). Brain lipids are composedof fatty acids and are a majorpart of its membranes. It hasbeen estimated that gray mattercontains 50% fatty acids that arepolyunsaturated in nature (about33% belong to the omega-3 family)and hence are suppliedthrough the diet. In one of thefirst experimental demonstrationsof the effect of nutrients on thestructure and function of theHEALTH SYSTEMS EDITIONHS-33U.S. Pharmacist • November 2009 • www.uspharmacist.com

NUTRITION AND CLINICAL DEPRESSIONHEALTH SYSTEMS EDITIONbrain, the omega-3 fatty acidalpha-linolenic was found tohave a major role. An importanttrend has been observed from thefindings of some recent studiesthat lowering plasma cholesterolby diet and medications mightincrease depression. Among thesignificant factors involved arethe quantity and ratio of omega-6 and omega-3 polyunsaturatedfatty acids (PUFAs) that affectserum lipids and alter the biochemicaland biophysical propertiesof cell membranes. It hasbeen hypothesized that sufficientlong-chain PUFAs, especiallyDHA, may decrease the developmentof depression. 15The glycerophospholipids inthe brain consist of a high proportionof PUFAs derived fromthe essential fatty acids, linoleicacid, and alpha-linolenic acid.The main PUFAs in the brainare DHA, derived from theomega-3 fatty acid alphalinolenicacid, arachidonic acid,and docosatetraenoic acid, bothderived from the omega-6 fattyacid and linoleic acid. Experimentalstudies have alsorevealed that diets lackingomega-3 PUFAs lead to considerabledisturbance in neuralfunction. 16Age, Depression, and CAMAnorexia in the elderly may playan important role in precipitatingdepression, either by reducingfood intake directly or inresponse to such adverse factorsas age-associated reductions insensory perception (taste andsmell), poor dentition, use ofmultiple prescription drugs, anddepression. Currently, to tacklethe problem of depression, manypeople are following the complementaryand alternative medicine(CAM) interventions. CAMtherapies are defined by theNational Center for Complementaryand Alternative Medicineas “a group of diverse medicaland health systems,practices, and products that arenot considered to be a part ofconventional medicine.” 17 Mentalhealth professionals need tobe aware that it is likely that afair number of their patientswith bipolar disorder might useCAM interventions. Some cliniciansjudge these interventionsto be attractive and safe alternativesor adjuncts to conventionalpsychotropic medications.Current research in psychoneuroimmunologyand brainbiochemistry indicates the possibilityof communication pathwaysthat can provide a clearerunderstanding of the associationbetween nutritional intake, thecentral nervous system, andimmune function, thereby influencingan individual’s psychologicalhealth status. These findingsmay lead to greater acceptance ofthe therapeutic value of dietaryintervention among health practitionersand health care providersin addressing depression andother psychological disorders. 18The Safety ofVitamin SupplementsVitamin C and the B-complexvitamins, discussed above, are allwater soluble; therefore, theycannot accumulate in the bodyor be stored for future use.Amounts above and beyond currentnutritional needs areexcreted through urine. As aresult, there is little danger ofoverdosing. Unlike water-solublevitamins, lipid-soluble vitaminsand minerals can be stored inbody tissues. For therapeuticdoses of these compounds, theadvice of a qualified nutritionconsultant is required. Do notexceed the recommended therapeuticdoses, since accumulationof certain minerals in the bodycan be dangerous. 19REFERENCES1. Shaheen Lakhan SE, Vieira KF. Nutritionaltherapies for mental disorders. Nutr J. 2008;7:2.2. National Institute of Mental Health. Depression.Bethesda, MD: US Department of Healthand Human Services; 2000 [reprinted September2002].3. Bourre JM. Effect of nutrients (in food) on thestructure and function of the nervous system:update on dietary requirements for brain, part 1:nicronutrients. J Nutr Health Aging. 2006;10:377-385.4. Massimo CM, Ferrara A, Boscati L, et al.Plasma and platelet amino acid concentrations inpatients affected by major depression and underFluvoxamine treatment. Neuropsychobiology.1998;37:124-129.5. Shaw K, Turner J, Del Mar C. Tryptophan and5-hydroxytryptophan for depression. CochraneDatabase of Systematic Reviews. 2002;1:articleCD003198.6. Rush AJ. The varied clinical presentations ofmajor depressive disorder. J Clin Psychiatry.2007;68:4-10.7. Firk C, Markus CR. Serotonin by stress interaction:a susceptibility factor for the developmentof depression? J Psychopharmacol. 2007;21:538-544.8. Ruhe HG, Mason NS, Schene AH. Mood isindirectly related to serotonin, norepinephrineand dopamine levels in humans: a meta-analysisof monoamine depletion studies. Mol Psychiatry.2007;12:331-359.9. Horrobin DF, Manku MS. Possible role ofprostaglandin E1 in the affective disorders and inalcoholism. Br Med J. 1980;280(6228):1363-1366.10. Bourre JM. Effect of nutrients (in food) onthe structure and function of the nervous system:update on dietary requirements for brain, part 1:micronutrients. J Nutr Health Aging.2006;10:377-385.11. Abou-Saleh MT, Coppen A. Folic acid andthe treatment of depression. J Psychosom Res.2006;61:285-287.12. Levenson CW. Zinc, the new antidepressant?Nutr Rev. 2006;6:39-42.13. Eby GA, Eby KL. Rapid recovery from majordepression using magnesium treatment. MedHypotheses. 2006;67:362-370.14. Benton D. Selenium intake, mood and otheraspects of psychological functioning. Nutr Neurosci.2002;5:363-374.15. Bourre JM. Dietary omega-3 fatty acids andpsychiatry: mood, behavior, stress, depression,dementia and aging. J Nutr Health Aging.2005;9:31-38.16. Sinclair AJ, Begg D, Mathai M, WeisingerRS. Omega-3 fatty acids and the brain: review ofstudies in depression. Asia Pac J Clin Nutr.2007;16:391-397.17. Roberts SB. Energy regulation and aging:recent findings and their implications. Nutr Rev.2000;58:91-97.18. Andreescu C, Mulsant BH, Emanuel JE.Complementary and alternative medicine in thetreatment of bipolar disorder: a review of the evidence.J Affect Disord. May 2, 2008 [Epub aheadof print].19. Eritsland J. Safety considerations of polyunsaturatedfatty acids. Am J Clin Nutr.2000;71:197S-201S.HS-34U.S. Pharmacist • November 2009 • www.uspharmacist.com

ProgressiveSupranuclear PalsyPARKINSON’S-LIKE SYMPTOMSDifficulty looking upwithout extendingthe neck ordifficulty climbingup and down stairsmay signal thiscondition.Progressive supranuclearpalsy (PSP) is an uncommonneurodegenerative disorderoften misdiagnosed, mostfrequently as Parkinson’s disease(PD). 1,2 Although PSP is lesscommon than PD, both are characterizedby progressive loss ofselected neurons in certain areasof the brain, which causes disease.3,4 Approximately 4% ofpatients experiencing parkinsoniansymptoms have PSP. 2 Few cliniciansare proficient at recognizingthe nonclassic presentationsof PSP and also at treating it. 5Pharmacists should be aware ofthis distinct condition with anunknown cause, also known asSteele-Richardson-Olszewski syndrome.Although PSP usuallystrikes individuals after age 50years, some patients can developsigns in their fourth decade. 1,2Mary Ann E. Zagaria, PharmD, MS, CGPSenior Care Consultant Pharmacist andPresident of MZ Associates, Inc.Norwich, New Yorkwww.mzassociatesinc.comRecipient of the Excellence in Geriatric PharmacyPractice Award from the Commission forCertification in Geriatric PharmacyDisability develops in PSPpatients within 3 to 5 years ofdiagnosis; death usually occurswithin 10 years of symptomonset, often secondary to infection(e.g., pneumonia) or othercomplications of immobility. 2,6,7Advance directives, such as a livingwill or durable power of attorney(see Reference 8), should beprepared by patients diagnosedwith PSP so that they have theopportunity to indicate the typeof medical treatment they wish toreceive as part of their end-of-lifecare plan. 6,8Pathophysiologyand DiagnosisWhile PD is slowly progressiveand primarily involves the substantianigra, patients with PSPshow a degeneration of neuronsthat occurs in the basal ganglia—the part of the brain that helpscoordinate and ensure smoothbody movements—and in thebrain stem, the part of the brainthat controls vital body functions(e.g., breathing, heart rate, swallowing)and eye movements. 1,6 Inaddition, neurofibrillary tanglesare detected (containing abnormaltau protein), and strokes (lacunar)may occur in the basal gangliaand deep white matter. 1According to Schneider andMandelkow, neurofibrillary tanglesare a hallmark of Alzheimer’sand other neurodegenerative diseases(e.g., PSP, Pick’s disease,frontotemporal dementia, andparkinsonism linked to chromosome17) referred to astauopathies, since neurofibrillarytangles are composed of intracellularaggregates of the microtubule-associatedprotein tau. 9While the mechanisms underlyingtau-mediated neurotoxicity arenot well understood, neurodegenerationand neuronal dysfunctionare associated with pathologichyperphosphorylation and aggregationof tau. 9 A shared characteristicof PD and PSP is the presenceof Lewy bodies (abnormalintracytoplasmic inclusiondeposits), although Lewy bodiesare found in a minority of PSPcases. 3Diagnosis of PSP is clinical, byhistory and physical examination. 2Neuroimaging is not required fordiagnosis since findings are notspecific. 2Signs and SymptomsA core feature of PSP is known asvertical supranuclear gaze palsy,where the voluntary vertical gazeis impaired; this causes difficultylooking up or down withoutextending or flexing the neck, ordifficulty climbing up and downstairs, and may be the first noticeablesymptom of the disease. 1,2Shortly after onset of the disorder,patients present with posturalinstability, causing gait unsteadinessand falls (typically backward).2,3 A staring, astonishedappearance may be caused byretraction of the upper eyelids. 2Other findings (TABLE 1) mayinclude dysphagia and dysarthriawith emotional lability(pseudobulbar palsy). Emotional20U.S. Pharmacist • November 2009 • www.uspharmacist.com

PROGRESSIVE SUPRANUCLEAR PALSYlability (with a propensity tolaugh or cry easily) is referred toas pseudobulbar affect. 2 Rigidity,bradykinesia, and dystonic neckextension may be present, andlanguage functions resemble thoseevident in PD (i.e., speech maybecome incomprehensible, repetitive/babbling,or mute). 1-3,7 Whileonly occasional, a subtle restingtremor may be present. 2Deficits, similar to those secondaryto multiple strokes, occurin a progressive and usually rapidfashion. 2 In terms of the patient’scognition, mental slowing, executivedysfunction (i.e., impairmentof volitional activities such asplanning, organizing, self-awareness,self-regulation, and initiationof action), and memoryimpairment (less severe than inAlzheimer’s disease) occur. 1,3,6Later in the disease, depressionand dementia are common, causingsome individuals to experiencesleep disturbances, agitation,and irritability. 2,3 Eventually, mostPSP patients require a wheelchairand a feeding tube. 7Upon initially seeing a patientwith symptoms of PSP, pharmacistsmay recognize symptomsthat resemble drug-inducedpseudoparkinsonism, most commonlyseen with the use of firstgenerationantipsychotic agents ofthe phenothiazine (e.g., chlorpromazine),thioxanthene (e.g., thiothixene),or butyrophenone (e.g.,haloperidol) classes. Based on theparkinsonian signs and symptomsand considering that the coresymptom of vertical supranucleargaze palsy is not always present inthe early stage of PSP, it is notdifficult to understand how thisdisease may be misdiagnosed asPD, especially since diagnosis isdetermined clinically and not byany substantiating diagnostic test.Schmidt et al note the mostimportant features that characterizeand differentiate PSP fromother parkinsonian syndromes asTable 1Potential Symptoms of ProgressiveSupranuclear Palsy• Loss of voluntary eye movements; particular difficulty with vertical movements,referred to as vertical supranuclear gaze palsy; inability to fix gaze on a stationaryor moving object (square wave jerks). Reflexive eye movements are unaffected• Other ophthalmic signs and symptoms include blurred vision, diplopia, photophobia,burning, tearing, and upper eyelid retraction• Postural instability causing falls (specifically a tendency to fall backward)• Bradykinesia• Muscular rigidity with progressive dyskinetic movements due to disorderedtonicity of muscle (e.g., dystonic neck extension); subtle resting tremor(usually absent)• Pseudobulbar palsy: difficulty swallowing (dysphagia) and speech disturbance(dysarthria) with emotional lability• Cognitive impairment (e.g., mental slowing, executive dysfunction, memoryimpairment)• Sleep disturbances (insomnia or hyposomnia)• Agitation, irritability, disinhibition• Depression (late in course)• Dementia (eventually occurs)Source: References 1-3, 6, 7, 16.the following: 1) supranucleargaze palsy; 2) postural instability;3) pseudobulbar palsy; and 4)cognitive disturbances. 10 Litvanet al indicate that which specificallydifferentiates PSP fromother diseases: 1) PSP from PD isunstable gait, absence of tremordominantdisease, and absence ofa response to levodopa; 2) PSPfrom diffuse Lewy body disease issupranuclear vertical gaze palsy,gait instability, and the absenceof delusions; 3) PSP from Pick’sdisease is postural instability; 4)PSP from multiple system atrophyis supranuclear vertical gazepalsy and increased age at symptomonset; and 5) PSP from corticobasaldegeneration is gaitabnormality, severe upward gazepalsy, bilateral bradykinesia, andabsence of alien limbsyndrome. 11Significant autonomic dysfunctionmay be seen in patients withPSP as well as in patients withPD. 10 According to Schmidt et al,the parasympathetic cardiovascularsystem appears to be involved to asimilar extent in patients with PDand patients with PSP, as comparedto sympathetic cardiovasculardysfunction, which is morefrequent and severe in patientswith PD but can also be seen inpatients with PSP. 10TreatmentPSP is an incurable condition.Treatment is supportive and far lesseffective than that for Parkinson’sdisease. 2 The treatment of PSPremains unsatisfactory, since onlyoccasionally do levodopa,dopamine agonists (TABLE 2),amantadine, or amitriptyline partiallyrelieve rigidity. 1,2 It is presumedthat the reason PSP is notresponsive to dopamine replacementor dopamine agonist therapiesis that dopamine receptorsare decreased as a result of postsynapticdamage beyond pathologicalchanges seen in PD. 12 Symptomatictreatment with drugs andother therapies should be targetedat reducing morbidity andimproving quality of life (e.g.,depression can be treated with21U.S. Pharmacist • November 2009 • www.uspharmacist.com

PROGRESSIVE SUPRANUCLEAR PALSYselective serotonin reuptakeinhibitors). 5,7 Pharmacistsshould note that prior toinitiating any treatment, theoverall benefit-to-risk ratioto the individual patientmust be considered.Due to adverse effectsassociated with dopamineagonists—including nausea,hypotension, confusion, andhallucinations—their utilityis severely limited. 4 Arecently published reassessmentof risks and benefits ofdopamine agonists in PD hasrevealed the occurrence of increasinglyrecognized adverse effectssuch as lower extremity edema,daytime somnolence, impulsecontrol disorders, and fibrosis. 13The antiviral agent amantadinewas accidentally discoveredto have an antiparkinsonismaction (e.g., increasing release ofdopamine among other effects). 4Adverse effects associated withamantadine therapy include restlessness,agitation, confusion,and hallucinations; high dosesmay result in an acute toxic psychosis.4 Peripheral edema, orthostatichypotension, urinary retention,dry mouth, and livedoreticularis (i.e., red to blue skindiscoloration on the limbs andtrunk that intensifies upon exposureto cold) may also occur. 1,4The geriatric patient populationmay be more susceptible toTable 2Dopamine Agonists Used in theTreatment of Parkinson’s Disease aApomorphine (Apokyn)Bromocriptine (Parlodel)Pramipexole (Mirapex)Ropinirole (Requip, Requip XL)Rotigotine transdermal (Neupro [DSC]) baRefer to manufacturer’s prescribing information for completedosing guidelines.bCurrently unavailable in the United States.Source: References 4, 14, 17.the central nervous system effectsof amantadine; the use of twodivided daily doses may minimizethis effect. 14 In patients with renalimpairment, amantadine requiresrenal dosing based on estimatedcreatinine clearance. Monitoringparameters for amantadine therapyinclude renal function, Parkinson’ssymptoms, mental status, andblood pressure. 14Nonpharmacologic measuresintroduced early in the course ofdisease may include weightedwalking aids or wheelchairs to preventfalls, and adaptive eyeglasses(e.g., bifocals, prisms) to improvevision. 2 Also important in theearly stage of the illness is theintroduction of physical therapy,occupational therapy, and speechtherapy as supportive measures. 2Thus far, surgical approaches toPSP have proven ineffective. 5A randomized, placebo-controlledtrial in Germany looked atthe short-term effects ofcoenzyme Q10 in PSP. 15Results indicated significantchanges in the occipital lobeand a consistent trend in thebasal ganglia. 15 Coenzyme Q10 treatment compared toplacebo showed clinicalimprovement according tothe PSP rating scale and theFrontal Assessment Battery;although the improvementwas slight, it was noted assignificant. 15 The researchersconcluded that since coenzyme Q10 appears to improve cerebralenergy metabolism in PSP, longtermtreatment might have a disease-modifying,neuroprotectiveeffect. 15ConclusionIn PSP, neurodegenerativechanges take place in the brainstem, basal ganglia, and elsewhere;neurofibrillary tangles arepresent. While PSP continues tobe an underrecognized disorderand is often misdiagnosed, it canbe differentiated from other akineticrigid syndromes such asPD. 5 Diagnosis of this debilitatingdisorder is clinical and treatment issupportive. Risks associated withpotential adverse effects of treatmentshould be considered in theformulation of an individualizedpharmaceutical care plan. Earlydiscussion about end-of-life issuesis advised.REFERENCES1. Beers MH, Porter RS, Jones TV, et al. The Merck Manualof Diagnosis and Therapy. 18th ed. Whitehouse Station,NJ: Merck Research Laboratories; 2006:1885.2. Progressive Supranuclear Palsy. In: Beers MH, JonesTV, Berkwits M, et al, eds. The Merck Manual of Geriatrics.Updated June 2006.www.merck.com/mkgr/mmg/sec6/ch46/ch46d.jsp.Accessed October 19, 2009.3. Craft S, Cholerton B, Reger M. Aging and cognition:what is normal? In: Hazzard WR, Blass JP, Halter JB, etal, eds. Principles of Geriatric Medicine and Gerontology.5th ed. New York, NY: McGraw-Hill, Inc; 2003:1355-1372.4. Howland RD, Mycek MJ. Pharmacology. 3rd ed.Philadelphia, PA: Lippincott Williams & Wilkins;2006:91-101.5. Lubarsky M, Juncos JL. Progressive supranuclear palsy:a current review. Neurologist. 2008 Mar;14(2):79-88.6. Beers MH, Jones TV, Berkwits M, et al, eds. TheMerck Manual of Health & Aging. Whitehouse Station,NJ: Merck Research Laboratories; 2004:367-369.7. Chand P, Litvan I. Progressive supranuclear palsy andcorticobasal degeneration: similarities and differences.Future Neurol. May 2008. www.medscape.com/viewarticle/578084.Accessed October 21, 2009.8. Zagaria ME. The dying patient: choices, control, andcommunication. U.S Pharm. 2009;34(10):32-34.9. Schneider A, Mandelkow E. Tau-based treatmentstrategies in neurodegenerative diseases. Neurotherapeutics.2008;5(3):443-457.10. Schmidt C, Herting B, Prieur S, et al. Autonomicdysfunction in patients with progressive supranuclearpalsy. Mov Disord. 2008;23(14):2083-2089.11. Litvan I, Campbell G, Mangone CA, et al. Whichclinical features differentiate progressive supranuclearpalsy (Steele-Richardson-Olszewski syndrome) fromrelated disorders? A clinicopathological study. Brain.1997;120(pt 1):65-74.12. Nelson MV, Berchou RC, LeWitt PA. Parkinson’s disease.In: DiPiro JT, Talbert RL, Yee GC, et al, eds. Pharmacotherapy:A Pathophysiologic Approach. 6th ed. NewYork, NY: McGraw-Hill, Inc; 2005:1075-1088.13. Antonini A, Tolosa E, Mizuno Y, et al. A reassment ofrisks and benefits of dopamine agonists in Parkinson’s disease.Lancet Neurol. 2009;8:929-937.14. Semla TP, Beizer JL, Higbee MD. Geriatric DosageHandbook. 14th ed. Hudson, OH: Lexi-Comp, Inc;2009.15. Stamelou M, Reuss A, Pilatus U, et al. Short-termeffects of coenzyme Q10 in progressive supranuclearpalsy: a randomized, placebo-controlled trial. Mov Disord.2008;23(7):942-949.16. Dorland’s Pocket Medical Dictionary. 28th ed. ElsevierSaunders; 2009.17. My Epocrates. Version 1.0. Updated October 6,2009.22U.S. Pharmacist • November 2009 • www.uspharmacist.com

FDA Fast FactsNew LeukemiaTreatment Fast TrackedThe FDA approved ofatumumab(Arzerra) fortreating patients withchronic lymphocyticleukemia (CLL), a bloodand bone marrow cancer.Ofatumumab wasapproved using the acceleratedapproval process forpatients with CLL whosecancer is uncontrolled byother types of chemotherapy.The effectiveness ofthe drug was evaluated in59 patients with CLLwhose disease no longerresponded to the availabletherapies. CLL, whicharises from B cells foundin the body’s immune system,mainly afflictspatients older than 50years, killing about 4,400people each year.“The approval ofArzerra illustrates FDA’scommitment to using theaccelerated approvalprocess to approve drugsfor patients who havelimited therapeuticoptions,” said RichardPazdur, MD, director ofthe Office of OncologyDrug Products in theFDA’s Center for DrugEvaluation and Research.The manufacturer, Glaxo-SmithKline, is currentlyconducting a clinical trialto verify that ofatumumabadded to standardchemotherapy delaysCLL progression.Marketing of IllegalOpioids HaltedThe FDA warned fourFDA Marks AIDS Program MilestoneThe U.S. Department of Health and Human Services (HHS) marked therecent approval of the 100th antiretroviral drug in association with thePresident’s Emergency Plan for AIDS Relief (PEPFAR), which is designedto prevent HIV/AIDS and to treat and care for patients and thoseaffected by the disease worldwide. The PEPFAR program is a joint effortinvolving the FDA and other HHS agencies, the State Department’sOffice of the U.S. Global AIDS Coordinator, the U.S. Department ofDefense, other federal agencies, host country governments, and otherinternational partners. “This milestone exemplifies the dedication, caring,and hard work of all who strive to better the lives of those infected withor affected by HIV/AIDS,” said HHS Secretary Kathleen Sebelius.Drug products used in PEPFAR receive a tentative approval and cannotbe approved for marketing in the United States due to current patentsand marketing exclusivity, yet the drugs must meet the same manufacturing,safety, and efficacy standards required for marketing in this country.As of October 6, 2009, more than 100 products had been assessed by theFDA as part of the PEPFAR program and either fully or tentativelyapproved. Of these, 29 were new products, 71 were versions of drugsapproved in the U.S., and 22 were new combinations or regimens notpreviously authorized in the U.S. In 2008, PEPFAR provided almost $1.6billion in support of HIV/AIDS treatment programs.companies that theymust stop marketingunapproved codeine sulfatetablets, opioid analgesicsused to treat pain.These particular productshave not receivedFDA approval, and theagency has no evidencethat they are safe andeffective. Another manufacturer,Roxane Laboratories,markets approvedcodeine sulfate tablets,and the FDA does notexpect a shortage in thesupply of these drugs.The products and themanufacturers and distributorsthat receivedthe warning letters are:Codeine Sulfate Tablets,30 mg, 60 mg (LehighValley Technologies Inc.,Allentown, Pennsylvania);Codeine SulfateTablets, 30 mg, 60 mg(Cerovene Inc., ValleyCottage, New York);Codeine Sulfate Tablets,30 mg (Dava InternationalInc., Fort Lee,New Jersey); andCodeine Sulfate Tablets,30 mg, 60 mg (GlenmarkGenerics Inc.USA, Mahwah, New Jersey).Companies receivingthe warning lettershave 15 days to give theFDA a plan to discontinuemarketing theunapproved drugs.New Web PageDetails DisposalInstructionsThe FDA launched aWeb page for consumerswith information onhow to dispose of certaindrugs, includinghigh-potency opioidsand other potentiallyharmful controlled substances.The FDA recommendsthat thesemedicines be disposed ofby flushing them downthe sink or toilet to keepthem away from childrenand others. Medicinesnot listed shouldbe thrown away in thehousehold trash aftermixing them with someunpalatable substance,such as coffee grounds,and sealing them in abag or other container.Another option is to disposeof them throughdrug take-back programs,federal and statelaw permitting.24U.S. Pharmacist • November 2009 • www.uspharmacist.com

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So Many Options,So Little Differencein EfficacyWhat Is the AppropriateAntidepressant?Uncertainty is high when it comes to selectingthe appropriate antidepressant for patients diagnosedwith major depressive disorder (MDD),not only because studies have reported no differences inefficacy between agents, but also because only 11% to30% of patients will reach remission with initial treatment,even after a year. 1,2 This consequently has led cliniciansto practice in a trial-and-error fashion to treatdepression. 3 Furthermore, the last major revision of theDiagnostic and Statistical Manual of Mental Disorders(DSM-IV-TR) was produced in 2000. 4 In 2005, a guidelinewatch was published to review important safety concernsthat had emerged about some agents, such asnefazodone, as well as to review two new antidepressantsapproved that year, escitalopram and duloxetine. 5 Revisionand update of the DSM-IV-TR (DSM-V manuscript)is not due until May 2012. Therefore, there is need foran up-to-date review to assist clinicians in deciding onthe appropriate agents to treat individual patients.The 2007 Sequenced Treatment Alternatives to RelieveDepression (STAR*D) study attempted to develop andevaluate feasible treatment strategies to improve clinicaloutcomes for patients with treatment-resistant depressionwho were identified with a current major depressiveepisode. 6 Specifically, STAR*D aimed to determine whichof several treatments is the most effective “next step” forpatients who do not reach remission with an initial orsubsequent treatment or who cannot tolerate the treatment.The overall results of this study demonstrated thatpharmacologic differences between psychotropic medicationsdid not translate into substantial clinical differences,although tolerability differed. 6The purpose of this article is to review treatment evidenceavailable in the literature inorder to provide a quick reference thatwill help clinicians decide on theappropriate agent, taking into considerationadverse effects, drug interactions,and medication safety, as wellas patient characteristics.Marjorie Rochette DeLucia, PharmD, MSPGY1 Pharmacy Practice ResidentBaptist Medical CenterJacksonville, FloridaMichael J. Schuh, PharmD, MBAAmbulatory Pharmacist, Mayo ClinicJacksonville, Florida© JUPITERIMAGESWhat Is Depression?Depression can be a chronic or recurrent mental disorderthat presents with several symptoms such asdepressed mood, loss of interest or pleasure, feelingsof guilt, disturbed sleep or appetite, low energy, anddifficulty thinking. 7 Depression can lead to substantialimpairment in an individual’s ability to take careof everyday responsibilities. Depression can also lead tosuicide, a tragedy accounting for the loss of about850,000 lives worldwide every year. 7Prevalence and At-Risk PopulationsThere are an estimated 121 million people worldwideaffected with depression. 7 In 2000, depression was thefourth leading contributor to the global burden of diseaseamong all diseases, and by 2020 it is anticipatedthat it will rise to the number-two leading contributorto the global burden of disease, second only to heartdisease. 7Populations at higher risk for developing depressioninclude women, people between the ages of 24 and 45years, and those with first-degree relatives with depression.Women are at increased risk for depression untiltheir 50s, and their lifetime risk is two times greater thanmen’s. People between the ages of 24 and 45 yearsexperience the highest rate of depression. Finally, firstdegreerelatives of depressed patients are 1.5 to 3 timesmore likely to experience depression than others. 4,8Pathophysiology andPharmacotherapy RationaleBiological and psychosocial causes have been hypothesizedin an attempt to describe the pathophysiology ofdepression. Pharmacologic agents willtarget the biological causes linked todysregulation in the neurotransmitters.This dysregulation is oftendescribed as a deficiency in brain neurotransmitterlevels. Norepinephrine,serotonin, and dopamine levels26U.S. Pharmacist • November 2009 • www.uspharmacist.com

WHAT IS THE APPROPRIATE ANTIDEPRESSANT?Table 1Selective Serotonin Reuptake InhibitorsMedications Initial/Max Dose Comments Adverse EffectsCitalopram 20 mg/60 mg daily t 1/2= 35 h; weak CYP2D6 inhibitor; anxiety symptoms(Celexa) (40 mg max effective) significantly improved compared to other SSRIsEscitalopram 10 mg/20 mg daily t 1/2= 35 h; most potent SSRI;(Lexapro) (10 mg max effective) like citalopram, fewer drug interactionsFluoxetine 20 mg/80 mg daily Long t 1/2= 7-15 days; active metabolite norfluoxetine;(Prozac)potent CYP2D6 inhibitor = drug interactions;may cause weight lossFluvoxamine 50 mg/300 mg in t 1/2= 16 h adults, 26 h elderly; potent CYP3A4, 2C19,(Luvox) divided doses 1A2 inhibitor = most drug interactions; primarilyused to treat OCD and panic disordersParoxetine 20 mg/60 mg daily t 1/2= 26 h; potent CYP2D6 inhibitor; mild affinity for(Paxil) (50 mg max effective) muscarinic receptors = more anticholinergic sideeffects than other SSRIs; sedatingSertraline 50 mg/200 mg daily t 1/2= 26 h; absorption increases when taken with food;(Zoloft)weak CYP2D6 inhibitor = less potential drug interactions;more likely than other SSRIs to cause nausea; mostcited reason for d/cWeight gain,insomnia,tremors,prolonged QTinterval, dizziness,constipation, drymouth, nausea,lightheadedness,syncope,confusion,agitation, sexualdysfunctiond/c: discontinuation; max: maximum; OCD: obsessive compulsive disorder; SSRI: selective serotonin reuptake inhibitor; t 1/2: half-life.Source: References 4, 10.may be decreased in patients with depression, thus associatinga decreased amount of neurotransmitters withthe disorder. 8 The pharmacotherapy rationale hasbeen to boost these deficiencies by blocking the reuptakeor preventing enzymatic metabolism of neurotransmittersvia antidepressants. Overall, these mechanismsaim at increasing the level of neurotransmitters eitherby forcing the neuron to fire more often and producemore neurotransmitters or by preventing degradationof the neurotransmitter itself.Pharmacologic AgentsSeveral classes of agents are currently available to treatdepression. They include selective serotonin reuptakeinhibitors (SSRIs), tricyclic antidepressants (TCAs),monoamine oxidase inhibitors (MAOIs), and serotoninnorepinephrinereuptake inhibitors (SNRIs), amongothers.Antidepressants have been associated with an increasedrisk of suicidal thinking and suicidality in children, adolescents,and young adults in short-term placebo controlledstudies of MDD. Anyone considering the useof any antidepressant in a child, adolescent, or youngadult must balance this risk with the clinical need. Shorttermstudies did not show an increase in the risk of suicidalitywith antidepressants compared to placebo inadults beyond age 24 years, and there was a reductionin risk with antidepressants compared to placebo inadults aged 65 years and older. Depression and otherpsychiatric disorders are themselves associated withincreased risk of suicide. Patients of all ages who arestarted on antidepressant therapy should be monitoredappropriately and observed closely for clinical worsening,suicidality, or unusual changes in behavior. 9Selective Serotonin Reuptake Inhibitors 4,10 : SSRIs areconsidered first-line agents when it comes to treatingpatients with depression. These drugs include citalopram,escitalopram, fluoxetine, fluvoxamine, paroxetine,and sertraline (TABLE 1). The major adverse effectsof this class include nausea, vomiting, and diarrhea,which are dose-dependent effects and tend to dissipateafter the first weeks of treatment. In some patients,SSRIs can cause agitation and sleep disturbances, whichwill also dissipate with time. Sexual dysfunction is aside effect present with all antidepressants, but seemsto be most common with SSRIs.Serotonin syndrome (i.e., abdominal pain, diarrhea,sweating, mental status change, renal failure, cardiovascularshock, and possibly death) is a rare adverse effectof SSRIs. Serotonin syndrome can occur with an increasein SSRI dose or by taking SSRIs with herbals such asSt. John’s wort or with illicit drugs. Finally, combiningSSRIs with MAOIs can also lead to lethal drug interactionswith development of serotonin syndrome. Whenclinicians feel the need to switch from one class of agentto the other, it is suggested that at least five half-liveselapse between the time the SSRI is stopped and theMAOI is started. 4 Of all agents in the class, fluvoxaminehas the highest rate of drug interactions, since it29U.S. Pharmacist • November 2009 • www.uspharmacist.com

WHAT IS THE APPROPRIATE ANTIDEPRESSANT?Table 2Tertiary and Secondary Amine Tricyclic AntidepressantsMedications Initial/Max Dose Comments Adverse EffectsTertiary Amine TCAsAmitriptyline (Elavil) 25-75 mg/200 mg daily 5HT > NEAmoxapine (Asendin) 50 mg bid/400 mg daily 5HT = NE, weak DAClomipramine (Anafranil) 25 mg/250 mg daily 5HT > NEDoxepin (Sinequan) 50-75 mg/300 mg daily 5HT = NE; highly sedatingImipramine (Tofranil) 50-100 mg/200 mg daily 5HT = NESecondary Amine TCAsDesipramine (Norpramin) 100-200 mg/300 mg daily NE > 5HT; metabolite of imipramineMaprotiline (Ludiomil) 25 mg tid/225 mg daily NE > 5HTNortriptyline (Pamelor) 25-50 mg/150 mg daily NE > 5HT; metabolite of amitriptylineOrthostatichypotension,drowsiness, weightgain, anticholinergic,QT prolongation (inoverdose)Same as above, butwith more drowsiness,somnolence, and weightgain than tertiaryDA: dopamine; 5HT: serotonin; max: maximum; NE: norepinephrine; TCA: tricyclic antidepressant. Source: References 4, 10.inhibits several hepatic enzymes such as CYP450 1A2,2C19, 2C9, 2D6, and 3A4. Fluoxetine follows fluvoxamine’sdrug interaction rate closely with inhibition ofCYP 2C9, 2D6, and 3A4. Finally, citalopram and escitalopramhave the least drug interactions, since theyinhibit 2D6 enzymes to a lesser extent.When considering patient characteristics andsafety, SSRIs are safe to use in most patient groups,including those with preexisting cardiac disease, asthma,dementia, and hypertension. The elderly, who are particularlyprone to orthostatic hypotension as well asweight loss, may benefit most from using SSRIs sincethose agents produce weight gain and lack anticholinergicactivity.Tricyclic Antidepressants 4,10 : TCAs block norepinephrineand serotonin reuptake, but they also have affinity foralpha 1, H 1, and muscarinic receptors, thus causing anticholinergicadverse effects. There are two subclasses ofagents available within this class, the tertiary and secondaryamine TCAs (TABLE 2). The secondary amineTCAs (desipramine, maprotiline, nortriptyline) haveless affinity for the alpha 1, H 1, and muscarinic receptors,therefore causing fewer anticholinergic adverseeffects than the tertiary amine TCAs (e.g., amitriptyline,amoxapine, clomipramine, doxepin, imipramine).The main adverse effects of this class of agents areorthostatic hypotension, QT prolongation, drowsiness,dry mouth, blurred vision, constipation, and weightgain. In general, tertiary amine TCAs have more serotoninactivity versus secondary amine TCAs, which havemore norepinephrine activity, thus causing less drowsiness,somnolence, and weight gain.It is known that TCAs inhibit both CYP 2C19 and2D6 enzymes. 11 They are also metabolized to a lesserextent by CYP 1A2 and 3A4 enzymes. 12 For this reason,although drug–drug interactions with these agentsmight not be the primary concern, it is advised to usecaution when combining TCAs with SSRIs, since thedrug plasma level of TCAs has the potential to increaseby up to fourfold, possibly leading to toxic effects. 13,14When considering patient characteristics andsafety, TCAs are contraindicated in some specific cardiacconditions such as patients with a history of arrhythmias,sinus node dysfunction, or conduction defects.Caution is advised with the elderly, as they are moresensitive to cholinergic blockade as well as orthostatichypotension. Furthermore, individuals also sufferingfrom dementia will be particularly susceptible to thetoxic effects of muscarinic blockade on memory andattention span and would generally do best if givenantidepressants with the lowest degree of anticholinergiceffects. Finally, caution should be exercised whenconsidering starting TCAs in patients with suicidalthoughts due to high lethality risks with overdose.The lethal dose is only eight times the therapeutic dose,so if TCAs are ingested in an overdose, they mayblock the sinoatrial node in the heart.Monoamine Oxidase Inhibitors 4,10 : The MAOIs thatare available include isocarboxazid, phenelzine, selegiline,and tranylcypromine (TABLE 3). Aside from selegiline,which is a selective MAO B inhibitor, all otheragents inhibit both MAO A and B enzymes responsiblefor serotonin, norepinephrine, and dopamine metabolismin the brain. Due to severe adverse effects and requireddiet restrictions, MAOIs are generally reserved for patientswho have failed other antidepressants.Hypertensive crisis can occur when patients takingMAOIs ingest foods containing tyramine, such as beer,30U.S. Pharmacist • November 2009 • www.uspharmacist.com

WHAT IS THE APPROPRIATE ANTIDEPRESSANT?Table 3Monoamine Oxidase InhibitorsMedications Initial/Max Dose Comments Adverse EffectsIsocarboxazid (Marplan) 10 mg bid/60 mg dailyDietary restrictions: no HTN crisis: palpitations,foods containing tyramine chest pain, muscle rigidity;Phenelzine (Nardil) 15 mg tid/90 mg daily(e.g., beer, wine, aged 5HT syndrome: nausea,Selegiline (Emsam) a 6 mg/12 mg (24-h transdermal patch)cheese, soy sauce, sedation, diaphoresis,bananas, smoked meat) confusion, HTNTranylcypromine (Parnate) 30 mg/60 mg (divided doses)aSelective monoamine oxidase B inhibitor. 5HT: serotonin; HTN: hypertension; max: maximum.Source: References 4, 10.wine, aged cheese, and smoked meat. This reactionpresents as an acute onset of severe headache, nausea,neck stiffness, heart palpitations, chest pain, and confusion.MAOIs can also cause serotonin syndrome. Asmentioned previously, this syndrome most commonlyoccurs when MAOIs are taken concomitantly with otherserotonergic agents such as SSRIs or if venlafaxine, anSNRI, is administered soon after an MAOI. Whenpatients are switched from an SSRI with a short halflifeto an MAOI, it is important that a 2-week washoutperiod be respected between the discontinuation of theSSRI and the start of the MAOI. If fluoxetine is theSSRI, which has a long half-life, the washout periodshould be 5 weeks. 4 Other adverse effects can occur withMAOIs such as orthostatic hypotension, weight gain,sexual dysfunction, and insomnia.Due to the high rate of drug interactions with theseagents, caution should be used when prescribed topatients with asthma using sympathomimetic bronchodilators.In patients with hypertension, MAOIs mayinduce orthostatic hypotension, especially with concurrentdiuretic treatments.Serotonin-Norepinephrine Reuptake Inhibitors 4,10 :The SNRIs such as desvenlafaxine, duloxetine, and venlafaxinemay also be used as first-line agents (TABLE 4).These medications are safer than TCAs, and their adverseeffects are similar to those of SSRIs, including nausea,vomiting, and sexual dysfunction, as well as elevatedblood pressure.Venlafaxine has been shown to cause an increase inblood pressure in 3% to 13% of cases, while desvenlafaxinewas reported to cause an increase in blood pressurein only 1% to 2% of cases. 10 Thus, it is recommendedto avoid using venlafaxine in patients withuncontrolled hypertension since the agent can exacerbatethe condition. Duloxetine has more norepinephrineactivity than both of the aforementioned agents, thusbeing useful with physical symptoms such as muscleaches, headaches, stomach issues, and generalized pain,often occurring with severely depressed patients. Dueto its effectiveness in pain symptoms, duloxetine hasalso been approved for other indications such as fibromyalgiaand diabetic peripheral neuropathic pain. 15 Finally,all three agents have more serotonin than norepinephrineTable 4Serotonin-Norepinephrine Reuptake InhibitorsMedications Initial/Max Dose Comments Adverse EffectsDesvenlafaxine 50 mg/100 mg Active metabolite of venlafaxine;(Pristiq) daily (50 mg max BP elevation reported to be lesseffective dose) common than with venlafaxineDuloxetine 40 mg/ t 1/2= 12 h; moderate inhibitor of(Cymbalta) 60 mg daily CYP2D6; GI adverse effects (nausea,dry mouth, constipation) are common;unique beneficial treatment for physicalpain associated with depressionVenlafaxine 25 mg tid/ 5HT > NE at lower doses; NE > 5HT at(Effexor) 225 mg daily higher doses; t 1/2= 11 h; inhibitor of CYP2D6Similar adverseeffects to SSRIs,except moreincidence of BPelevation withSNRIsBP: blood pressure; 5HT: serotonin; GI: gastrointestinal; max: maximum; NE: norepinephrine; SNRI: serotonin-norepinephrinereuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; t 1/2: half-life.Source: References 4, 10.36U.S. Pharmacist • November 2009 • www.uspharmacist.com

WHAT IS THE APPROPRIATE ANTIDEPRESSANT?Table 5Other AntidepressantsMedications Initial/Max Dose Comments Adverse EffectsNDRIsBupropion IR (Wellbutrin) 100 mg bid/ Contraindicated in patients with anorexia,150 mg tid bulimia, or seizure disordersBupropion SR (Budeprion SR,Wellbutrin SR, Buproban)Bupropion XL (Wellbutrin XL,Budeprion XL)Mixed-Action Antidepressants150 mg/200 mg bid150 mg/450 mg dailySimilar to SSRIs butwith less 5HT adverseeffects such as nausea,somnolence, andweight gain; no sexualdysfunctionMirtazapine (Remeron) 15 mg/ Blocks alpha 2, 5HT 2a,c, 5HT 3, More weight gain, less45 mg daily and H 1receptors sexual dysfunction,insomniaNefazodone (Serzone) 100 mg bid/ Blocks 5HT 2aand 5HT reuptake; Black box warning =300 mg bid 3A4 inhibitor = many drug hepatotoxicityinteractions will limit useTrazodone (Desyrel) 150 mg/ Blocks 5HT 2and alpha 1receptors Too much sedation600 mg daily limits use5HT: serotonin; IR: immediate release; max: maximum; NDRI: norepinephrine-dopamine reuptake inhibitor; SR: sustained release;SSRI: selective serotonin reuptake inhibitor; XL: extended release. Source: References 4, 10.activity at lower doses and more norepinephrine thanserotonin activity at higher doses, thus having dosedependentadverse effects.Other Antidepressants 4,10 : Several other antidepressantsare available that differ in their mechanism of actionfrom the classes of medications described previously.The norepinephrine-dopamine reuptake inhibitors(NDRIs) such as bupropion immediate-release (IR)branded Wellbutrin (also available in long-acting dosageforms such as Wellbutrin XL, Wellbutrin SR, BudeprionSR, Budeprion XL, and Buproban) may be usedas first-line agents to treat depression (TABLE 5). Theiradverse effects are similar to those of SSRIs, with minimalserotonin effects such as nausea and weight gainand little or no sexual dysfunction. Bupropion has beenshown to exert beneficial effects on Parkinson’s diseasesymptoms in some patients, but it may also induce somepsychotic symptoms, perhaps because of its agonisticaction on the dopaminergic system. 16Finally, there are three more antidepressants withmixed action available: mirtazapine, nefazodone, andtrazodone (TABLE 5). All three agents block differentserotonin receptors, thus having distinct effects. Mirtazapinecauses more weight gain by increasing appetite.Nefazodone has limited uses because of hepatotoxicityand CYP3A4 enzyme inhibition, which leads to druginteractions. Trazodone blocks serotonin receptors toa great extent, with poor binding to muscarinic receptors.Adverse effects such as sedation, headache, memoryimpairment, dry mouth, and constipation may occur.Caution is also advised with trazodone use in men dueto risk of priapism.ConclusionIn general, antidepressant medications have beenshown to be equally efficacious; therefore, medicationchoice should be based on adverse effects, drug interactions,safety, and patient preferences. Several algorithmsare available to guide the clinician during the patient’streatment, particularly the recently updated Texas Departmentof State Health Services algorithm for the treatmentof MDD (updated July 2008). 17 If patients showpartial response, clinicians may choose to increase thedose, change to an alternative agent, or give a combinationof antidepressants. On the contrary, if patients donot respond or cannot tolerate the drug, switching toan alternative agent is also appropriate, taking into considerationthat therapeutic effects will usually occurbetween 4 to 6 weeks, even though adverse effectsmight appear after 1 week of treatment. 4,17 In addition,while the adverse effects appear early in treatment, theygenerally dissipate after 2 to 3 weeks. 4,17 Nonetheless, theantidepressant that will most likely ensure a patient’simprovement and safety may be determined, at least partially,by trial and error. Given the difficulty in predictingwhat medication will be both efficacious for andtolerated by an individual patient, familiarity with a broadspectrum of antidepressants is prudent and useful.References available online at www.uspharmacist.com.39U.S. Pharmacist • November 2009 • www.uspharmacist.com

MedicationsUsed in OpioidMaintenanceTreatmentFor the community pharmacist, the ability to aidin the management of opioid dependence is vitalto closing the gap between treated and untreatedopioid-dependent individuals. In the United States,approximately 2 million adults are dependent onheroin or other nonmedically prescribed opioids, yet onlyabout 14% receive treatment. 1,2 In an effort to providecare to a greater number of patients with dependence oraddiction treatment needs, the Drug Addiction TreatmentAct of 2000 (DATA 2000) was passed. DATA 2000states that physicians who qualify can treat opioid dependencein the office setting with a schedule III, IV, or Vdrug that is FDA-approved for this indication. 3 In 2002,buprenorphine (Subutex) and buprenorphine/naloxone(Suboxone) sublingual tablets were approved for the managementof opioid dependence. As the practice of treatingopioid dependence expands, pharmacists must becomefamiliar with this chronic condition and stay up-to-datewith current treatment options for patients on maintenancetherapy.NEUROBIOLOGY OF OPIOIDDEPENDENCE AND WITHDRAWALOver the past 30 years, much has been discoveredabout opioid dependence that has improved our understandingof addiction as a chronic disease. Opioids activatespecific opioid receptors (mu, delta, and kappa). Initially,when heroin or other short-acting opioids are taken,receptor agonists induce euphoria. Subsequent doses willquickly produce tolerance—the need for increasinglyhigher doses to induce the same effect—and physicaldependence. Currently, it is believed that tolerance is aresult of a reduction in either the number or theresponsivity of opioid receptors. 4,5Chronic exposure to opioids causes upregulation of thecyclic adenosine monophosphate signaling pathways inneurons that are responsible for therelease of noradrenaline. When theinhibitory opioid is no longer present,the firing rates of these neurons areunopposed and result in adrenergic overactivation,which manifests as the constellationof withdrawal symptoms. 4,5Christie Choo, PharmD, BCPSAssistant Clinical ProfessorCollege of Pharmacy and Allied HealthProfessions, St. John’s UniversityJamaica, New YorkClinical Manager–Internal MedicineNew York–Presbyterian/Columbia UniversityMedical Center, New York, New York© MEDI-MATION LTD / PHOTO RESEARCHERS, INCMany characteristics of opioids, especially onset ofaction and half-life, contribute to the potential for dependenceand to the onset of withdrawal. Withdrawal maypresent as anxiety, bone pain, chills, piloerection, sweating,nervousness, nausea, diarrhea, rhinorrhea, or constantyawning. More severe symptoms include hot andcold flashes, increased blood pressure and pulse, mydriasis,abdominal and muscle cramps, and vomiting. Symptomscontinue for 48 to 96 hours after the last dose, butmay persist for weeks to months in some individuals. 6 SeeTABLE 1 for withdrawal profiles of various opioids.PHARMACOLOGIC TREATMENTThere are three major approaches to opioid dependence:opioid detoxification, agonist maintenance, and antagonistmaintenance. Opioid detoxification, also known asmedically supervised withdrawal, is utilized mainly totransition into or out of a maintenance program, over avery short period of time. In antagonist maintenance,naltrexone—an opioid antagonist like naloxone—is used.Unlike naloxone, it can be used orally because of its superiorbioavailability. Unfortunately, neither opioiddetoxification nor antagonist maintenance has proved tobe as efficacious as agonist maintenance for producinglong-term abstinence. 7 However, research is being conductedusing novel approaches like rapid detoxificationunder general anesthesia and subcutaneous naltrexoneimplantation. 8,9To be an effective option for maintenance treatment,an agent must be able to do the following: block theeuphoric and sedating effects of dependent opioids; relievethe cravings (the major cause of relapse); relieve andprevent withdrawal symptoms; permit the patient to participatein society; and allow for at least once-daily dosing.10 The pharmacologic agents that embody these characteristicsand have proven their efficacy are buprenorphine,buprenorphine/naloxone, and methadone(see TABLE 2).Methadone and Levo-AlphaAcetyl Methadol (LAAM)Methadone, a schedule II controlledsubstance, has been the most frequently40U.S. Pharmacist • November 2009 • www.uspharmacist.com

OPIOID MAINTENANCE TREATMENTTable 1Comparison of Opioid Withdrawal ProfilesDose Equivalent to Time for Effects Onset of Peak of End ofDrug Methadone 1 mg to Wear off Withdrawal Withdrawal WithdrawalFentanyl 0.01 mg 1 h 3-5 h 8-12 h 4-5 daysMeperidine 20 mg 2-3 h 4-6 h 8-12 h 4-5 daysOxycodone 1.5 mg 3-6 h 8-12 h 36-72 h ≈7-10 daysHydromorphone 0.5 mg 4-5 h 4-5 h 36-72 h ≈7-10 daysHeroin 1-2 mg 4 h 8-12 h 36-72 h 7-10 daysMorphine 3-4 mg 4-5 h 8-12 h 36-72 h 7-10 daysCodeine 30 mg 4 h 8-12 h 36-72 h ≈7-10 daysHydrocodone 0.5 mg 4-8 h 8-12 h 36-72 h ≈7-10 daysMethadone NA 8-12 h 36-72 h 96-144 h 14-21 daysNA: not applicable.Source: Reference 6.used medication in opioid treatment programs. Accessto methadone for the treatment of opioid dependenceis available only through DEA-licensed methadoneclinics. LAAM is no longer being produced or marketedbecause of the increased risk of cardiac death.Clinical Pharmacology: Both methadone and LAAMare synthetic mu-opioid receptor agonists, like heroin,and serve to replace heroin or other opioids’ occupationof mu-opioid receptors. Methadone also is an N-methyl-D-aspartate antagonist.Methadone is a highly fat-soluble drug that israpidly and extensively absorbed. The oral suspensionhas variable bioavailability (range 36% to 100%) andreaches its peak effects 1 to 7.5 hours after intake. 11Methadone is a 50:50 racemic mixture. The R-enantiomerhas a significantly higher affinity to mu and kappareceptors. Methadone has an average half-life of 24 hours(range 13 to 50 hours). Metabolism of the drug occursthrough the CYP450 system—mainly CYP3A4, but alsoCYP2B6, CYP2C9, CYP2C19, and CYP2D6. Methadoneis an inhibitor of CYP2D6. 12,13Dosing: In an opioid-naïve patient beginning methadonemaintenance, the first dose should not exceed 40 mgowing to the risk of death from respiratory depression.A common starting dose is 20 mg to 30 mg. Thepatient usually is monitored for 2 to 4 hours to allow themethadone to peak. After the first day, additional dosesof 5 mg to 10 mg may be given if withdrawal symptomspersist. The dose may be slowly titrated over thenext couple of weeks to achieve a dose that prevents withdrawaland drug cravings without oversedating or causingother side effects. Most patients can be maintainedon a dose of 60 mg to 120 mg, although some patientswill need doses outside this range. 6For maintenance, methadone should be dispensed tothe patient as a 1-mg/mL solution. Doses of less than50 mg/day have been associated with increased relapserates and less retention in programs. 14,15Side Effects: Because methadone acts upon central opioidreceptors, its side-effect profile mirrors that of otheropioids. These effects include sweating, somnolence, dizziness,mild nausea, anorexia, constipation, and pruritus.The most serious adverse effects are respiratory depressionand cardiac arrhythmias. There also have been reportsof increased risk of cardiac death. Patients should becounseled regarding possible weight gain, sexual dysfunction,and oligomenorrhea or amenorrhea. 10,14Interactions: There are numerous potential drug interactionswith methadone (see TABLE 3). Methadone’s druginteractions occur primarily through inhibition or inductionof liver enzymes and changes in protein binding. 12,13No clinically significant protein-binding drug interactionhas been reported.Giving methadone with opioid antagonists, mixedagonist/antagonists, and partial agonists (i.e., naloxone,naltrexone, pentazocine, nalbuphine, butorphanol, andbuprenorphine) may precipitate withdrawal. Somnolenceand respiratory depression may be potentiated if methadoneis taken with other opioids.Buprenorphine and NaloxoneSome of the drawbacks of methadone treatment arethat the drug has increased risks of respiratory depression,death from overdose, QT prolongation, divergence,and difficult withdrawal. Buprenorphine is a partial agonistthat carries fewer risks than methadone. 16 Naloxoneis formulated in combination with buprenorphineto decrease the abuse potential: When taken correctlysublingually, naloxone has no clinical effect because ofpoor bioavailability; if injected, however, naloxone precipitateswithdrawal.Pharmacology: Buprenorphine is a synthetic opioid withpartial mu-opioid receptor agonism and kappa-receptorantagonism. It has a higher affinity for mu-opioid receptors;therefore, it displaces morphine, methadone, andother full agonists from the receptor site. This partial41U.S. Pharmacist • November 2009 • www.uspharmacist.com

KAPIDEX WORKS ASECOND SHIFTTO HELP SHUT DOWN ACID PUMPS

KAPIDEX is the first and only PPI with aDual Delayed Release (DDR) formulation,which provides a second release of drugMean plasma concentration (in healthy subjects; day 5; ng/mL) 112001000800600400200KAPIDEX 60 mgKAPIDEX 30 mg00 6 12 18 24Time (h)• KAPIDEX 30 mg provided full 24-hour heartburn relief in a majority of symptomaticnon-erosive gastroesophageal reflux disease patients at week 4 1• KAPIDEX 60 mg provided consistently high erosive esophagitis healing ratesat week 8 1• KAPIDEX offers a safety and tolerability profile similar to lansoprazole 1• KAPIDEX can be taken without regard to food 1KAPIDEX should be swallowed whole. Alternatively, capsules can be opened,sprinkled on 1 tablespoon of applesauce, and swallowed immediately. WhileKAPIDEX can be taken without regard to food, some patients may benefit fromadministering the dose prior to a meal if post-meal symptoms do not resolveunder post-fed conditions.Conclusions of comparative efficacy cannot be drawn from this information.IndicationsKAPIDEX is indicated for healing all grades of erosive esophagitis (EE) forup to 8 weeks, maintaining healing of EE for up to 6 months, and treatingheartburn associated with symptomatic non-erosive gastroesophageal refluxdisease (GERD) for 4 weeks.Important Safety InformationKAPIDEX is contraindicated in patients with known hypersensitivity toany component of the formulation. Hypersensitivity and anaphylaxis havebeen reported with KAPIDEX use. Symptomatic response with KAPIDEXdoes not preclude the presence of gastric malignancy. Most commonlyreported treatment-emergent adverse reactions (≥2%): diarrhea (4.8%),abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%),vomiting (1.6%), and flatulence (1.6%). Do not co-administer atazanavir withKAPIDEX because atazanavir systemic concentrations may be substantiallydecreased. KAPIDEX may interfere with absorption of drugs for which gastricpH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts,ketoconazole). Patients taking concomitant warfarin may require monitoringfor increases in international normalized ratio (INR) and prothrombin time.Increases in INR and prothrombin time may lead to abnormal bleeding, whichcan lead to serious consequences.Please see adjacent brief summary of prescribing information for KAPIDEX.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATIONKAPIDEX (dexlansoprazole) delayed release capsulesINDICATIONS AND USAGEKAPIDEX is indicated for: CONTRAINDICATIONS [see Adverse Reactions]WARNINGS AND PRECAUTIONSGastric Malignancy ADVERSE REACTIONSClinical Trials Experience Table 2: Incidence of Treatment-Emergent AdverseReactions in Controlled StudiesPlaceboKAPIDEX30 mg(N=455)%KAPIDEX60 mg(N=2218)%KAPIDEXTotal(N=2621)%Lansoprazole30 mg(N=1363)%(N=896)Adverse Reaction % Tract Infection Blood and Lymphatic System Disorders: CardiacDisorders: Ear and Labyrinth Disorders: Endocrine Disorders: Eye Disorders: Gastrointestinal Disorders: General Disorders and Administration Site Conditions: Hepatobiliary Disorders: Immune System Disorders: Infections and Infestations: Injury, Poisoning and Procedural Complications: Laboratory Investigations: Metabolism and NutritionDisorders: Musculoskeletaland Connective Tissue Disorders: Nervous System Disorders: PsychiatricDisorders: Renal and Urinary Disorders: ReproductiveSystem and Breast Disorders: ; Respiratory, Thoracic and Mediastinal Disorders: Skin and Subcutaneous TissueDisorders: Vascular Disorders: DRUG INTERACTIONSDrugs with pH-Dependent Absorption Pharmacokinetics Warfarin USE IN SPECIFIC POPULATIONSPregnancyTeratogenic Effects

Nursing Mothers [see Carcinogenesis, Mutagenesis, Impairment of Fertility] Pediatric Use Geriatric Use ]Renal Impairment .Hepatic Impairment .OVERDOSAGE CLINICAL PHARMACOLOGYPharmacodynamics [see Nonclinical Toxicology ] c c NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility [see Clinical Pharmacology]. PATIENT COUNSELING INFORMATION[see FDA-Approved Patient Labeling in the full prescribing information]Information for Patients Takeda Pharmaceuticals America, Inc. KAPIDEX and Dual Delayed Release are trademarks of Takeda Pharmaceuticals North America, Inc.,and are used under license by Takeda Pharmaceuticals America, Inc.Reference: 1. KAPIDEX (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc.©2009 Takeda Pharmaceuticals North America, Inc.LPD-00250 6/09 Printed in U.S.A.

OPIOID MAINTENANCE TREATMENTTable 2Characteristics of Options for Maintenance TreatmentBuprenorphine andBuprenorphine/NaloxoneMethadonePharmacologic Action Buprenorphine: partial agonist Full agonistNaloxone: full antagonistRoute of Administration Sublingual OralDosing Buprenorphine: 2-32 mg; naloxone: 20-30 mg initially, then 60-120 mg0.5-8 mg; combination: 4:1 ratioAdministration Daily to 3 times/wk DailyCommon Side Effects Headache, nausea, sweating, rhinitis, Cardiac dysrhythmia, hypotension, diaphoresis,constipationconstipation, nausea, vomiting, dizziness,sedationContraindications Need for ongoing opioid agonists for Hypersensitivitypain relief, hypersensitivityPregnancy Concerns Category C; combination not Category C; current standard of care inrecommended in pregnancy—replace pregnancywith methadone or buprenorphineAccessibility Physician’s office or opioid Opioid treatment programtreatment programRegulatory Concerns Physician may prescribe only with Physician may prescribe only to opioid-DEA-issued registration certificate code; dependent patients for up to 72 h as bridge30-patient census/prescriber, then 100- to treatment entry; only licensed opioidpatient census after 1st y; pharmacy treatment programs may dispense; federalmay dispense up to 30-day supply regulations govern dispensing frequencybased on schedule III(e.g., daily, 3 times/wk, wkly)Insurance Coverage Specific to type of insurance Specific to type of insuranceDEA: Drug Enforcement Administration.Source: Reference 25.agonism allows buprenorphine to have a ceiling effect onthe opioid effects at higher doses, making it safer in theevent of overdose.Naloxone is a mu-opioid receptor antagonist withpoor oral bioavailability owing to limited absorption andextensive first-pass metabolism. It has a rapid onset ofaction when given intravenously. Because it has ahigher affinity for mu-opioid receptors than heroin, morphine,or methadone, naloxone displaces these drugs fromreceptors and blocks their effects. 17Buprenorphine/naloxone (Suboxone) is available asa 4:1 fixed combination. Subutex (buprenorphine), awhite tablet, is available in 2-mg and 8-mg strengths;Suboxone is an orange tablet and is available in 2/0.5-mg and 8/2-mg formulations. Buprenorphine israpidly absorbed sublingually, and peak effects are reached90 minutes after administration. Naloxone does notaffect the pharmacokinetics of buprenorphine. The meanhalf-life of buprenorphine is 37 hours; that of naloxoneis 1.1 hours. 18Dosing: Because buprenorphine displaces the other opioidfrom mu-receptor sites and induces withdrawal, itshould be initiated only when the patient already hasevident signs of withdrawal; otherwise, the patient mightassociate the buprenorphine with withdrawal, therebyreducing adherence. The buprenorphine/naloxone combinationis the drug of choice for initiating therapy inboth U.S. and European guidelines. Buprenorphine maybe started alone at doses of 4 mg to 8 mg or in combinationin a 4:1 ratio to naloxone. A second dose of 4mg may be given in 2 to 4 hours, and the patient maybe given an additional dose of 2 mg to 4 mg to takehome in case of withdrawal within the next 24 hours.The physician should monitor for buprenorphine-precipitatedwithdrawal while the patient is in the office.This is not to be confused with withdrawal from underdosingof buprenorphine, which usually occurs in thesecond half of the 24-hour dosing interval. 16The maintenance dose may be achieved by doublingthe dose each day, to a maximum of 24 mg to 32 mg.If withdrawal symptoms arise at any time during the24-hour dosing interval, the dose is too low and needsto be increased. If induction occurs too slowly, thepatient may prematurely terminate treatment. Therefore,it is important for the practitioner to be diligentin monitoring the patient. When converting to or fromthe naltrexone combination, a 1:1 ratio of the buprenorphinedose may be used. 16When the maintenance dose is achieved, buprenor-46U.S. Pharmacist • November 2009 • www.uspharmacist.com

Table 3Potential Drug Interactions forMethadone and Buprenorphinephine may be administered from every other day to 3times weekly (e.g., Monday, Wednesday, and Friday) inorder to increase compliance and patient satisfaction.Every-4-day regimens have been associated with increasedwithdrawal symptoms. The daily dose may be doubledfor every-other-day dosing and also for thrice-weekly dosing,but Friday’s dose would be 2.5 times the daily dose. 16New patients should be advised that sublingual tabletsmust be dissolved under the tongue, as the medicationis much less effective if swallowed. 18 No more than twotablets should be taken at one time, to avoid swallowingthem by mistake. Wetting the mouth before placingthe tablets under the tongue may help them dissolvefaster. Full absorption may take up to 10 minutes.Patientsshould refrain from smoking for 10 to 15 minutes beforetaking the medication, as this seems to help the tabletsdissolve faster. 18Side Effects: Buprenorphine/naloxone is generally welltolerated. Side effects are associated mainly with buprenorphine,since naloxone is not readily absorbed. In clinicaltrials, the most common adverse effects were headache,withdrawal syndrome, pain, nausea, insomnia, sweating,rhinitis, constipation, abdominal pain, flulike syndrome,and flushing. 17OPIOID MAINTENANCE TREATMENTInteraction Methadone BuprenorphineIncrease Effects Alcohol Alcoholof Opioid Substitute Antidepressants Antiretrovirals• Fluoxetine • Atazanavir• Fluvoxamine • Indinavir• Paroxetine • Nevirapine• Sertraline• RitonavirAnti-infectives • Saquinavir• Ciprofloxacin Benzodiazepines• Erythromycin Fluvoxamine• Fluconazole Ketoconazole• KetoconazoleBenzodiazepinesCimetidineDecrease Effects Anti-infectives Carbamazepineof Opioid Substitute • Fusidic acid Phenobarbital• RifampinPhenytoinAntiretrovirals Rifampin• Abacavir• Amprenavir• Efavirenz• Nevirapine• Ritonavir• SaquinavirBarbituratesCarbamazepinePhenytoinSource: References 12, 16.Interactions: Buprenorphine goes through hepaticmetabolism via CYP3A4. The drug has thepotential for many of the same interactions asmethadone (see TABLE 3). One dangerous interactionto monitor for is the potentially fatalinteraction with benzodiazepines. 19 Concomitantadministration should be avoided. Compared withmethadone, buprenorphine may be a safer choicein patients receiving antiretrovirals. 20CLINICAL EFFICACY OF METHADONEVERSUS BUPRENORPHINEIt is well established that both methadone andbuprenorphine are effective for decreasing illicitdrug use. It is worthwhile to consider the resultsof studies examining the efficacy of methadoneversus buprenorphine. 7The 2008 Cochrane review determined thatmethadone dosed at 60 mg/day to 120 mg/dayhas superior efficacy compared with buprenorphine.21 The specific studies yield varied results.One study found less illicit heroin use withbuprenorphine than with methadone, but themethadone arm had higher retention rates. 22Another study concluded that high-dose methadonehad a higher retention rate and less illicit opioiduse compared with buprenorphine 8 mg. 23 A double-blind,randomized trial comparing an averagedose of buprenorphine (10 mg/day) versusmethadone (70 mg/day) showed a higher retentionrate with methadone, but found that thedrugs had equal efficacy in reducing illicit heroin use. 24However, a study from 1992 concluded that buprenorphinehad better retention rates than methadone at 25weeks. 26 Overall, it is accepted that buprenorphine andmethadone have comparable efficacy and that treatmentshould be individualized.CONCLUSIONBecause of DATA 2000 and ongoing research on opioiddependence, pharmacists must be prepared to facean increase in the number of prescriptions being writtenfor opioid maintenance treatment. When presentedwith a new prescription, a pharmacist may visit the sitewww.buprenorphine.samhsa.gov to confirm physicianeligibility. Pharmacists must monitor and counsel patientsabout withdrawal symptoms and overdose possibilities.Because buprenorphine is a partial agonist, the risk ofoverdose is smaller, and its use in combination with naloxonefurther reduces the risk of intravenous abuse. Historically,daily visits to methadone clinics have been themost frequently utilized method of treating opioid dependence,but with the current availability of sublingualbuprenorphine products, more patients will be able toreceive treatment in a convenient office-based setting.References available online at www.uspharmacist.com.53U.S. Pharmacist • November 2009 • www.uspharmacist.com

Generic TrendsGenerics WillHave ModestNegative Impact onHypertension DrugMarket SalesThrough 2018Despite the generic erosionof many hypertensiondrug productsexpected over the nextdecade, it is estimatedthat the overall hypertensiondrug marketwill experience only amodest decline. Accordingto DecisionResources, a researchand advisory firm forpharmaceutical andhealth care issues, themarket will decrease1.4% annually through2013, and thereafter theannual decline will slowto 1% through 2018 inthe United States,France, Germany, Italy,Spain, the United Kingdom,and Japan.According to a companyreport, a majorcontributor to the marketdecline will be anincrease in the genericavailability of antihypertensiveagents. Forexample, by 2018,Novartis’s Diovan alonewill lose more than $1billion in sales beginningnext year when thedrug goes off patent.Other hypertensiondrug classes will sufferas well, includingangiotensin-convertingenzyme inhibitors (ACEinhibitors), angiotensinII receptor antagonists,Hatch-Waxman Act Turns 25Twenty-five years ago a bill introduced by Senator Orrin Hatch and Rep.Henry Waxman that would change the generic industry forever was signedinto law at a White House Rose Garden ceremony. While not perfect, theHatch-Waxman Act continues to receive accolades from industry observersand government officials.“Our industry is proud of how far it has come in the past 25 years,” saidKathleen Jaeger, president and CEO of the Generic Pharmaceutical Association,commenting on the law. “Today, generic medicines represent 72% ofthe total prescriptions dispensed in the U.S., but only 17% of all dollarsspent on prescription drugs. One billion dollars is saved every three days byusing generics. That’s extraordinary savings—far more than anyone predictedor could have even imagined 25 years ago.”Health and Human Services Secretary Kathleen Sebelius also offeredkudos, particularly in the context of health care reform proposals currentlyin front of Congress.“I think that it’s appropriate this year that as we look at what’s pendingin Congress on health reform that we are also celebrating the quarter centuryanniversary of the Hatch-Waxman Act, which really began to transformthe pharmaceutical industry and made generic drugs much morewidely available to Americans.”And from the bill’s authors comes admission that they didn’t always seeeye-to-eye from across the aisle, but were able to still produce a bipartisanpiece of legislation that has withstood many challenges over its relativelyshort 25-year history.“Henry and I put our differences aside to work in a bipartisan mannerto get the bill passed,” admits Senator Hatch. “In the end, we passed a billthat has not only worked well, but has saved consumers, state, and federalgovernments billions of dollars.”“When Senator Hatch and I developed the legislation 25 years ago toproduce generic drugs, we thought that the result of this law would saveperhaps a billion dollars…in reality generic drugs have saved consumer andbusinesses, and state and federal governments $734 billion,” said RepresentativeWaxman.calcium channel blockers,and diuretics.Mylan SettlesWith Pfizer OverVfend GenericMylan Pharmaceuticalsand Matrix Laboratorieshave entered into a settlementand licenseagreement with PfizerInc. relating to voriconazoletablets, 50 mg and200 mg, the generic versionof Pfizer’s VfendTablets, a triazole antifungalagent.Mylan’s Matrix wasthe first company tosubmit a substantiallycomplete AbbreviatedNew Drug Applicationcontaining a ParagraphIV certification to theFDA and thereforebelieves it will be eligiblefor 180 days of marketingexclusivity uponcommercial marketing ofthe product.Pursuant to the agreement,Mylan will havethe right to marketvoriconazole tablets inthe U.S. in the firstquarter of 2011.54U.S. Pharmacist • November 2009 • www.uspharmacist.com

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Generic Trends“Free Generic Fill”Provision in HealthCare ReformLegislationApplauded by GPhA“GPhA applauds theSenate Finance Committeefor approving the‘Free Generic Fill’ provision[in health carereform legislation],which would savepatients and the federalgovernment more than$6 billion over 10years,” commentedKathleen Jaeger, presidentand CEO of theGeneric PharmaceuticalAssociation (GPhA).The “free generic fill”provision creates anexception that wouldallow health plan sponsorsto encourage beneficiariesto utilize genericdrugs by allowing themto waive copays as anincentive to try a genericdrug.“Clearly, Congress hasrecognized that expandingaccess to genericmedicines is the key tolowering health carecosts...,” said Jaeger.Innovative PharmacyBenefit PlanDesign Can OptimizeGeneric UtilizationData from research conductedby CVS Caremarkand presented at theAcademy of ManagedCare Pharmacy (AMCP)Annual Educational Conferenceshowed that innovativepharmacy benefitplan design can impactgeneric utilization. Specifically,the study foundthat implementing a $0copay structure forgeneric medications canbe an effective strategy toincrease generic dispensing,with the generic dispensingrate increasing to60.8% (which representsa 4.2% increase).“The data presented atAMCP illustrate anexample of how we canwork with our plan sponsorsto change and optimizeparticipant behaviorin order to achieveincreased generic utilization,”said Jack Bruner,executive vice president,CVS Caremark.Some other datauncovered by the studyshowed that the averageparticipant cost share forgeneric medicationsdecreased almost 10%and the average plan costper 30 days of therapyalso exhibited a slightdecline, despite thereduction in genericcopayment rates.Call for PapersU.S. Pharmacist is seeking authors to write clinical articles and continuing education lessons on a variety of topics. While we willentertain all subject matter, we are particularly interested in articles that correspond to our “Editorial Focus” therapeutic areas. Thetherapeutic categories and the months for which they are planned are listed below:Cardiovascular Diseases – FebruaryEndocrinology – JuneGastroenterologic Diseases – DecemberInfectious Diseases – AugustNeurologic Diseases – JanuaryNew Drugs – OctoberOphthalmology – AprilPain Management – MayPediatric and Adolescent Health – MarchPsychotropics – NovemberRespiratory Diseases – JulyWomen’s Health – SeptemberIn addition to these topics, we also publish supplements each yearcovering oncology and hematology, diabetes, the generic drugindustry, and OTC drugs.In the majority of cases, articles are peer-reviewed and an honorariumis offered based on their complexity and length. As a generalguideline, we would like the articles to be approximately 2,500–2,800 words, including references and tables. Continuingeducation lessons should be approximately 6,000 words, includingreferences, tables, and exam. Prospective authors are urged toreview the “Author Guidelines” on the U.S. Pharmacist Web siteat www.uspharmacist.com.Interested authors should contact Rob Davidson, Executive Editor(rdavidson@jobson.com), with the topic(s) they would like to cover.All articles must be original and exclusive to U.S. Pharmacist.

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Contemporary CompoundingKetamine Hydrochloride10-mg TrochesIn lozenge form, this analgesic and anesthetic agent can beprepared to suit the patient’s individual flavor preference.●FORMULAKetamine Hydrochloride 10-mg TrochesRx (for 100 troches):IngredientKetamine hydrochloride1 gSilica gel1 gStevia750 mgAcacia1.65 gCitric acid1.2 gFlavorqsPolyethylene glycol 1450qsMethod of Preparation:Calibrate the mold beingused to determine theamount of polyethyleneglycol (PEG) 1450needed. Calculate thequantity of each ingredientfor the amount to beprepared. Accuratelyweigh or measure eachingredient. Melt the PEG1450 at 50°-55°C. Blendthe powders (ketaminehydrochloride [HCl], silicagel, stevia, acacia, citricacid) and slowly sprinkleinto melted basewhile mixing; mix untiluniform. Remove fromheat, add flavor (whichcan be based on thepatient’s preference), andmix well. Pour intomolds and let mixturecool. Trim (if necessary),package, and label.Loyd V. Allen, Jr, PhDProfessor Emeritus, College ofPharmacy, University ofOklahoma, Oklahoma CityUse: Ketamine HCltroches have been usedto treat moderate-toseverepain.Packaging: Package inwell-sealed, light-resistantcontainers.Labeling: Keep out of thereach of children. Useonly as directed.Stability: A beyond-usedate of up to 6 monthsmay be used for thispreparation. 1Quality Control: Quality-controlassessment caninclude weight, specificgravity, active drug assay,color, texture–surface,appearance, feel, meltingtest, dissolution test,physical observation, andphysical stability. 2Discussion: KetamineHCl (C 13H 16ClNO.HCl,MW 274.2), an analgesicand anesthetic, occurs asa white, crystalline powderwith a slight characteristicodor. ≈1.15 mg isequivalent to 1 mg ketaminebase. It is soluble 1g in 4 mL water, 14 mLalcohol, and 60 mLabsolute alcohol. 1,3Silica gel is obtainedby insolubilizing the dissolvedsilica in sodiumsilicate solution. It occursas a fine, white, hygroscopic,odorless, amorphouspowder with ausual particle size of 2-10mu. It is insoluble inalcohol, other organicsolvents, and water, andsoluble in hot solutionsof alkali hydroxides. It isused as a desiccant, suspendingagent, and viscosity-increasingagent. 4Stevia (honey leaf,yerba dulce) is a naturalsweetening agentextracted from the Steviarebaudiana Bertoni plant.Nontoxic and safe, itoccurs as a white, crystalline,hygroscopic powder.It can be used in hotand cold preparations. 5Acacia (gum acacia,gum arabic) is the driedgummy exudate obtainedfrom some species of theacacia tree. It is a complexaggregate of sugars andhemicelluloses, with MWfrom 240,000 to 580,000.It is used as an emulsifyingagent (5%-10% concentration[conc]),pastillebase (10%-30% conc),suspending agent (5%-10% conc), and tabletbinder (1%-5% conc), aswell as in cosmetics andfood products. It shouldbe preserved when inaqueous solution, as it issubject to bacterial orenzymatic degradation.Boiling its solution brieflywill inactivate anyenzymes and enhance itsstability. Some substancesthat are incompatible withacacia are cresol, ethanol(95%), morphine, phenol,and thymol. Some saltsreduce the viscosity ofaqueous acacia solutions.Since acacia is negativelycharged in solution, it willform a coacervate withpositively charged moleculessuch as those in gelatin.Acacia may coagulatein the presence of trivalentsalts. 6Citric acid (citric acidmonohydrate,C 6H 8O 7.H 2O) occurs ascolorless or translucentcrystals or as a white, crystalline,efflorescent, odorlesspowder with a strong,tart, acidic taste. It is presentat about the 5%-8%58U.S. Pharmacist • November 2009 • www.uspharmacist.com

Contemporary Compoundinglevel in lemon juice. In0.3%-2% concentration,it is used to improve flavorin liquid formulationsand as a sequesteringagent. It may be used toprepare effervescent granulesand solid and semisolid(chewable) dosageforms. The hydrated formmay contain up to 8.8%water, and the pH of a1% w/v aqueous solutionis ≈2.2. Its density is1.542 g/mL. Thehydrated form will effloresceand the anhydrousform will be hygroscopic,depending upon thehumidity. If stored in airthat is too dry, it may loseits water if the temperaturereaches ≈40°C. Itsmelting point is ≈100°C,but it softens at ≈75°C.One g is soluble in

Pharmacologic Managementof Alcohol Dependence© JUPITERIMAGESAlcohol dependence is a serious health concernthat is associated with many long-term consequences.Alcohol dependence not only affectsan individual’s physical health, but also may impactmental health and social well-being. Alcohol use is commonin the American population. According to the2008 National Survey on Drug Use and Health, morethan 50% of Americans aged 12 and older reporteddrinking, 23% reported binge drinking, and 6.9% wereheavy alcohol drinkers. 1 The prevalence rate of alcoholabuse or dependence in the United States is estimatedat 5% to 14%. 1-3Alcohol dependence is a chronic disorder that mayrequire maintenance treatment, similar to other medicalconditions such as hyperlipidemia and diabetes. 4It is believed that multiple neurotransmitters such asendogenous opioids, dopamine, serotonin, gammaaminobutyricacid (GABA), and glutamate may beeither directly or indirectly affected by alcohol. 4 Riskfactors such as genetics, environmental factors, and culturalattitudes may play a significant role in thedevelopment of alcohol dependence. 2The intent of this article is to review the pharmacologicmanagement of alcohol dependence; thereforealcohol withdrawal, although a crucial part of treatment,will not be discussed.Pharmacologic TherapyThe ultimate goals for patients with alcohol dependenceare to achieve abstinence and prevent relapse.Currently, the four pharmacologic agents that mayaid in accomplishing these goals are disulfiram, oralnaltrexone, injectable extended-release naltrexone, andacamprosate.Krina H. Patel, PharmDAssistant ProfessorPharmacy PracticeNesbitt College of Pharmacy and NursingWilkes UniversityWilkes Barre, PennsylvaniaDisulfiram: Disulfiram is an aversion-based treatmentthat acts by blocking aldehyde dehydrogenase(ALDH). This results inan increase in acetaldehyde levelswhen alcohol is consumed and inducesnegative effects such as dizziness,flushing, nausea, vomiting, hypotension,arrhythmia, convulsions, respiratory depression,and myocardial infarction. 4-6 The effects of this drugare sufficiently unpleasant to the patient to serve as adeterrent to consuming alcohol.Disulfiram in the absence of alcohol tends to causeminimal effects; however, drowsiness, metallic aftertaste,and hepatotoxicity may occur. 5 Severe cardiovasculardisease and concurrent use of metronidazole aretwo major contraindications associated with disulfiram.5 It is important not to administer disulfiram untilthe patient has abstained from alcohol for at least 12hours. Furthermore, since disulfiram irreversibly inhibitsALDH, alcohol consumption must be avoided for 2weeks after the last dose. 5There is a substantial amount of literature regardingthe use of disulfiram for alcohol dependence, butmany of these trials have significant methodologic weaknesses.6,7 Some of the data are inconsistent and maybe conflicting. 4,6 A Veterans Administration CooperativeStudy assessed 605 subjects assigned to disulfiram250 mg, disulfiram 1 mg, or placebo. 8 Thisstudy, conducted over 1 year, concluded that there wereno significant between-group differences in abstinencerates or time to first drink. The study did find, however,that patients receiving disulfiram 250 mg whoended up drinking reported fewer drinking days comparedwith the other two groups. 8Disulfiram is still utilized despite the conflictingdata. Disulfiram’s unique mechanism of action may bea powerful advantage for patients. Disulfiram may helpwith drinking outcomes such as reduced drinking daysor frequency; however, other outcomes, such as timeto first drink, abstinence, and alcohol consumption perunit of time, lack consistent evidence. 4,6 Althoughnot appropriate for all patients, disulfiram has a placein therapy for individuals seeking help with cessationof heavy drinking.Naltrexone: Naltrexone is a competitiveopioid receptor antagonist.Endogenous opioids are released inresponse to alcohol intake, thereby60U.S. Pharmacist • November 2009 • www.uspharmacist.com

PHARMACOLOGIC MANAGEMENT OF ALCOHOL DEPENDENCEcausing alcohol’s acute rewarding properties. Naltrexone’smechanism of action reduces cravings and alsois likely to minimize the “high” that individuals experiencewith alcohol intake, which may result in loweralcohol consumption. 7,9-12Naltrexone’s adverse-effect profile tends to bemild, but gastrointestinal side effects, headache,dizziness, anxiety, and decreased appetite may occur. 5Rarely, naltrexone may cause dose-related hepatotoxicity,so frequent monitoring is recommended. Owingto naltrexone’s mechanism of action, current opiatetreatment may induce withdrawal symptoms, so patientsshould be opioid-free for at least 7 to 10 days beforenaltrexone is initiated. 5Several studies have concluded that naltrexone is aneffective treatment option for alcohol dependence. In a12-week, double-blind, placebo-controlled trial, 70 malepatients were treated with naltrexone or placebo. 9 Patientswho received naltrexone experienced fewer cravings andconsumed less alcohol. The percentage of patients whorelapsed was significantly less in the naltrexone groupcompared with the placebo group (54% vs. 23%). Additionally,95% of placebo patients who sampled alcoholrelapsed, versus 50% of naltrexone patients. 9 Anothertrial established that naltrexone was superior toplacebo when outcomes such as number of drinkingdays, abstinence rates, relapse rates, and severity of alcohol-relatedproblems were compared. 12 This study foundthat abstinence rates were higher in the naltrexone groupversus the placebo group (61% vs. 19%). 12There are also some less compelling data regardingnaltrexone. One trial evaluated the use of naltrexonefor 3 months or 12 months in 627 veterans. 13 Naltrexonewas not significantly better than placebo in decreasingpercentage of drinking days or drinks per day,and it did not improve days to relapse. The trial concludedthat the use of naltrexone in this populationbase was not supported. 13Overall, naltrexone is an effective treatment optionfor patients with alcohol dependence. Based on the literature,naltrexone can help improve outcomes by lesseningcravings, decreasing heavy alcohol consumption,decreasing relapse, and potentially enhancing abstinencerates. 7,9-12Intramuscular (IM) Naltrexone: In 2006, the FDAapproved a long-acting IM formulation of naltrexone.Previous trials of naltrexone suggested that nonadherenceto treatment may be a concern, resulting indecreased effectiveness and suboptimal treatment outcomes.10,14 Use of the IM formulation may helpovercome problems with adherence. One concernregarding this formulation is the potential for injection-sitereactions such as cellulitis, hematoma, andnecrosis. 5Several trials support positive outcomes associatedwith the use of IM naltrexone. In one multicenter,randomized, placebo-controlled trial, 315 patientsreceived either IM naltrexone or placebo. 15 The trial,conducted over 3 months, found that IM naltrexonesignificantly improved abstinence rates compared withplacebo (18% vs. 10%), and also prolonged the timeto first drinking day. 15 Overall, IM naltrexone appearsto be a safe and effective treatment option that maybe especially beneficial for patients who have adherenceproblems. 16Acamprosate: In 2004, acamprosate became availablein the U.S. for the treatment of alcohol dependence.It is hypothesized that acamprosate restores GABA andglutamate imbalances caused by alcohol intake. 5,11 Italso is proposed that acamprosate has some effects onthe N-methyl-D-aspartic acid receptor. 11Some common adverse effects associated withacamprosate are diarrhea, headache, insomnia, anxiety,and muscle weakness. 5 Patients treated with acamprosateshould try their best to avoid alcohol; however, alcoholintake does not affect the pharmacokinetics of acamprosate,and therefore no disulfiram-type reaction willoccur. 5 In addition, acamprosate may be a safer optionthan disulfiram or naltrexone in patients with hepaticimpairment. The drug should be used with caution inpatients with renal impairment, however. 5Currently, there is insufficient U.S. literature stronglyevidencing the effectiveness of acamprosate, althoughan adequate amount of European literature supportsits use. 17-20 The COMBINE study, conducted in theU.S., concluded that acamprosate failed to show evidenceof efficacy with regard to time to first heavy drinkor abstinent days. 17 In another U.S.-based double-blind,placebo-controlled study, patients received acamprosate2 g, acamprosate 3 g, or placebo. 18 This study foundthat percentage of abstinent days did not differamong treatment groups; however, a post-hoc analysisthat controlled baseline covariates and measuredhighly motivated patients as a subset found that acamprosateyielded a greater number of abstinent days thanplacebo. 18A European meta-analysis of 20 trials suggested thatcontinuous abstinence rates at 6 months were significantlyhigher for acamprosate-treated patients versuspatients given placebo (36.1% vs. 23.4%). 19 Dataalso indicate that acamprosate confers improvedabstinence rates for up to 48 weeks. 20It is not clear why outcomes associated with acamprosateare inconsistent between the U.S. and Europeanstudies. Certain factors, such as the severity ofthe alcohol dependence, may be potential reasons. 4Based on the literature, acamprosate is associatedwith an improved rate of complete abstinence and mayhave other positive outcomes, such as decreased drinkingfrequency and rate of relapse. 7,18-20 The drug appears61U.S. Pharmacist • November 2009 • www.uspharmacist.com

Day 1Day 2 Day 3 Day 4 Day 5TAKE Z-PAK ® FOR 5 DAYS 1 OR...(azithromycin) 250 mgTAKE AZITHROMYCIN TO1 DAY. 1 DOSE.2Please see accompanying Zmax brief summary.Zmax is indicated for mild to moderate acute bacterialsinusitis in adults due to Haemophilus influenzae, Moraxellacatarrhalis, or Streptococcus pneumoniae and is also indicatedfor community-acquired pneumonia due to Chlamydophilapneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae,oror Streptococcus pneumoniae in adult and pediatric patientsaged 6 months and over, deemed appropriate for oral therapy.Zmax and Zithromax are contraindicated in patients withknown hypersensitivity to azithromycin, erythromycin, or anymacrolide or ketolide antibiotic. If an allergic reaction occurs,appropriate therapy should be instituted. Physicians should beaware that reappearance of the allergic symptoms may occurwhen symptomatic therapy is discontinued.There have been rare reports of serious allergic reactions includingangioedema, anaphylaxis, Stevens Johnson syndrome, and toxicepidermal necrolysis in patients on other formulations ofazithromycin therapy. Rarely, fatalities have been reported.Clostridium difficile associated diarrhea (CDAD) has beenreported with use of nearly all antibacterial agents, includingazithromycin, and may range in severity from mild diarrheato fatal colitis. CDAD must be considered in all patients whopresent with diarrhea following antibiotic use. Carefulmedical history is necessary since CDAD has been reported tooccur over two months after the administration ofantibacterial agents. If CDAD is suspected or confirmed,ongoing antibiotic use not directed against C. difficile may needto be discontinued, and appropriate management and treatmentof C. difficile should be instituted as clinically indicated.As with all macrolides, including Zmax, exacerbations ofmyasthenia gravis have been reported.

Zmax: 1 product — indicated for bothadult and pediatric patients 2PediatricpatientsAdultpatientsA higher incidence of gastrointestinal adverse events (8 of 19subjects) was observed when Zmax was administered to alimited number of subjects with GFR

Zmax ® (azithromycin extended release) for oral suspensionBrief Summary of Prescribing InformationINDICATIONS AND USAGEZmax is indicated for the treatment with mild to moderate infections caused by susceptible isolatesof the designated microorganisms in the specific conditions listed below.Acute bacterial sinusitis in adults due to Haemophilus influenzae, Moraxella catarrhalis orStreptococcus pneumoniae.Community-acquired pneumonia in adults and pediatric patients six months of age or older due toChlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcuspneumoniae, in patients appropriate for oral therapy. Pediatric use in this indication is based onextrapolation of adult efficacy.To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zmax and otherantibacterial drugs, Zmax should be used only to treat infections that are proven or strongly suspectedto be caused by susceptible bacteria. When culture and susceptibility information are available, theyshould be considered in selecting or modifying antibacterial therapy. In the absence of such data, localepidemiology and susceptibility patterns may contribute to the empiric selection of therapy.Appropriate culture and susceptibility tests should be performed before treatment to determine the causativeorganism and its susceptibility to Zmax.Therapy with Zmax may be initiated before results of these tests areknown; once the results become available, antimicrobial therapy should be adjusted accordingly.CONTRAINDICATIONSZmax is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or anymacrolide or ketolide antibiotic.WARNINGS AND PRECAUTIONSAllergic and skin reactionsSerious allergic reactions, including angioedema, anaphylaxis, Stevens Johnson syndrome, and toxicepidermal necrolysis have been reported rarely in patients on azithromycin therapy using otherformulations. Although rare, fatalities have been reported. Despite initially successful symptomatictreatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptomsrecurred soon thereafter in some patients without further azithromycin exposure.These patientsrequired prolonged periods of observation and symptomatic treatment. The relationship of theseepisodes to the long tissue half-life of azithromycin and subsequent exposure to antigen hasnot been determined.If an allergic reaction occurs, appropriate therapy should be instituted. Physicians should be awarethat reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.Clostridium difficile-associated diarrheaClostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterialagents, including Zmax, and may range in severity from mild diarrhea to fatal colitis. Treatment withantibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producingstrains of C. difficile cause increased morbidity and mortality, as these infections can be refractory toantimicrobial therapy and may require colectomy. CDAD must be considered in all patients who presentwith diarrhea following antibiotic use. Careful medical history is necessary since CDAD has beenreported to occur over two months after the administration of antibacterial agents.If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may needto be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotictreatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.Exacerbation of myasthenia gravisExacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have beenreported in patients receiving azithromycin therapy.Gastrointestinal DisturbancesA higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Zmaxwas administered to a limited number of subjects with GFR

PHARMACOLOGIC MANAGEMENT OF ALCOHOL DEPENDENCEto be a logical option given the evidence of lastingeffects and improved drinking outcomes. 20Combination TreatmentIt has been proposed that combination therapy mayresult in improved efficacy compared with monotherapy.17,21,22 Owing to their different mechanisms ofaction, it may be theoretically appropriate to combinethese agents for added benefit. Based on the literature,the combination of disulfiram and naltrexoneappears to offer no additional benefits over treatmentwith either medication alone. 23 Studies examiningthe combination of disulfiram and acamprosate indicatethat this combination may result in improved efficacy,but there is not much literature regarding concomitantuse of these drugs. 21The bulk of the literature centers on the combinationof naltrexone and acamprosate. The COMBINEtrial concluded that the concomitant use of these twomedications appeared to be safe and well tolerated, butprovided no additional therapeutic benefit versus naltrexonealone. 17 In another trial, 160 patients were randomizedto receive acamprosate, naltrexone, naltrexoneplus acamprosate, or placebo. 22 The combinationgroup had significantly lower relapse rates comparedwith the placebo group and the acamprosate group,but the combination was not more effective than naltrexoneonly. 22Overall, the combination of naltrexone and acamprosateappears to be safe and well tolerated, butthere may be an increase in certain adverse effects, suchas diarrhea and nausea. 22 The combination seems toprovide some benefit compared with acamprosate alone.Combination therapy may be a valid option for somepatients who are not responding to monotherapy. Furtherresearch is needed to clarify the utility of combinationtherapy in the treatment of alcohol dependence.Off-Label and Investigational TreatmentsRecently there has been a growing interest in exploringother potential treatments for alcohol dependence.Most new research focuses on agents that are proposedto target neurotransmitters that are affected by alcohol.These different classes of medications have beenused off-label in the hope that some new agents mayprovide promising treatments in the future.Topiramate, oxcarbazepine, lithium, carbamazepine,gabapentin, and divalproex are some of the mood stabilizersand anticonvulsants that have been evaluatedfor the treatment of alcohol dependence. 4,6,10 It isbelieved that some anticonvulsants, such as topiramate,are responsible for enhancing GABA activity and antagonizingglutamate activity, which may lead to decreasedalcohol consumption. 4,10,24 Topiramate appears to bethe best studied of the anticonvulsants thus far. Severalrandomized, controlled trials of topiramate havereported positive drinking outcomes (such as decreasedheavy drinking days and drinks per day) and increasedabstinent days compared with placebo. 10,24,25 One trialfound that patients treated with topiramate achieved26% more abstinent days than patients given placebo. 24Topiramate appears to hold promise as a treatmentfor alcohol dependence.Most of the other abovementioned drugs, such asoxcarbazepine and divalproex, do not have conclusivedata concerning their utility in treating alcohol dependence,and further research is needed. 10 Lithium currentlydoes not have supportive evidence as a treatmentfor alcohol dependence. 7Serotonergic agents constitute another medicationclass that has been researched for its value in treatingalcohol dependence. It is theorized that serotonin playsa role in alcohol consumption. 4,26 Literature exists concerningthe use of selective serotonin reuptake inhibitors(SSRIs) for the treatment of alcohol dependence; however,results are inconsistent and do not support theuse of SSRIs to treat alcohol dependence as a primarycondition. 4,6,7,26 It is thought that SSRIs may improvepsychiatric illness, which may have an effect ondrinking behavior. 27 Ondansetron has been associatedwith positive drinking outcomes such as fewer drinksper day, fewer drinks per drinking day, more abstinentdays, and more abstinent days per week. 6Dopamine antagonists may be involved in the treatmentof alcohol dependence. Olanzapine has exhibitedsome positive outcomes. 10 Other agents, such as baclofenand galantamine, also have been researched, but dataregarding their use are either mixed or negative. 10Currently, there are only a few options availablefor the treatment of alcohol dependence. The agentsmentioned above may hold some promise for the future,but more research is needed. Many of the current trialsof these agents are methodologically weak or haveinconclusive findings. For those reasons, further investigationis needed before these agents can be recommendedor used for the treatment of alcohol dependence.There is a great need for the discovery of newpotential options to treat alcohol dependence.ConclusionAlcohol dependence is a chronic disorder that has manyconsequences. Optimal treatment with pharmacologicagents may help achieve desired outcomes. The currentlyavailable treatments for alcohol dependence areall valid options, and their use should be individualized.Pharmacists can optimize treatment by recommendingagents based on the expected outcomesassociated with each medication. Pharmacists also canprovide care by educating patients regarding expectedoutcomes, adverse effects, and precautions associatedwith the pharmacologic agents.References available online at www.uspharmacist.com.65U.S. Pharmacist • November 2009 • www.uspharmacist.com

Criminalization ofMedication ErrorsA recent casethat equates apharmacist’s mistakewith manslaughteralso raises thequestion ofpharmacy technicianresponsibility.Here is a sobering thought.A pharmacist makes a mistake.The error results inthe death of a patient, and the pharmacistis charged with negligenthomicide. He is found guilty ofinvoluntary manslaughter and facesup to 5 years in prison and a maximumfine of $10,000. Of course,his pharmacist license is revokedand chances are he will never workin the profession again. His crime?He did not check the accuracy ofcalculations used by a pharmacytechnician under his charge to compoundthe concentration of sodiumchloride in a prescription for a cancerchemotherapy solution.Negligent? Yes. Accountabilityand responsibility? Yes and Yes. Malpractice?Yes. Loss of license? Yes.Guilty? Yes. But a crime? Prisonterm? For a mistake, albeit a mistakewith a worst-case outcome? That istough medicine to swallow. MoreJesse C. Vivian, BS Pharm, JDProfessor, Department of Pharmacy PracticeCollege of Pharmacy and Health SciencesWayne State UniversityDetroit, Michiganimportant, how is justice served byputting this pharmacist in jail? Themessage to pharmacists and perhapsall other health care practitioners—watch out. There may be prosecutorsout there just itching to putyou away.Facts of the CaseOn February 24, 2006, while workingat the Rainbow Babies andChildren’s Hospital in Cleveland,Ohio, licensed pharmacist EricCropp received a prescription for achemotherapy solution of Eposin(etoposide phosphate) that was supposedto be mixed in an IV bag ofnormal saline containing 0.9%sodium chloride. 1 The patient,Emily Jerry, was diagnosed with ayolk sac tumor when she was abouta year and a half old. The tumorwas the size of a grapefruit andstemmed from the base of her spineinto her abdomen. Her team ofdoctors and nurses assured the parentsthat Emily’s cancer was notonly treatable but curable. Emilyendured months of surgeries, testing,and rigorous chemotherapy sessions,each of which lasted for 5 or6 days. Emily’s treatment had beenso successful that her last MRIclearly showed that the tumor hadshrunk dramatically, with minimalresidual scar tissue. However, herphysicians still felt one final treatmentwas necessary to prevent thetumor from reappearing. She wasscheduled to begin her lastchemotherapy session on her secondbirthday. This last treatment wasjust to be sure that there were notraces of cancer left.The medication was to be thefourth and final round of treatment.Two days later, after the IV therapywas started, the child collapsed inher mother’s arms, crying in painand vomiting. She grabbed her headand said, “Mommy, it hurts, ithurts.” The IV was started at 4:30PM. By 5:30 PM, she was on life support.She went into a coma anddied on March 1, 2006. 2 The infusioncaused intense cerebral edema.For reasons that have never beenexplained, the technician who madethe mixture, Katie Dudash, used asaline base solution of 23.4%sodium chloride instead of the commerciallyavailable standard bag ofnormal saline. She told investigatorsthat she did not recall why shedecided to make a new solution ofsaline from scratch instead of grabbinga premade bag of normal salinethat was available right there in thepharmacy. She said she was distractedbecause she was talking onher cell phone just before the incidenthappened, busy making plansfor her upcoming wedding.An investigation into the incidentdisclosed that many circumstancescontributed to the error’soccurrence. The pharmacy computersystem was not working and abacklog of physician orders was pilingup. The pharmacy was shortstaffedand everyone in the pharmacywas busy. The employeeshortage meant that normal workand meal breaks were altered or notavailable. The technician was distractedfrom her normal routine. Afloor nurse called the pharmacy andasked the pharmacist to send the66U.S. Pharmacist • November 2009 • www.uspharmacist.com

CRIMINALIZATION OF MEDICATION ERRORSsolution early. As a result, he feltrushed. Ironically, it was later determinedthat the IV bag was notneeded for several hours.As can well be imagined, thisincident took a terrible toll on theparents. They sued the hospital formalpractice and obtained a $7 millionsettlement. 3 Soon afterward,the parents separated, and theydivorced a year later. The mother,Kelly Jerry, had to obtain restrainingorders against Emily’s father, ChrisJerry. He violated at least one of theorders and lost custody of both ofhis other children. In 2008, he wasarrested for possession of marijuanaand charged with resisting arrest.His case was diverted to a mentalhealth court for sentencing. Hesought psychological counseling ashe looked for a way to workthrough his problems.Then, in 2009, Chris Jerryfound a way to make something outof this tragedy. Mr. Jerry begancounseling families in local hospitalswhose children were on life-supportsystems. He made himself presentsimply as one who understandswhat they were going through. “Ican speak to these people because Ihave gone through something similar,I know what they need to hear,”he said. “I can relate to them inevery way.” 4 He also started Emily’sFoundation, a charity he hopes touse to push for a national law togovern the work of pharmacy techniciansand help prevent medicalerrors like the one that killed hisdaughter. 5Kelly Jerry attended all of thecivil and criminal proceedings andmade a compelling statement at theboard of pharmacy hearing on theadministrative complaint against thepharmacist. Chris Jerry did notattend any of the legal actions,although now he no longer feels anyanger against the pharmacist. In facthe has been quoted as saying, “I feelvery sorry for the pharmacist. Thisguy is facing a prison sentence, andI know it was an accident.” 6Unprofessional ConductThe pharmacist and the technicianwere dismissed by the hospitalabout 1 month after the incident.The tech went to back to work atCVS/pharmacy where she had beenemployed before working at thehospital. The pharmacist found ajob at a local retail pharmacy just afew weeks later. There, according torecords, he made an additional 13more dispensing errors over a 10-month period. One of those errorscaused harm to another child. 7The Ohio State Board of Pharmacyheld a hearing on a formalcomplaint against the pharmacist onApril 11, 2007, a little over a yearafter the incident that caused thedeath of Emily Jerry. 8 For this error,Stateregulations varytremendouslywith respectto pharmacytechnicians.the board found him responsible formisbranding and mislabeling a drugin violation of Ohio law. 9 But thisincident was actually only thebeginning of Mr. Cropp’s problems.On April 26, 2006, while workingat a community pharmacy, EricCropp misbranded a prescriptionfor Compazine (prochlorperazine)10-mg tablets prescribed for “nauseaand vomiting.” 10 He typed thelabel indicating the medication wasto be taken “as needed for pain.”While at the same store, on July 18,he dispensed tramadol with acetaminopheninstead of the prescribedVicoprofen (hydrocodone andibuprofen). On July 25, he dispensedmetformin ER 500-mgtablets to a patient instead of theBiaxin XL (clarithromycin) 500-mgtablets that were prescribed. Onthat same day, he gave the Biaxin tothe patient who should have beengiven the metformin. On August18, he received a prescription forPhenergan (promethazine) 25-mgsuppositories with directions to beused “rectally every 8 hours.”Instead, he typed a label indicatingthe medication was to be “taken bymouth.” On September 19, he dispensedAdderall XR (amphetamineand dextroamphetamine) 5-mg capsulesto an 8-year-old child whohad been prescribed Focalin XR(dexmethylphenidate) 5-mg capsules.The child suffered undisclosedinjuries. On November 13,he received a prescription for Disalcid(salsalate) 500 mg. He dispensedAzulfidine (sulfasalazine)500 mg instead. On November 18,he received a prescription for VoSolHC (hydrocortisone and aceticacid) from an ear, nose, and throatphysician with indications that themedication was to be used “in theear.” He labeled the drug as for use“in the eye.” On December 12, hereceived a prescription for Zoloft(sertraline) 100-mg tablets withdirections that the patient shouldtake “two tablets every evening.”He labeled the medication to betaken “twice daily.” On December15, he received a prescription forAvelox (moxifloxacin) 400 mg. Helabeled and dispensed the drug tothe wrong patient. On December26, he received a prescription forZoloft (sertraline) 100-mg tablets.Instead, he dispensed 50-mgtablets. On February 3, 2007, hereceived a prescription for E.E.S.(erythromycin ethylsuccinate) 200mg/5 mL suspension. Instead, hedispensed erythromycin with sulfisoxazolesuspension. Finally, onthe following day, he received a prescriptionfor two boxes of Imitrex(sumatriptan) 6 mg/0.5 mL anddispensed a quantity less than whatwas called for by the prescription.The Ohio Board of Pharmacyfound that all of the above conductconstitutes “unprofessional conduct”in violation of state law and thenpermanently revoked the pharma-67U.S. Pharmacist • November 2009 • www.uspharmacist.com

CRIMINALIZATION OF MEDICATION ERRORScist’s license. 11 The vote was six infavor of this resolution with twoboard members in opposition.In May 2009, the pharmacistpleaded no contest to a charge ofinvoluntary manslaughter forimproperly supervising the technician.On August 14, 2009, Mr.Cropp was sentenced to 6 monthsin prison, 6 months of home confinementwith electronic monitoring,400 hours of community service,a $5,000 fine, and payment ofcourt costs. 12 Part of the communityservice sentence requires himto seek out medical and legalorganizations where he can tell hisstory and, hopefully, help preventothers from making a similar mistake.Remember that his pharmacistlicense was permanentlyrevoked, so he will have a significantloss of future income. Andthen, of course, there are the undisclosedattorney fees that the pharmacistincurred in his hearing infront of the Board of Pharmacy andhis criminal prosecution.Oh, and by the way, what happenedto the pharmacy tech thatmade the fatal error? Katie Dudashwas charged by the prosecutor withnegligent homicide, but the grandjury gave her a “get out of jail freecard.” She gets off with no realpenalty and is now working in aretail pharmacy. She was notlicensed, registered, or certified bythe state to work as a technician, sothere were no administrative sanctionsavailable. She has no accountabilityor responsibility. She was justan employee doing a job. She didnot do her job right, but there wereno consequences—other than losingher job and maybe having to livewith the idea that her actionsdirectly caused the death of anotherhuman being.Emily’s LawAt the time, Ohio was one of manystates that had no minimum training,licensing, registration, or certificationrequirements for pharmacytechnicians. State regulations varytremendously with respect to pharmacytechnicians. Currently, onlyeight states license technicians, 31states have registration, and fivestates certify techs. Twenty stateshave no educational requirements(training, continuing education, orcertification exam) for technicians. 13On January 7, 2009, the governorof Ohio signed SB 203, known as“Emily’s Law,” which establishesstandards for qualified pharmacytechnicians and requires them toundergo a criminal backgroundcheck. 14 They must also pass a competencytest. It also establishespenalties for certain activities,including compounding, packaging,and preparing a drug by an individualwho is not a pharmacist, pharmacyintern, or qualified pharmacytechnician. 15The downside of making thismistake, awful as it was, into acriminal case with incarcerationfor the offender is that it discouragesothers from ever wanting toreport errors with serious consequences.“We need to change thesystem. I’m hopeful that we canfind something meaningful interms of safety from this child’sdeath,” said Bona Benjamin, directorof medication use qualityimprovement at the AmericanSociety of Health-System Pharmacists(ASHP). 16 Some pharmacygroups are beginning to push forgreater standardization of techniciantraining. ASHP has developeda model curriculum for pharmacytechnician training programaccreditation as the first effort todevelop a national standard. Inaddition, the National PharmacyTechnician Association, the Institutefor the Certification of PharmacyTechnicians, and the PharmacyTechnician CertificationBoard have all worked to developtechnician training standards. 17If nothing else, this case shouldsend a loud and serious message topharmacists. You can delegateactivities associated with the practiceof pharmacy to technicians andothers. But you can never delegateresponsibility or accountability. Itis your name on the license, andthere are no excuses for mistakes ofthis type.REFERENCES1. Emily’s Story. Emily Jerry Foundation.http://emilyjerryfoundation.org/emilys-story/.Accessed October 11, 2009.2. Robins M. Fatal dose: Ohio girl is killed by medicalmistake. January 31, 2007. www.firstcoastnews.com/news/usworld/news-article.aspx?storyid=75102.Accessed October 4, 2009.3. Whitley M. Chris Jerry, whose daughter Emily diedfrom a pharmacy technician’s mistake, starts foundation topush for national law. June 13, 2009. http://blog.cleveland.com/metro/2009/06/chris_jerry_whose_daughter_emi.html. Accessed October 11, 2009.4. News. Emily Jerry Foundation. October 7, 2009.http://emilyjerryfoundation.org/chris-jerry-whosedaughter-emily-died-from-a-pharmacy-techniciansmistake-starts-foundation-to-push-for-national-law/.Accessed October 11, 2009.5. See note 4, supra. The Web site states, in part: “Thecore of the Emily Jerry Foundation focuses on protectingour nation’s babies and children from the all too redundantmedical errors that keep occurring over and overagain in hospitals across the nation. These countless mistakesare killing our children and are most often avoidable.We are increasing public awareness of these issues andstriving to get better legislation in place across the UnitedStates. The Emily Jerry Foundation is helping to savecountless lives, as well as make our world-renowned medicalfacilities much safer.”6. See note 4, supra.7. Failure to track pharmacy mistakes may be“prescription for trouble.” NewsNet5. March 23, 2009.www.newsnet5.com/news/18917359/detail.html.Accessed October 11, 2009.8. Minutes of the April 9-11, 2007 meeting of the OhioState Board of Pharmacy. Docket Number D-061108-012.http://pharmacy.ohio.gov/minutes/mins07040911.pdf.Accessed October 11, 2009.9. ORC § 3715.52(A)(2) and OHC Rule 4729-17-10.10. See note 8, supra.11. ORC § 4729.16.12. Not a wonderful life: no George Bailey for pharmacistEric Cropp or his patient. September 5, 2009.http://jparadisirn.com/2009/09/05/not-a-wonderful-lifeno-george-bailey-for-pharmacist-eric-cropp-or-his-patient/.Accessed October 4, 2009.13. Reid P. Former pharmacist indicted for manslaughterafter med error. Drug Topics. September 17, 2007.http://drugtopics.modernmedicine.com/drugtopics/Community+Pharmacy/Former-pharmacist-indicted-formanslaughter-after-/ArticleStandard/Article/detail/456584.Accessed October 11, 2009.14. Sangiacomo M. Ohio governor signs “Emily’s Law”forcing standards for pharmacy technicians. ClevelandPlain Dealer. January 7, 2009. www.cleveland.com/medical/index.ssf/2009/01/emilys_law_enacted_by_gov_stri.html. Accessed October 11, 2009.15. Governor signs “Emily’s Law” legislation.www.governor.ohio.gov/News/PressReleases/2009/January2009/News1709/tabid/956/Default.aspx.Accessed October 11, 2009.16. See note 13, supra.17. See note 13, supra.68U.S. Pharmacist • November 2009 • www.uspharmacist.com

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2 CE CreditsThis activity is supported by an educational grant fromTeva Women’s Health.© JUPITERIMAGESEmergencyContraceptionAn Update of Clinicaland Regulatory ChangesEmergency contraception (EC),sometimes referred to as the“morning-after pill,” is a safeand effective method of preventingpregnancy after intercourse. Levonorgestrel,a hormone found in manybirth control pills, is the active ingredientin most emergency contraceptiveproducts used in the U.S. TheFood and Drug Administration (FDA)approved the first levonorgestrel-onlyemergency contraceptive, Plan B (levonorgestrel0.75 mg oral tablets), in1999 for prescription use. In 2006,the FDA widened access to EC byapproving over-the-counter (OTC)sale to consumers 18 years of age orolder. 1,2 At the time, Plan B was thefirst product to be approved in theU.S. with dual status (a single productapproved for OTC sale or prescription-onlyaccess to consumersbased on age). More recently, the FDAfurther increased access to EC byreducing the age for OTC access toanyone 17 years and older, continuingaccess to girls under age 17 byprescription only. Two new EC productsrecently became available inthe U.S. In July 2009, the FDAapproved a one-dose emergency contraceptive,Plan B One-Step (levonorgestrel1.5 mg tablet) for OTCKathleen H. Besinque, PharmD, MSEdAssociate Professor of Clinical PharmacySchool of PharmacyUniversity of Southern CaliforniaLos Angeles, CaliforniaU.S. Pharmacist Continuing EducationGOAL: The goals of this educational program are to update pharmacists and other healthcare professionals on the current clinical and regulatory information related to levonorgestrelbasedemergency contraception and to provide effective strategies for educating consumersabout emergency contraception.OBJECTIVES: After completing this activity, participants should be able to:1. Discuss the clinical indications for emergency contraception.*2. Compare available levonorgestrel-only emergency contraceptive regimens and therequirements associated with the nonprescription sale of these products.*3. Describe the evidence for the mechanism of action and safety profile of levonorgestrel-onlyemergency contraceptive regimens.*4. Discuss opportunities for pharmacists to provide improved access to emergency contraception,including identification of and reduction of barriers in the pharmacy environment.*5. Describe strategies to improve education and counseling of consumers regarding theeffective use of levonorgestrel emergency contraception regimens.** Also applies to pharmacy technicians.sale to consumers age 17 and olderand by prescription to girls under age17. 3 Next Choice (levonorgestrel 0.75mg tablets) was also approved in 2009and is a generic formulation of theoriginal Plan B. Although three levonorgestrelEC products may be currentlyavailable—Plan B, Plan B One-Step, and Next Choice— the distributionof Plan B will cease as Plan B One-Step launches into the marketplace.All EC products are approved to preventpregnancy when a contraceptivemethod has failed or was not usedduring intercourse.Unintended pregnancies are associatedwith many personal and publichealth related consequences. Inthe U.S., approximately half of allpregnancies occurring each year areunintended and as many as half ofthe unintended pregnancies are terminatedby elective abortion. 4 Whentaken within 72 hours of unprotectedintercourse, levonorgestrel-only ECreduces the risk of pregnancy by asmuch as 89%. 2,3 Studies to date havenot been able to show that havingEC available without a prescriptionhas reduced the rates of unintendedpregnancy in the U.S. as was originallyanticipated. 5,6 The reason forthe lower-than-anticipated impact onunintended pregnancy rates may berelated to the persistence of barriersto EC access, including misunderstandingby consumers about whento use EC.Pharmacists and other health careprofessionals can help to reduce bar-70U.S. Pharmacist • November 2009 • www.uspharmacist.com

Table 1Early Barriers PreventingUtilization of EC Methods• Lack of awareness by consumers that a method toprevent pregnancy after intercourse was available• Failure of doctors to discuss EC during medicalappointments• Lack of information about EC among health careprofessionals• Misconceptions about how EC works• Confusion of EC and the “abortion pill”• Difficulty obtaining EC by prescription within thenarrow window of efficacyriers that limit the use of EC by improving patient accessand being available to answer questions about the useof EC. Pharmacists, as the “most accessible” healthcare provider, are in a unique position and play a crucialrole in providing timely access to and informationabout EC to consumers. OTC availability in the pharmacyto consumers age 17 and over improves access toEC by reducing the delays that were associated withobtaining a prescription in the limited time frame neededfor efficacy of the product.EMERGENCY CONTRACEPTION: AN UPDATETable 2Products Approved for Emergency ContraceptionLevonorgestrelBrand Manufacturer Dose per Dose (mg)One-Dose RegimenPlan B One-Step Barr Pharmaceuticals 1 tablet per dose 1.5Two-Dose Regimens (administered immediately and 12 h later)Plan BBarr PharmaceuticalsNext Choice Watson Pharmaceuticals 1 tablet per dose 0.75Background and Clinical History of ECLevonorgestrel has been extensively studied as anemergency contraceptive worldwide since the 1970s.After almost 40 years of EC use, the high degree ofefficacy in preventing pregnancy (up to 89% reduction)and the low rate of adverse effects have been well documented.5,7-10 A 2009 update to a Cochrane review ofEC interventions included more than 88 studies andconcluded that levonorgestrel is both safe and effectivein preventing pregnancy after intercourse. 7The first products approved by the FDA for EC werePreven (ethinyl estradiol 0.25 mg/levonorgestrel 0.5 mgtablets) in 1998 and Plan B (levonorgestrel 0.75 mgtablets) one year later. Both products were approved foruse by prescription and to be taken in a two-dose regimeninitiated within 72 hours of unprotected intercourse.Despite FDA approval, an increase in the utilizationof EC by women was hampered by a numberof barriers (TABLE 1).To improve access, a request was made to move PlanB to OTC status. Plan B appeared to satisfy FDA requirementsfor conversion from prescription to OTC status,which include a minimum of two years of prescriptionuse with a high degree of safety and studies establishingthat consumers can interpret labeled instructions correctly.Although an FDA Advisory Committee voted in2003 in support of the request for nonprescriptionstatus, the FDA approved a change for Plan B in 2006to “dual status” instead. 11 Under dual status, Plan B wasmade available without prescription to consumers at orabove a certain age (originally 18 years but now 17) andremained available by prescription to younger women.Packaging for the product was approved to meet therequirements for both prescription and nonprescriptionproducts. Since then, Next Choice and Plan B One-Step have also been approved for dual status distributionin pharmacies and clinics (TABLE 2).Before the approval of dedicated products for EC,commercially available oral contraceptives containingethinyl estradiol with either norgestrel or levonorgestrel(often referred to as the “Yuzpe regimen”) were used forEC. More recent studies have shown these combinationsto be less effective (ranging from 49% to 75%)than levonorgestrel-only regimens. 7,9 Furthermore,the Yuzpe regimen has more side effects, especially nauseaand vomiting, which often require the addition ofan antiemetic medication. Production of Preven, a commerciallyavailable equivalent to the Yuzpe regimen, wasstopped in 2004. Because of its lower efficacy andincreased frequency of side effects, use of the Yuzpe typecombination regimens has declined but remains anoption when levonorgestrel is not available.Several other methods have been evaluated for EC,including combinations of estrogen with norethindrone,combining levonorgestrel with the COX-2 inhibitormeloxicam, Yuzpe or levonorgestrel regimens using differenttime intervals or doses, insertion of a copper IUD,an investigational progesteronemodulator ulipristal (availableas ellaOne in Europe) andlow doses of mifepristone. 7,12Combination regimens usingnorethindrone appear to be lesseffective than levonorgestrelregimens. 13 Regimens usingmifepristone in doses rangingfrom 10 mg to 50 mg appearto be effective; however, thesedoses are not available in theU.S. 7 Insertion of a copper IUDup to 10 days after intercourse71U.S. Pharmacist • November 2009 • www.uspharmacist.com

EMERGENCY CONTRACEPTION: AN UPDATEappears to have a low failure rate (0.01% to 0.02%),but IUD insertion requires a clinician visit and may notbe suitable for some women. 8 The investigational progesteronereceptor modulator recently approved inEurope, ulipristal, may be as effective with similar sideeffects as levonorgestrel. 14 Studies evaluating the useof levonorgestrel as a single dose (1.5 mg) did not finda significant difference in efficacy compared with 0.75mg two-dose regimens. 7 The newly approved Plan BOne-Step (1.5 mg) is a single-dose regimen that maybe more convenient and easier to use.Table 3Indications for Useof Emergency Contraception• Unprotected intercourse (including forgetting to use acondom or diaphragm)• If a condom breaks or tears during intercourse• Missing one or more doses of an oral contraceptive• Being 2 or 3 days late to resume an ongoinghormonal contraceptive regimen• While taking medication that may reduce theeffectiveness of a hormonal contraceptive• After exposure to a teratogen• After a sexual assaultMechanism of ActionLevonorgestrel, the only active ingredient in Plan B,Plan B One-Step, and Next Choice, is a syntheticprogestin also available in hormonal contraceptives.The mechanisms by which levonorgestrel prevent pregnancyare likely similar to those of other hormonal contraceptives.All currently available hormonal methodsof contraception have been shown to act by one ormore of the following mechanisms: altering the endometriallining, altering cervical mucus, interfering withfertilization or transport of an egg, or preventing implantation.There is good evidence that levonorgestrelprevents or delays ovulation as its primary mechanismof action; however, it is possible that additionalmechanisms may be involved. 15-20 There are no datasupporting the view that levonorgestrel can impair thedevelopment of the embryo or prevent implantation. 20A number of publications have shed light on the mechanismsof action for levonorgestrel-only EC. 15-20 Levonorgestrel-onlyEC has been shown to inhibit the preovulatorysurge of luteinizing hormone (LH), therebyinhibiting follicular development and/or the release ofthe egg. A properly timed and sufficient surge of LH isrequired for the release of an ovum or ovulation. Ovulationmust take place for fertilization to be possible.Research has demonstrated that EC inhibits the midcyclesurge of LH from the pituitary and, if taken at leasttwo days before ovulation, ovulation is delayed or prevented.Ovulation may occur if the administration oflevonorgestrel is delayed until ovulation is imminent. 20If levonorgestrel is taken later in the cycle, the effect onthe LH surge may be equal to that of a placebo and pregnancymay occur. These time-sensitive events may explainwhy taking EC as soon as possible after unprotected intercourseis critical for maximizing its effectiveness.Studies of levonorgestrel and its potential effects onendometrial function have not shown changes that wouldprevent the implantation of a fertilized ovum. 17 Womenwho have used Plan B to prevent a pregnancy early intheir menstrual cycle remain at risk for pregnancy laterin the same cycle if contraception is not resumed or failsagain. This indicates that the endometrium is still intactand capable of implanting a fertilized ovum. 19It has been speculated that levonorgestrel may alterthe movement of a fertilized egg, which would be expectedto increase the risk of an ectopic pregnancy. Studieshave not supported this assumption. The risk of anectopic pregnancy after levonorgestrel use may be slightlylower than national ectopic pregnancy rates. 21 TheCochrane review found only five cases of ectopic pregnancyreported in more than 45,000 uses of EC andconcluded that ectopic pregnancy was not associatedwith any specific type of EC or a likely consequencefrom using EC. 7The International Consortium for Emergency Contraception(ICEC), in a 2008 Policy Statement on mechanismof action, reported that levonorgestrel-only ECpills inhibit, delay, or interfere with ovulation and maypossibly prevent the sperm and egg from meeting byaffecting cervical mucus or the ability of sperm to bindto the egg. 22 The ICEC also stated that there are no directclinical data to support mechanisms other than theinhibition, delay, or alteration of ovulation. 22 LevonorgestrelonlyEC does not cause abortion or interfere with anestablished pregnancy and, if inadvertently taken by awoman who is pregnant, the pregnancy will not be harmed.The ICEC noted that EC might actually prevent abortionsby reducing unplanned pregnancies. 22Indications and ContraindicationsEC is the use of a contraceptive method to prevent pregnancyafter intercourse. Levonorgestrel products areapproved for use within 72 hours after intercourse.There is evidence that taking EC as soon as possiblemay maximize its effectiveness and that use up to 120hours may be effective. Consumers who are unsure ofwhen to use EC or whether EC is needed may ask thepharmacist about its appropriateness. Circumstanceswhere EC is indicated are listed in TABLE 3.Pharmacists can reassure women that EC is safeand effective and can be used when needed to preventpregnancy after unprotected intercourse. A myth thatmay present a barrier to access to EC is belief that itcan only be used once in a lifetime, once per year, or72U.S. Pharmacist • November 2009 • www.uspharmacist.com

EMERGENCY CONTRACEPTION: AN UPDATEonly once during a menstrual cycle. Pharmacists shouldnot restrict the purchase of EC based on prior use orout of concern that repeated use of EC is not safe. 12There is no evidence that repeat use of EC poses increasedrisk to patients. 23 Because EC is less effective as birthcontrol than ongoing methods of contraception (suchas condoms or birth control pills), it is recommendedonly as a backup method and not as a substitute forongoing, more effective methods. EC can be purchasedin advance and kept at home in case the need arises, asthis avoids the delay of going to the pharmacy.There are few contraindications to the use of EC.The WHO Medical Criteria for Contraceptive Use 2005stated that there are “no conditions where the risks ofEC outweigh the benefits.” 23 Product labeling lists thecontraindications as an established pregnancy or knownallergy to the ingredients in EC. There are no studiesof EC use by women with migraine headaches, smokersover age 35, or other precautions applicable to theregular use of combination oral contraceptives. However,these conditions should not limit the use of EC.Timing of the EC DoseLevonorgestrel is thought to be more effective the soonerit is taken, therefore pharmacists should encouragewomen take EC as soon as possible after unprotectedintercourse. 24 The FDA-approved dosing recommendsinitiating therapy within 72 hours of unprotected intercourse.For levonorgestrel 0.75 mg tablets, a seconddose is required 12 hours after the initial dose. 5,8 Althoughthere is evidence of efficacy as late as 120 hours afterintercourse, women should be encouraged to seek treatmentas soon as possible, preferably within the 72-hourtimeframe. 21,25-28 Since the time required from intercourseor ovulation to implantation is approximately6 to 7 days, use of hormonal EC beyond 120 hours isnot likely to be effective. 13Studies evaluating single-dose levonorgestrel (1.5mg) have concluded that the single dose is not less effectivethan the two-dose regimen. 21,28,29 Plan B One-Stephas been approved for use as a single 1.5 mg dose forEC. The single dose formula may improve complianceby simplifying the EC regimen and will replace the PlanB 0.75 mg levonorgestrel preparation.Concerns have been raised that providing EC towomen in advance of need to keep on hand “just incase” of a contraceptive failure might lead to an increasein unprotected intercourse or encourage women to discontinuethe use of their usual method of contraception.However, studies evaluating the outcomes ofproviding EC in advance of need have not found thatwomen engage in more unprotected intercourse or abandontheir usual method. 6,7,30,31 These studies havereported that women are more likely to use EC afterunprotected intercourse if it is provided in advance ofneed. Based upon the findings of the studies, providingEC in advance of need can be recommended toimprove timely access to the product.Dual Status: EC in the PharmacyThe dual status of levonorgestrel-only EC necessitatesthat products be kept within the pharmacy or behindthe counter. In the pharmacy a consumer has access tothe pharmacist, a knowledgeable health care provider,to answer questions regarding the use of EC. ECproducts must only be sold in pharmacies or licensedclinics and are not available at other types of retail establishments.Keeping EC hidden behind the pharmacycounter may pose a barrier to some consumers becausethey may expect to find the products on pharmacyshelves or within sight behind the pharmacy counter.Pharmacists are encouraged to provide shelf tags or displayEC products in a conspicuous location to facilitateaccess by consumers who may be reluctant to askif they do not easily see the product in the pharmacy.“CARE” Program: ConvenientAccess, Responsible EducationThe terms of the FDA approval of Plan B for OTCaccess by consumers age 17 and older included requirementsrestricting the distribution of EC, meeting labelingrequirements for both OTC and prescription use,and for the manufacturer to provide support and educationabout the use of the product to health careproviders and consumers and to continue ongoing monitoring.The dual-labeled, behind-the-counter labelinglaunched with the approval of Plan B was the firsttime the FDA had approved the same product packagefor both OTC and prescription-only use. Theapproved packaging includes room for a prescriptionlabel (to be used when the product is dispensed byprescription), as well as the required Drug Facts box forOTC sales.The CARE program specifies that EC is to be soldonly from behind the counter in the pharmacy andnot be available through nonpharmacy retail outlets.The FDA approval allows EC to be sold without aprescription to women or men 17 or over as long asthey can show proof of age. 2 Pharmacies must have apharmacist on duty and available for consumer consultationin order to sell EC. Although the pharmacistmust be available, it is not required that the pharmacistbe the person who sells the product, or for the consumerto consult with the pharmacist. Any member ofthe pharmacy staff working behind the pharmacy countermay sell the products to eligible consumers as long asa pharmacist is on duty and available for consultationif requested by the purchaser.Medical clinics may also sell EC if there is alicensed health care provider on the premises for consumerconsultation at the time of sale. Retail outletswith pharmacies where the retail store has longer73U.S. Pharmacist • November 2009 • www.uspharmacist.com

hours of business than the pharmacy are not able to sellEC when the pharmacy is closed.There is no limit to the number of packages thatmay be sold to an eligible consumer. A consumer maypurchase one or more packages of the product in asingle transaction. In addition, there is no requirementthat this OTC product must be used by the purchaser,and men may purchase it as long as they are atleast 17 years of age. There is no requirement for purchasersof EC to sign a registry in the pharmacy or toprovide photo identification for purchases.Pharmacist ConsultationProviding an environment where consumers can feelcomfortable asking questions can greatly improve accessto EC. Because all members of the pharmacy staff canprovide EC to consumers, they should be aware of whereit is stocked in the pharmacy, how consumers mightEMERGENCY CONTRACEPTION: AN UPDATETable 4Most Common Adverse Events Experienced byWomen Receiving Plan B and Plan B One-StepMost Common Plan B (levonor- Plan B One-StepAdverse Events in gestrel 0.75 mg (levonorgestrel 1.5>4% of Women oral tablets) (%) mg oral tablet) (%)Nausea 23.1 13.7Abdominal pain 17.6 13.3Fatigue 16.9 13.3Headache 16.8 10.3Heavier menstrual bleeding 13.8 30.9Lighter menstrual bleeding 12.5aDizziness 11.2aBreast tenderness 10.7 9.6Other complaints 9.7aVomiting 5.6aDiarrhea 5.0aDelay of menses >7 daysa4.5aReported in

EMERGENCY CONTRACEPTION: AN UPDATEsure women that changes in menses, while common,are self-limiting. Women can be advised to obtain follow-upcare if menses does not occur within sevendays of the expected onset date or, for women withirregular menses, within three weeks after using EC.Emergency contraceptives are less effective and aremore costly than routine methods of contraceptionand thus should not be relied upon as an ongoingmethod of contraception. Contraceptive use is neededfor future acts of intercourse if pregnancy is not desired.Women may resume the use of barrier or oral contraceptivesright away after taking EC.The pharmacist should be aware that using EC reducesthe risk of pregnancy but does not provide protectionfrom sexually transmitted infections (STIs). When requested,the pharmacist should be prepared to make referral toclinics or health care providers that provide testing andtreatment for STIs. The use of condoms for protectionfrom STIs should be encouraged, when applicable.Pharmacists may advise consumers to keep EC productsat home and available in case of a contraceptivefailure. Keeping EC at home may be more convenientFrequently Asked Questions (FAQ) About Emergency ContraceptionA Reference for PharmacistsWho can use levonorgestrel foremergency contraception (EC)?Levonorgestrel can be used by women after unprotectedintercourse to prevent pregnancy. Women who arealready pregnant or who have experienced an allergicreaction to a levonorgestrel-containing product in thepast should not use this form of EC. Women with ahistory of migraine headaches, smokers over age 35, orother contraindications to the use of combination oralcontraceptives may use EC. EC should not be used bywomen who are already pregnant because it is noteffective. If EC is taken by a woman who is alreadypregnant or becomes pregnant after taking EC, it will notharm the fetus or disrupt the pregnancy. Women whoare pregnant should consult a health care provider.How effective is levonorgestrel for EC?Plan B and Plan B One-Step have been shown to reduce therisk of pregnancy by up to 89% when taken within 3 days(72 hours) of a contraceptive failure or unprotectedintercourse. If taken within the first 24 hours afterunprotected sex, EC may be more effective. One way toexplain the effectiveness of EC is: if 100 women hadunprotected intercourse during week 2 or 3 of theirmenstrual cycle and no contraception was used, eightwomen would be expected to become pregnant. If all 100women used EC, only one woman would be pregnant, thusthere is an 89% reduction in the pregnancy rate (oneinstead of 8 women become pregnant). The effectiveness ofEC for an individual may vary depending on the timing ofintercourse, delay in taking EC, and the inherent fertility ofthe couple.How long should I wait to take EC?For best results, EC should be taken as soon as possibleafter unprotected intercourse or contraceptive failure. ForPlan B and Next Choice, the first tablet (0.75 mglevonorgestrel) should be taken within 72 hours ofunprotected intercourse followed by a second tablet 12hours later. For Plan B One-Step, a single tablet (1.5 mglevonorgestrel) should be taken within 72 hours ofunprotected intercourse. Taking EC as soon as possible ishighly recommended.What if it has been more than 72 hourssince intercourse?Although EC has only been approved for use up to 72 hoursafter unprotected intercourse, the available research indicatesthat levonorgestrel retains significant activity in reducing therisk of pregnancy for at least 120 hours after unprotectedintercourse. 6 While EC is more effective when taken earlier,using it up to 120 hours after intercourse may still preventpregnancy. (Please note that the use of levonorgestrel only ECproducts after 72 hours for EC has not been approved by theFDA.) Users of EC should be aware that the product may beless effective when taken later than 72 hours afterunprotected intercourse.What can I expect after using EC?Most women do not experience side effects from taking EC.Some mild side effects that may occur include: nausea,headache, fatigue, mild abdominal discomfort, or a change inthe timing/bleeding of the next menstrual cycle. These areself-limited and do not require treatment. Most women shouldexpect to have their period within about 1 week of when itwould be expected. If a woman does not menstruate within 3weeks of using EC, she should consult her health careprovider and/or use a home pregnancy test.Is EC also known as the “abortion pill”?No, the “abortion pill,” Mifeprex (mifepristone) or RU486, iscompletely different from EC. Levonorgestrel (the hormone inEC) does not cause an abortion and will not be effective iftaken by a woman who is already pregnant. Similar to oralcontraceptives, EC has been shown to work by preventingovulation. Once implantation of an embryo begins, EC is noteffective.What if I have taken EC more than once?Women may use EC once or more than once depending ontheir regular birth control method and their personalcircumstances. Levonorgestrel for EC is safe and may beused when needed to prevent pregnancy. EC is not aseffective as other methods of contraception (such ascondoms, oral contraceptives) and therefore the routine useof EC is not recommended. EC is intended to be a backupmethod of contraception.75U.S. Pharmacist • November 2009 • www.uspharmacist.com

EMERGENCY CONTRACEPTION: AN UPDATEand better facilitate timely administration. Although ECis indicated for use after unprotected intercourse, consumersdo not need to wait to purchase it until after theyhave experienced a contraceptive emergency.Pharmacists who are available to consumers withquestions about EC will have an opportunity to makereferrals to community resources. Pharmacists are inan excellent position to serve as a resource for consumersand provide information about other methodsof contraception that, when used before or during intercourse,are more effective than EC in preventing unintendedpregnancies. Pharmacists should have availablethe name, address, and phone number for local referralservices when the consumer’s contraceptive needscannot be met in the pharmacy. This may include consumerslacking proof of age needed to purchase ECwithout a prescription, girls under the age of 17, consumersunable to pay for EC, or those who want tobe examined for STIs. In the event that the pharmacydoes not have EC in stock, the pharmacy staff shouldbe prepared to provide consumers with contact informationfor a nearby pharmacy, after verifying the productis in stock, to avoid delays in starting therapy.Pharmacists should be aware that some women seekingEC may be victims of sexual assault. If a womandiscloses violence to the pharmacist, whether in thecontext of purchasing EC or first aid supplies such asbandages, offering access to a private phone andreferral information for support services is indicated.Every pharmacist should also have national and localdomestic and sexual violence service agency contactinformation readily available for consumers.Pharmacy Access ProgramsIn states with pharmacy access programs, women seekingEC who are unable to show proof of age or whoneed a prescription for insurance purposes may beable to have a prescription for EC initiated by a pharmacist.Direct access from a pharmacist is currentlypermitted in nine states: Alaska, California, Hawaii,Maine, Massachusetts, New Mexico, New Hampshire,Vermont, and Washington. 31 States permittingpharmacists to initiate prescriptions have specificrequirements for pharmacist participation that mayinclude training and/or collaborative protocol arrangements.In some states with pharmacy access it maybe permitted to provide other prescription oral contraceptiveproducts for use as EC under certain circumstances,such as when levonorgestrel-only productsare unavailable (TABLE 5).Pharmacy access programs are not available to malesunder age 17 seeking EC because only the person takingthe medication can receive a prescription fromthe pharmacist. If EC products are out of stock orotherwise unavailable, there are alternative regimenssuch as oral contraceptive combinations that can beprovided by the pharmacist under some access programs.These regimens have more side effects and maybe less effective; however, if there are no other options(such as referral to a nearby pharmacy or clinic) theymay serve as a backup option. 8,25,32Summary and ConclusionsLevonorgestrel-only EC is safe and effective for preventingunintended pregnancy after intercourse.The OTC sale to consumers at least 17 years of ageis a major step toward improving access and removingbarriers to the use of EC in the U.S. The timesensitivenature of EC means that ready access towomen is an essential component of successful use.Pharmacists serve a critical role in expanding accessto EC and are relied upon for up-to-date informationregarding the safety and efficacy of EC. The role ofthe pharmacist includes: providing information andcounseling to consumers seeking EC, maintaining anadequate supply of EC at all times, and in states wherecollaborative practice allows pharmacists to provideEC directly to those under age 17, becoming an ECdirectprovider. By understanding the appropriate useand distribution of EC products, pharmacists can significantlyreduce barriers preventing consumers fromusing these products.REFERENCES1. FDA. Plan B (levonorgestrel 0.75 mg) [Letter FDA to Sponsor]. August26, 2005. www.fda.gov/bbs/topics/news/2005/duramed_ ltr.html. AccessedSeptember 2009.2. FDA. Plan B (levonorgestrel 0.75 mg) [Approval letter]. August 24,2006. www.fda.gov/cder/foi/nda/2006/021045s011_Plan_B_APPROV.pdf.Accessed September 2009.3. FDA. Plan B One-Step (levonorgestrel 1.5 mg) [Approval letter]. July10, 2009. www.accessdata.fda.gov/drugsatfda_docs/appletter/2009/021998s000ltr.pdf. Accessed September 2009.4. Finer LB, Henshaw SK. Disparities in the rates of unintended pregnancyin the United States 1994-2001. Perspect Sex Reprod Health. 2006;38:90-96.5. Plan B One-Step (levonorgestrel 1.5 mg tablets) package insert. Pomona,New York: Duramed Pharmaceuticals, Inc. July 2009.6. Trussell J, Schwarz EB, Guthrie K, Raymond E. No such thing as aneasy (or EC) fix. Contraception. 2008;78:351-354.7. Cheng L, Gulmezoglu AM, Piaggio G, et al. Interventions for emergencycontraception. Cochrane Database Syst Rev. 2008;(2):CD001324.8. ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists,Number 69, December 2005. Emergency oral contraception.Obstet Gynecol. 2005;106:1443-1452.9. Task Force on Postovulatory Methods of Fertility Regulation. Randomisedcontrolled trial of levonorgestrel versus the Yuzpe regimen of combinedoral contraceptives for emergency contraception. Lancet.1998;352:428-433.10. Turner A, Ellertson C. How safe is emergency contraception? DrugSafety. 2002;25;695-706.11. Minutes of the FDA Joint Advisory Committee Meeting December 16,2003. www.fda.gov/ohrms/dockets/ac/03/transcripts/4015T1.htm. AccessedSeptember 2009.12. Abuabara K, Becker D, Ellertson C, Blanchard K, et al. As often asneeded: appropriate use of emergency contraceptive pills. Contraception.2004:69:339-342.13. Ellertson C, Webb A, Blanchard K, et al. Modifying the Yuzpe regimenof emergency contraception: a multicenter randomized controlled trail.Obstet Gynecol. 2003;101:1160-1167.76U.S. Pharmacist • November 2009 • www.uspharmacist.com

EMERGENCY CONTRACEPTION: AN UPDATE14. Creinin MD, Schlaff W, Archer DF, et al. Progesterone receptor modulatorfor emergency contraception. A randomized controlled trial. ObstetGynecol. 2006;108:1089-1097.15. Croxatto HB. Emergency contraception pills: how do they work? IPPFMed Bull. 2002;36:1-2.16. Gemzell-Danielsson K, Marions L. Mechanisms of action of mifepristoneand levonorgestrel when used for emergency contraception. HumReprod Update. 2004;10:341-348.17. Croxatto HB, Brache V, Pavez M, et al. Pituitary-ovarian function followingthe standard levonorgestrel emergency-contraception dose or a single0.75 mg dose given on the days preceding ovulation. Contraception.2004;70:442-450.18. Durand M, del Carmen Cravioto M, Raymond EG, et al. On the mechanismsof action of short-term levonorgestrel administration in emergencycontraception. Contraception. 2001;64:227-234.19. Davidoff F, Trussell J. Plan B and the politics of doubt. JAMA.2006;296:1775-1778.20. Baird DT. Emergency contraception: how does it work? Reprod BiomedOnline. 2009;18(suppl 1):32-36.21. Trussell J, Hedley A, Raymond E. Ectopic pregnancy following use ofprogestin-only ECPs. J Fam Plann Reprod Health Care. 2003;29:249.22. International Consortium for Emergency Contraception and the InternationalFederation of Gynecology & Obstetrics. How do levonorgestrelonlyemergency contraceptive pills work to prevent pregnancy? October2008. www.cecinfo.org. Accessed September 2009.23. WHO Fact Sheet 244. Emergency contraception. Revised October2005. www.who.int/mediacentre/factsheets/fs244/en/ index.html. AccessedOctober 2009.24. Piaggio G, Von Hertzen H, Grimes DA, Van Look PF. Timing of emergencycontraception with levonorgestrel or the Yuzpe regimen. Lancet.1999;353:721.25. Ellertson C, Evans M, Ferden S, et al. Extending the time limit for startingthe Yuzpe regimen of emergency contraception to 120 hours. ObstetGynecol. 2003;101:1168-1171.26. Rodrigues I, Grou F, Joly J. Effectiveness of emergency contraceptive pillsbetween 72 and 120 hours after unprotected sexual intercourse. Am J ObstetGynecol. 2001;184:531-537.27. Von Hertzen H, Piaggio G, Ding J, et al. Low dose mifepristone and tworegimens of levonorgestrel for emergency contraception: a WHO multicentrerandomized trial. Lancet. 2002;360:1803-1810.28. Arowojulu AO, Okewolw IA, Adekunle AO. Comparative evaluation ofthe effectiveness and safety of two regimens of levonorgestrel for emergencycontraception in Nigerians. Contraception. 2002;66:269-273.29. Hamoda H, Ashok PW, Stalder C, et al. A randomized trial of mifepristone(10 mg) and levonorgestrel for emergency contraception. Obstet Gynecol.2004;104:1307-1313.30. Raine TR, Harper CC, Rocca CH, et al. Direct access to emergency contraceptionthrough pharmacies and effect on unintended pregnancy and STIs:a randomized controlled trial. JAMA. 2005;293:54-62.31. GO2EC. Comparison of EC pharmacy access states. Models for EC pharmacies.www.go2ec.org/ModelsForECPharmacies.htm. Accessed September2009.32. International Consortium for Emergency Contraception. Emergency ContraceptivePills: Medical and Service Delivery Guidelines. 2nd ed. Washington,DC; 2004. www.cecinfo.org/publications/PDFs/resources/MedicalServiceDliveryGuidelines_Eng.pdf. Accessed September 2009.■ Disclosure Statements:Kathleen H. Besinque, PharmD, MSEd, has no real or apparent conflicts ofinterest in relation to this program.U.S. Pharmacist does not view the existence of relationships as an implicationof bias or that the value of the material is decreased. The content of theactivity was planned to be balanced, objective, and scientifically rigorous.Occasionally, authors may express opinions that represent their own viewpoint.Conclusions drawn by participants should be derived from objectiveanalysis of scientific data.■ Disclaimer:Participants have an implied responsibility to use the newly acquired informationto enhance patient outcomes and their own professional development. Theinformation presented in this activity is not meant to serve as a guideline forpatient management. Any procedures, medications, or other courses of diagnosisor treatment discussed or suggested in this activity should not be used by clinicianswithout evaluation of their patients’ conditions and possible contraindicationsor dangers in use, review of any applicable manufacturer’s productinformation, and comparison with recommendations of other authorities.EXAMINATIONSelect one correct answer for each question and recordyour responses on the examination answer sheet. Mail itto U.S. Pharmacist, address shown on the answer sheet(photocopies are acceptable). Please allow four weeks forprocessing. Alternatively, this exam can be taken online atwww.uspharmacist.com. Please contact CE Customer Serviceat (800) 825-4696 or cecustomerservice@jobson.comwith any questions.2 CE CreditsEmergency Contraception:An Update of Clinical andRegulatory Changes1. Which of the following statements accuratelydescribes emergency contraception (EC) withlevonorgestrel?A. A hormonal method of contraception afterintercourseB. A method of contraception that hasbeen studied since the 1970sC. A safe and effective method for preventingunintended pregnancyD.All of the above2. Which of the following describes whenEC is indicated?A. After a condom fails (dislodges/breaks) duringintercourseB. After a sexual encounter when a woman hasmissed one or more doses of her oralcontraceptiveC. When a contraceptive method was not usedduring intercourseD.All of the above3. Clinical studies have demonstrated thatlevonorgestrel-based emergency contraceptivesprevent pregnancy by which of the followingmechanisms?A. Inhibition or delay of ovulationB. Disruption of an implanted embryoC. Changes to endometrial lining of the uterusD.All of the above77U.S. Pharmacist • November 2009 • www.uspharmacist.com

EMERGENCY CONTRACEPTION: AN UPDATE4. Which of the following statements bestdescribes the effectiveness of levonorgestrelEC regimens?A. Efficacy is increased by initiating EC as soonas possible after unprotected intercourseB. Studies have shown a 30% reduction in the riskof pregnancy when EC is taken within 72 hoursof unprotected intercourseC. The products have demonstrated efficacy whentaken up to 7 days after unprotected intercourseD.The products are as effective as barrier methodsof contraception5. The FDA approved regimen forPlan B One-Step is:A. One tablet to be taken within 120 hours afterunprotected intercourseB. Two doses of one tablet taken 12 hours apart,started within 72 hours of unprotectedintercourseC. One tablet to be taken within 72 hours ofunprotected intercourseD.Two doses of one tablet taken 12 hours apart,started within 120 hours of unprotectedintercourse6. The most common side effects resulting fromthe use of levonorgestrel for EC include:A. Severe headache or eye painB. Mild nausea and fatigueC. Increased risk of blood clotsD.All of the above7. The use of levonorgestrel for EC between 72and 120 hours after unprotected intercourse:A. Has been shown to be ineffectiveB. Is less effective than when used within 72 hoursand has not been approved by the FDAC. Has been shown to cause more side effects thanuse within 72 hoursD.Is not permitted in the U.S.8. Medical contraindications to the use oflevonorgestrel-based emergency contraceptioninclude:A. A history of migraine headachesB. An established pregnancyC. Age over 35 yearsD.All of the above9. Outcomes reported in studies evaluatingadvanced provision of EC include:A. A reduction in the use of other contraceptivemethodsB. An increase in the frequency of unprotectedintercourseC. An increase in the use EC after unprotectedintercourseD.An increased rate of sexually transmittedinfections10. Which statement best describes requirementsfor nonprescription sales of EC in a pharmacy?A. Only one package can be sold at a time toconsumers without a prescriptionB. Plan B but not Plan B One-Step can besold to menC. EC can be provided to a 17-year-old withouta prescriptionD.EC products can be kept on shelves with otherOTC products for women11. Pharmacy staff members able to sellnonprescription EC to eligible consumersinclude:A. A licensed pharmacistB. A pharmacy technicianC. A pharmacy clerk working behind thepharmacy counterD.All of the above12. When selling EC without a prescriptionto a man, pharmacists:A. Need to check for proof that he is at least 17years of ageB. Must limit sales to one packageC. Must ask for the name and age of the womanwho will be taking the productD.Keep a log with his name and signature at thepoint of purchase13. Which of the following is appropriatefor a pharmacist to say to a woman askingto purchase nonprescription EC?A. Have you had unprotected intercourse?EC can only be sold after a contraceptiveemergencyB. It is important to take a pregnancy test beforeusing ECC. You may not purchase more than one packageat a timeD.Do you have any questions about the useof this product?14. Nonprescription sale of EC requires:A. The purchaser to present proof that he/she is atleast 17 years of ageB. The person who will be taking the medicationto come to the pharmacyC. The purchaser’s signature on a registry keptin the pharmacyD.Consultation by the pharmacist78U.S. Pharmacist • November 2009 • www.uspharmacist.com

Examination Answer SheetCredits: 2.0 hours (0.20 ceu)Expires: November 30, 2011This exam can be taken online at www.uspharmacist.com. Upon passing, you can printout your statement immediately and view your test history. Alternatively, you can mailthis answer sheet to the address below. Please contact CE Customer Service at (800)825-4696 or cecustomerservice@jobson.com with any questions.Emergency Contraception:An Update of Clinical and Regulatory ChangesDirections: Select one answer for each question in the exam and completely darkenthe appropriate circle. A minimum score of 70% is required to earn credit. An identifieris required to process your exam. This is used for internal processing purposes only.Mail to: U.S. Pharmacist–CE, PO Box 487,Canal Street Station, New York, NY 100131. A B C D2. A B C D3. A B C D4. A B C D5. A B C D6. A B C D7. A B C D8. A B C D9. A B C D10. A B C D11. A B C D12. A B C D13. A B C D14. A B C D15. A B C D16. A B C D17. A B C D18. A B C D19. A B C D20. A B C DSupported by an educational grant fromTeva Women’s Health.1 = Excellent 2 = Very Good 3 = Good 4 = Fair 5 = PoorRate the effectiveness of how well the activity:21. Met objective 1:*22. Met objective 2:*23. Met objective 3:*24. Met objective 4:*25. Met objective 5:*26. Related to your educational needs:27. The active learning strategies(questions, cases, discussions) wereappropriate and effective learning tools:28. Avoided commercial bias:29. How would you rate the overallusefulness of the material presented?30. How would you rate the quality of the faculty?31. How would you rate the appropriatenessof the examination for this activity?32. Comments on this activity:1111111111122222222222333333333334444444444455555555555* Also applies to pharmacy technicians.Please retain a copy for your records. Please print clearly.You must choose and complete ONE of the following three identifier types:1 SS # - -✁EMERGENCY CONTRACEPTION15. Which of the following may be barriersfor consumers to access EC?A. The requirement to keep EC behind thepharmacy counterB. Embarrassment about asking the pharmacy stafffor the productC. Misinformation about when to use ECD.All of the above16. Which of the following actions shouldbe taken when a woman requests EC, but thepharmacy is out of stock?A. Tell her you will order the medication and sheshould come back in a couple of daysB. Direct her to a nearby pharmacy where themedication is availableC. Tell her you are out of stockD.A and C only17. Which of the following emergencycontraceptive products contains a single doseof 1.5 mg levonorgestrel?A. Plan BB. Plan B One-StepC. Next ChoiceD.All of the above18. Pharmacists can improve access to EC by:A. Placing emergency contraceptive products in aneasy to see location in the pharmacyB. Educating the pharmacy staff about ECC. Being available to answer consumer questionsD.All of the above2 Last 4 digits of your SS # and date of birth -3 State Code and License #(Example: FL12345678)First NameLast NameE-MailThe following is your: Home Address Business AddressBusinessNameAddressCityState19. In states with Pharmacist Accessprograms for EC, the participatingpharmacist is able to:A. Provide Plan B or Plan B One-Step to menof all agesB. Initiate a prescription for Plan B to those withoutproof of age or who need a prescription forinsurance purposesC. Provide women of any age with routine hormonalcontraceptionD.Test women for STIs in the pharmacyZIPTelephone # - -Fax # - -Profession: Pharmacist Pharmacy Technician OtherBy submitting this answer sheet, I certify that I have read the lesson in its entirety andcompleted the self-assessment exam personally based on the material presented.I have not obtained the answers to this exam by any fraudulent or improper means.SignatureDatePostgraduate Healthcare Education, LLC is accredited by theAccreditation Council for Pharmacy Education as a providerof continuing pharmacy education.®0430-0000-09-027-H01-PLesson 106417 Type of Activity: Knowledge 0430-0000-09-027-H01-T20. Which of the following statement(s) areimportant for consumer education regardingthe use of EC?A. Taking EC as soon as possible may increase itseffectivenessB. EC is not intended to replace your other methodsof birth controlC. Taking EC reduces the risk of pregnancy but notthe risk of sexually transmitted infectionsD.All of the above79U.S. Pharmacist • November 2009 • www.uspharmacist.com

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Product NewsValstar Reintroduction FillsBladder Cancer Treatment GapEndo Pharmaceuticals announcedthe reintroduction and availabilityof a reformulated version of Valstar.Widely used to treat anaggressive type of recurrent bladdercancer before it becameunavailable in 2002, the drug wasreapproved by the FDA in February2009 for bacille Calmette-Guérin (BCG) vaccine–refractorycarcinoma in situ of the urinarybladder. Valstar represents a newtreatment option for patients whomay otherwise have exhausted allother FDA-approved treatmentalternatives, including BCG.Medi-Dose/EPS AnnouncesThree New ProductsTo complement their popularButterfly labels for syringes,ampules, and small containers,Medi-Dose, Inc., has introducedButterfly labels in five new colorsto call attention to medicationrequiring special handling. Medi-Dose labels can be printed with aregular laser printer, and theirunique hourglass design providespractitioners with ample area formedication identification.To reduce the number oferrors in operating rooms due tomishandling of look-alike medications,EPS, Inc., has released twonew ShrinkSafe ID Bands forchemotherapy and high-alertdrugs. ShrinkSafe was designed toeasily wrap around various-sizedvials and is available in brightcolors to indicate medicationsrequiring special handling.In addition to its EnglishPharmacy Warning and InstructionLabels, Medi-Dose/EPS hasintroduced a line of SpanishPharmacy and Nursing AuxiliaryLabels. These labels call attentionto the same special informationand indications for medicationsas the company’s English versions.CBI AnnouncesTruTag TechnologyCellular Bioengineering, Inc.,announced the development of anovel technology that can helpprevent counterfeiting of medicineand pharmaceutical products. Tru-Tag is an edible, microscopic,nanoporous silica microtag thatcan be used to safely and directlymark medicine.Paddock LabsReleases New ProductPaddock Laboratories, Inc.,announced the addition of hyoscyaminesulfate extended-releasetablets to its product line. Availableby prescription only, hyoscyaminetablets come in bottles of100 in 0.375-mg strength.Bioniche andSynerx LaunchFomepizoleInjectionBioniche Pharmaand Synerx Pharma,LLC, announced thelaunch of fomepizoleinjection, thegeneric equivalent ofAntizol (PaladinLabs, Inc.). Fomepizoleis available in1.5-g/1.5-mL vials.Par Receives Approvalto Market StarlixPar Pharmaceutical Companies,Inc., has received FDA approvalfor nateglinide tablets. Nateglinideis a generic version of Starlix(Novartis) and is indicated as anadjunct to diet and exercise toimprove glycemic control inadults with type 2 diabetesmellitus.Perrigo Announces Approvalfor Polyethylene Glycol 3350Perrigo Company announcedFDA approval for OTC PolyethyleneGlycol 3350, Powder forSolution. The product is indicatedfor the treatment of occasionalconstipation and is comparableto MiraLax Products(Schering-Plough).82U.S. Pharmacist • November 2009 • www.uspharmacist.com

ONGLYZA (saxagliptin) tabletsBrief Summary of Prescribing Information. For complete prescribinginformation consult official package insert.INDICATIONS AND USAGEMonotherapy and Combination TherapyONGLYZA (saxagliptin) is indicated as an adjunct to diet and exercise to improveglycemic control in adults with type 2 diabetes mellitus. [See Clinical Studies(14).]Important Limitations of UseONGLYZA should not be used for the treatment of type 1 diabetes mellitus ordiabetic ketoacidosis, as it would not be effective in these settings.ONGLYZA has not been studied in combination with insulin.CONTRAINDICATIONSNone.WARNINGS AND PRECAUTIONSUse with Medications Known to Cause HypoglycemiaInsulin secretagogues, such as sulfonylureas, cause hypoglycemia. Therefore,a lower dose of the insulin secretagogue may be required to reduce the riskof hypoglycemia when used in combination with ONGLYZA. [See AdverseReactions (6.1).]Macrovascular OutcomesThere have been no clinical studies establishing conclusive evidence ofmacrovascular risk reduction with ONGLYZA or any other antidiabetic drug.ADVERSE REACTIONSClinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adversereaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may not reflect therates observed in practice.Monotherapy and Add-On Combination TherapyIn two placebo-controlled monotherapy trials of 24-weeks duration, patientswere treated with ONGLYZA 2.5 mg daily, ONGLYZA 5 mg daily, and placebo.Three 24-week, placebo-controlled, add-on combination therapy trials werealso conducted: one with metformin, one with a thiazolidinedione (pioglitazoneor rosiglitazone), and one with glyburide. In these three trials, patients wererandomized to add-on therapy with ONGLYZA 2.5 mg daily, ONGLYZA 5 mgdaily, or placebo. A saxagliptin 10 mg treatment arm was included in one ofthe monotherapy trials and in the add-on combination trial with metformin.In a prespecified pooled analysis of the 24-week data (regardless of glycemicrescue) from the two monotherapy trials, the add-on to metformin trial, theadd-on to thiazolidinedione (TZD) trial, and the add-on to glyburide trial, theoverall incidence of adverse events in patients treated with ONGLYZA 2.5 mgand ONGLYZA 5 mg was similar to placebo (72.0% and 72.2% versus 70.6%,respectively). Discontinuation of therapy due to adverse events occurred in2.2%, 3.3%, and 1.8% of patients receiving ONGLYZA 2.5 mg, ONGLYZA 5 mg,and placebo, respectively. The most common adverse events (reported in atleast 2 patients treated with ONGLYZA 2.5 mg or at least 2 patients treatedwith ONGLYZA 5 mg) associated with premature discontinuation of therapyincluded lymphopenia (0.1% and 0.5% versus 0%, respectively), rash (0.2%and 0.3% versus 0.3%), blood creatinine increased (0.3% and 0% versus 0%),and blood creatine phosphokinase increased (0.1% and 0.2% versus 0%). Theadverse reactions in this pooled analysis reported (regardless of investigatorassessment of causality) in ≥5% of patients treated with ONGLYZA 5 mg, andmore commonly than in patients treated with placebo are shown in Table 1.Table 1: Adverse Reactions (Regardless of Investigator Assessmentof Causality) in Placebo-Controlled Trials* Reported in 5%of Patients Treated with ONGLYZA 5 mg and MoreCommonly than in Patients Treated with PlaceboNumber (%) of PatientsONGLYZA 5 mg PlaceboN=882 N=799Upper respiratory tract infection 68 (7.7) 61 (7.6)Urinary tract infection 60 (6.8) 49 (6.1)Headache 57 (6.5) 47 (5.9)* The 5 placebo-controlled trials include two monotherapy trials and oneadd-on combination therapy trial with each of the following: metformin,thiazolidinedione, or glyburide. Table shows 24-week data regardless ofglycemic rescue.In patients treated with ONGLYZA 2.5 mg, headache (6.5%) was the onlyadverse reaction reported at a rate ≥5% and more commonly than in patientstreated with placebo.In this pooled analysis, adverse reactions that were reported in ≥2% of patientstreated with ONGLYZA 2.5 mg or ONGLYZA 5 mg and ≥1% more frequentlycompared to placebo included: sinusitis (2.9% and 2.6% versus 1.6%,respectively), abdominal pain (2.4% and 1.7% versus 0.5%), gastroenteritis(1.9% and 2.3% versus 0.9%), and vomiting (2.2% and 2.3% versus 1.3%).In the add-on to TZD trial, the incidence of peripheral edema was higher forONGLYZA 5 mg versus placebo (8.1% and 4.3%, respectively). The incidenceof peripheral edema for ONGLYZA 2.5 mg was 3.1%. None of the reportedadverse reactions of peripheral edema resulted in study drug discontinuation.Rates of peripheral edema for ONGLYZA 2.5 mg and ONGLYZA 5 mg versusplacebo were 3.6% and 2% versus 3% given as monotherapy, 2.1% and 2.1%versus 2.2% given as add-on therapy to metformin, and 2.4% and 1.2% versus2.2% given as add-on therapy to glyburide.The incidence rate of fractures was 1.0 and 0.6 per 100 patient-years,respectively, for ONGLYZA (pooled analysis of 2.5 mg, 5 mg, and 10 mg) andplacebo. The incidence rate of fracture events in patients who receivedONGLYZA did not increase over time. Causality has not been established andnonclinical studies have not demonstrated adverse effects of saxagliptin onbone.An event of thrombocytopenia, consistent with a diagnosis of idiopathicthrombocytopenic purpura, was observed in the clinical program. Therelationship of this event to ONGLYZA is not known.Adverse Reactions Associated with ONGLYZA (saxagliptin)Coad ministered with Metformin in Treatment-Naive Patients withType 2 DiabetesTable 2 shows the adverse reactions reported (regardless of investigatorassessment of causality) in ≥5% of patients participating in an additional24-week, active-controlled trial of coadministered ONGLYZA and metforminin treatment-naive patients.Table 2: Initial Therapy with Combination of ONGLYZA and Metforminin Treatment-Naive Patients: Adverse Reactions Reported(Regardless of Investigator Assessment of Causality) in 5%of Patients Treated with Combination Therapy of ONGLYZA5 mg Plus Metformin (and More Commonly than in PatientsTreated with Metformin Alone)Number (%) of PatientsONGLYZA 5 mg + Metformin* Metformin*N=320 N=328Headache 24 (7.5) 17 (5.2)Nasopharyngitis 22 (6.9) 13 (4.0)* Metformin was initiated at a starting dose of 500 mg daily and titrated upto a maximum of 2000 mg daily.HypoglycemiaAdverse reactions of hypoglycemia were based on all reports of hypoglycemia;a concurrent glucose measurement was not required. In the add-on toglyburide study, the overall incidence of reported hypoglycemia was higher forONGLYZA 2.5 mg and ONGLYZA 5 mg (13.3% and 14.6%) versus placebo(10.1%). The incidence of confirmed hypoglycemia in this study, defined assymptoms of hypoglycemia accompanied by a fingerstick glucose value of≤50 mg/dL, was 2.4% and 0.8% for ONGLYZA 2.5 mg and ONGLYZA 5 mg and0.7% for placebo. The incidence of reported hypoglycemia for ONGLYZA2.5 mg and ONGLYZA 5 mg versus placebo given as monotherapy was 4.0%and 5.6% versus 4.1%, respectively, 7.8% and 5.8% versus 5% given asadd-on therapy to metformin, and 4.1% and 2.7% versus 3.8% given asadd-on therapy to TZD. The incidence of reported hypoglycemia was 3.4% intreatment-naive patients given ONGLYZA 5 mg plus metformin and 4.0% inpatients given metformin alone.Hypersensitivity ReactionsHypersensitivity-related events, such as urticaria and facial edema in the5-study pooled analysis up to Week 24 were reported in 1.5%, 1.5%, and 0.4%of patients who received ONGLYZA 2.5 mg, ONGLYZA 5 mg, and placebo,respectively. None of these events in patients who received ONGLYZA requiredhospitalization or were reported as life-threatening by the investigators. Onesaxagliptin-treated patient in this pooled analysis discontinued due togeneralized urticaria and facial edema.Vital SignsNo clinically meaningful changes in vital signs have been observed in patientstreated with ONGLYZA.Laboratory TestsAbsolute Lymphocyte CountsThere was a dose-related mean decrease in absolute lymphocyte countobserved with ONGLYZA. From a baseline mean absolute lymphocyte count ofapproximately 2200 cells/microL, mean decreases of approximately 100 and120 cells/microL with ONGLYZA 5 mg and 10 mg, respectively, relative toplacebo were observed at 24 weeks in a pooled analysis of fiveplacebo-controlled clinical studies. Similar effects were observed whenONGLYZA 5 mg was given in initial combination with metformin compared tometformin alone. There was no difference observed for ONGLYZA 2.5 mgrelative to placebo. The proportion of patients who were reported to have alymphocyte count ≤750 cells/microL was 0.5%, 1.5%, 1.4%, and 0.4% in thesaxagliptin 2.5 mg, 5 mg, 10 mg, and placebo groups, respectively. In mostpatients, recurrence was not observed with repeated exposure to ONGLYZAalthough some patients had recurrent decreases upon rechallenge that led todiscontinuation of ONGLYZA. The decreases in lymphocyte count were notassociated with clinically relevant adverse reactions.The clinical significance of this decrease in lymphocyte count relative toplacebo is not known. When clinically indicated, such as in settings of unusualor prolonged infection, lymphocyte count should be measured. The effect ofONGLYZA on lymphocyte counts in patients with lymphocyte abnormalities(e.g., human immunodeficiency virus) is unknown.PlateletsONGLYZA did not demonstrate a clinically meaningful or consistent effect onplatelet count in the six, double-blind, controlled clinical safety and efficacytrials.DRUG INTERACTIONSInducers of CYP3A4/5 EnzymesRifampin significantly decreased saxagliptin exposure with no change in thearea under the time-concentration curve (AUC) of its active metabolite,5-hydroxy saxagliptin. The plasma dipeptidyl peptidase-4 (DPP4) activityinhibition over a 24-hour dose interval was not affected by rifampin. Therefore,dosage adjustment of ONGLYZA is not recommended. [See ClinicalPharmacology (12.3).]Inhibitors of CYP3A4/5 EnzymesModerate Inhibitors of CYP3A4/5Diltiazem increased the exposure of saxagliptin. Similar increases in plasmaconcentrations of saxagliptin are anticipated in the presence of other moderateCYP3A4/5 inhibitors (e.g., amprenavir, aprepitant, erythromycin, fluconazole,fosamprenavir, grapefruit juice, and verapamil); however, dosage adjustmentof ONGLYZA is not recommended. [See Clinical Pharmacology (12.3).]Strong Inhibitors of CYP3A4/5Ketoconazole significantly increased saxagliptin exposure. Similar significantincreases in plasma concentrations of saxagliptin are anticipated with otherstrong CYP3A4/5 inhibitors (e.g., atazanavir, clarithromycin, indinavir,itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin).The dose of ONGLYZA should be limited to 2.5 mg when coadministered witha strong CYP3A4/5 inhibitor. [See Dosage and Administration (2.3) and ClinicalPharmacology (12.3).]USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category BThere are no adequate and well-controlled studies in pregnant women.Because animal reproduction studies are not always predictive of humanresponse, ONGLYZA (saxagliptin), like other antidiabetic medications, shouldbe used during pregnancy only if clearly needed.Saxagliptin was not teratogenic at any dose tested when administered topregnant rats and rabbits during periods of organogenesis. Incompleteossification of the pelvis, a form of developmental delay, occurred in rats at adose of 240 mg/kg, or approximately 1503 and 66 times human exposure tosaxagliptin and the active metabolite, respectively, at the maximumrecommended human dose (MRHD) of 5 mg. Maternal toxicity and reducedfetal body weights were observed at 7986 and 328 times the human exposureat the MRHD for saxagliptin and the active metabolite, respectively. Minorskeletal variations in rabbits occurred at a maternally toxic dose of 200 mg/kg,or approximately 1432 and 992 times the MRHD. When administered to ratsin combination with metformin, saxagliptin was not teratogenic norembryolethal at exposures 21 times the saxagliptin MRHD. Combinationadministration of metformin with a higher dose of saxagliptin (109 times thesaxagliptin MRHD) was associated with craniorachischisis (a rare neural tubedefect characterized by incomplete closure of the skull and spinal column) intwo fetuses from a single dam. Metformin exposures in each combination were4 times the human exposure of 2000 mg daily.Saxagliptin administered to female rats from gestation day 6 to lactation day20 resulted in decreased body weights in male and female offspring only atmaternally toxic doses (exposures ≥1629 and 53 times saxagliptin and itsactive metabolite at the MRHD). No functional or behavioral toxicity wasobserved in offspring of rats administered saxagliptin at any dose.Saxagliptin crosses the placenta into the fetus following dosing in pregnant rats.Nursing MothersSaxagliptin is secreted in the milk of lactating rats at approximately a 1:1 ratiowith plasma drug concentrations. It is not known whether saxagliptin issecreted in human milk. Because many drugs are secreted in human milk,caution should be exercised when ONGLYZA is administered to a nursingwoman.Pediatric UseSafety and effectiveness of ONGLYZA in pediatric patients have not beenestablished.Geriatric UseIn the six, double-blind, controlled clinical safety and efficacy trials of ONGLYZA,634 (15.3%) of the 4148 randomized patients were 65 years and over, and59 (1.4%) patients were 75 years and over. No overall differences in safety oreffectiveness were observed between patients ≥65 years old and the youngerpatients. While this clinical experience has not identified differences inresponses between the elderly and younger patients, greater sensitivity ofsome older individuals cannot be ruled out.Saxagliptin and its active metabolite are eliminated in part by the kidney.Because elderly patients are more likely to have decreased renal function, careshould be taken in dose selection in the elderly based on renal function. [SeeDosage and Administration (2.2) and Clinical Pharmacology (12.3).]OVERDOSAGEIn a controlled clinical trial, once-daily, orally-administered ONGLYZA in healthysubjects at doses up to 400 mg daily for 2 weeks (80 times the MRHD) had nodose-related clinical adverse reactions and no clinically meaningful effect onQTc interval or heart rate.In the event of an overdose, appropriate supportive treatment should beinitiated as dictated by the patient’s clinical status. Saxagliptin and its activemetabolite are removed by hemodialysis (23% of dose over 4 hours).PATIENT COUNSELING INFORMATIONSee FDA-approved patient labeling.InstructionsPatients should be informed of the potential risks and benefits of ONGLYZAand of alternative modes of therapy. Patients should also be informed aboutthe importance of adherence to dietary instructions, regular physical activity,periodic blood glucose monitoring and A1C testing, recognition andmanagement of hypoglycemia and hyperglycemia, and assessment of diabetescomplications. During periods of stress such as fever, trauma, infection, orsurgery, medication requirements may change and patients should be advisedto seek medical advice promptly.Physicians should instruct their patients to read the Patient Package Insertbefore starting ONGLYZA therapy and to reread it each time the prescriptionis renewed. Patients should be instructed to inform their doctor or pharmacistif they develop any unusual symptom or if any existing symptom persistsor worsens.Laboratory TestsPatients should be informed that response to all diabetic therapies shouldbe monitored by periodic measurements of blood glucose and A1C, with agoal of decreasing these levels toward the normal range. A1C is especiallyuseful for evaluating long-term glycemic control. Patients should be informedof the potential need to adjust their dose based on changes in renal functiontests over time.Manufactured by:Princeton, NJ 08543 USAMarketed by:Bristol-Myers Squibb CompanyPrinceton, NJ 08543andAstraZeneca Pharmaceuticals LPWilmington, DE 198501256316 1256317 SA-B0001A-07-09 Iss July 2009

For your adult patients with type 2 diabetes strugglingto gain glycemic controlSignificant reductions in A1C whenpartnered with key oral antidiabetic agents*• Onglyza is weight neutral• Discontinuation of therapy due to adverse eventsoccurred in 3.3% and 1.8% of patients receivingOnglyza and placebo, respectively• Convenient, once-daily dosing• Rapidly growing formulary access 1Indication and Important Limitations of UseONGLYZA is indicated as an adjunct to diet andexercise to improve glycemic control in adults withtype 2 diabetes mellitus.ONGLYZA should not be used for the treatment oftype 1 diabetes mellitus or diabetic ketoacidosis.ONGLYZA has not been studied in combinationwith insulin.Important Safety Information• Use with Medications Known to CauseHypoglycemia: Insulin secretagogues, suchas sulfonylureas, cause hypoglycemia. Therefore,a lower dose of the insulin secretagogue may berequired to reduce the risk of hypoglycemia whenused in combination with ONGLYZA• Macrovascular Outcomes: There have beenno clinical studies establishing conclusive evidenceof macrovascular risk reduction with ONGLYZAor any other antidiabetic drugMost common adverse reactions (regardless ofinvestigator assessment of causality) reported in≥5% of patients treated with ONGLYZA and morecommonly than in patients treated with controlwere upper respiratory tract infection (7.7%, 7.6%),headache (7.5%, 5.2%), nasopharyngitis (6.9%,4.0%) and urinary tract infection (6.8%, 6.1%).When used as add-on combination therapy witha thiazolidinedione, the incidence of peripheraledema for ONGLYZA 2.5 mg, 5 mg, and placebowas 3.1%, 8.1% and 4.3%, respectively.*metformin, glyburide, or thiazolidinedione (pioglitazone or rosiglitazone)Onglyza – A Welcome PartnerPlease read the adjacent Brief Summary of the Product Information.For more information about Onglyza, a DPP-4 inhibitor, visit www.onglyza.com.Reference:1. Fingertip Formulary ® data as of October 2, 2009. Data on File, October 2009.©2009 Bristol-Myers Squibb 422US09AB12901 10/09Onglyza is a trademark of Bristol-Myers Squibb278130