Clinical Guidelines/Recommendations

Volume 1, Issue Number 12; July 8, 2005 News Highlights from June 20 – July 1, 2005

Coming in August … TrendsRx® Drug Pipeline and News will be getting a new look! Look for the same up-to-date information with a fresh new format!

PIPELINE

Generic Medicines for the Treatment of HIV Tentatively Approved Under the Government’s Emergency Plan for AIDS Relief On June 20, 2005, the United States Food and Drug Administration (FDA) announced tentative approval of two applications for nevirapine tablets, manufactured by Ranbaxy Laboratories Limited (Guragon, India) and Aurobindo Pharma Limited (Hyderabad, India).1 These products will be the first generic versions of Viramune® tablets, manufactured by Boehringer Ingelheim. Generic nevirapine will be available for purchase under the President’s Emergency Plan for AIDS Relief (PEPFAR).1 This plan allows for the availability of safe and effective AIDS treatments quicker and at a lower cost as part of worldwide HIV/AIDS relief.1-3 It is designed to prevent new HIV infections, treat HIV-infected people, and care for HIV-affected individuals.1-3 Tentative approval under PEPFAR means that although existing patents and/or exclusivity prevent marketing of these products in the United States, they meet the FDA standards for quality, safety and efficacy.1-3

On June 24 and July 1, 2005, respectively, the FDA also announced tentative approval of efavirenz tablets and stavudine capsules manufactured by Aurbindo Pharma LTD. (Hyderabad, India).2 These are the first generic versions of Sustiva® and Zerit®, respectively, manufactured by Bristol-Myers Squibb. Both generic products will also be considered for purchase under the PEPFAR.2

Nevirapine and efavirenz are non-nucleoside reverse transcriptase inhibitors (NNRTIs) used in combination with other medicines for the treatment of HIV-1 infection.1-2 Stavudine is a nucleoside reverse transcriptase inhibitor (NRTI) also used in combination with other medicines for the treatment of HIV-1 infection.3

© Copyright 2005 Caremark. All rights reserved. For more information, contact your Caremark Account Representative. Please note: This document provides a brief overview of various subjects. This document is provided as a reference only, and is based in part on information derived from third parties. Recent New Drug Application (NDA) Approvals4* Approval Route of Drug Name Indication(s) Drug Class Comments Date Administration Levemir® (insulin Treatment of Long-acting basal 06/16/2005 Injection- Product is available in vials, detemir [rDNA origin] adult patients with diabetes insulin analog subcutaneous PenFill® cartridge, FlexPen®, injection) 100 mellitus who require basal and Innolet® devices. Units/mL (long acting) insulin for the subcutaneous injection; control of Manufactured by Novo hyperglycemia Nordisk Aptivus® (tipranavir) For co-administration with 200 Non-peptidic 06/22/2005 Oral Aptivus received accelerated 250 mg capsule; mg of ritonavir for protease inhibitor FDA approval. In order for the Manufactured by combination antiretroviral product to receive traditional Boehringer Ingelheim treatment of HIV-1 infected FDA approval, longer term adult patients with evidence of data will be needed. viral replication, who are highly treatment-experienced or have HIV-1 strains resistant to multiple protease inhibitors BiDil® (isosorbide The improvement in survival, Nitric oxide 06/23/2005 Oral Both drugs in this combination dinitrate 20mg/ prolongation of time to donor/vasodilator are available generically, hydralazine 37.5 mg) hospitalization for heart failure however, hydralazine is not tablets; Manufactured and improvement in patient- available generically in this by NitroMed reported functional status, as strength. The product is an adjunct to current standard anticipated in pharmacies heart therapy in self-identified during the third quarter of black patients 2005.

Recent sNDA Approvals4* Approval Route of Drug Name Indication(s) Drug Class Comments Date Administration Alinia® (nitazoxanide) Treatment of diarrhea caused Anti-infective 06/16/2005 Oral The product was already 500 mg tablets and by Cryptosporidium parvum in approved for this indication in 100 mg/5 mL oral non-HIV infected patients 12 patients aged one to 11 years of . suspension; years of age and older Manufactured by Romark Laboratories Topamax® Treatment of patients ten years Anticonvulsant 06/29/2005 Oral This is a new indication for an (topiramate) Tablets of age and older with partial- already approved product. and Sprinkle Capsules; onset or primary generalized Manufactured by tonic-clonic seizures as initial Ortho-McNeil monotherapy Keppra® (levetiracetam) As add-on therapy in the Pyrrolidine 06/21/2005 Oral This is a new indication for an 100 mg/mL oral treatment of partial-onset already approved product. solution and 250 mg, seizures in children four years 500 mg, and 750 mg of age and older with epilepsy tablets; Manufactured by UCB Pharma Avelox® (moxifloxacin) Treatment of complicated skin Fluoroquinolone 06/13/2005 Oral/intravenous This is a new indication for an 400 mg tablet and and skin structure infections infusion already approved product. 160 mg/mL (cSSSI) in adults caused by intravenous infusion; methicillin-susceptible Manufactured by Staphylococcus aureus, Escherichia Schering-Plough coli, Klebsiella pneumoniae or Enterobacter cloacae sNDA= supplemental new drug application

Recent NDA Submissions4* Submission Route of Drug Name Indication(s) Drug Class Comments Date Administration pioglitazone/glimepiride; Treatment of type 2 Thiazolidinedione/ 06/30/2005 Oral Manufactured by Takeda diabetes sulfonylurea Neurodex™ Treatment of Sigma-1 receptor First section Oral The FDA granted (dextromethorphan/quinidine); pseudobulbar affect agonist and NMDA of the NDA Avanir a "rolling" Manufactured by Avanir (PBA) receptor antagonist/ was submitted submission of their enzyme inhibitor in December NDA for Neurodex 2004, the final for this indication. section was The FDA also submitted on granted the NDA a 06/30/2005 priority review once the submission was complete.

Recent Product Launches4* Launch Route of Drug Name Indication(s) Drug Class Comments Date Administration Naglazyme™ (galsulfase) Treatment of Enzyme 06/20/2005 Injection- This product was 5 mg/5mL intravenous mucopolysaccharidosis VI replacement therapy intravenous formerly known as infusion; (MPS VI) infusion Aryplase™. Manufactured by BioMarin Pharmaceutical

* Adapted from RxPipeline Services, for more information contact: [email protected]

DRUG SAFETY

Iressa® (gefitinib) Labeling Changes5 On June 17, 2005, the FDA announced approval of new product labeling for Iressa limiting the indication to cancer patients who, in the opinion of their treating physician, are currently benefiting, or have previously benefited, from Iressa treatment. In addition, previously enrolled patients or new patients in non-Investigational New Drug clinical trials approved by an Institutional Review Board prior to June 17, 2005 are eligible for Iressa therapy. There will be a limited distribution of Iressa via a risk management program known as the Iressa Access Program. The FDA is not considering market withdrawal of Iressa at this time. The new labeling information is a result of clinical trial evidence that failed to show Iressa therapy helped people live longer. Further evaluation of new, ongoing and completed clinical trials will determine the future role of Iressa treatment. Iressa has been used for the treatment of NSCLC that has progressed after, or failed to respond to, two other types of chemotherapy. There are other medicines for non-small cell lung cancer (NSCLC) that have shown an ability to improve survival.

Paxil CR® (paroxetine) Tablets Return to Market, Avandamet® (rosiglitazone/metformin) to Follow Shortly On June 27, 2005, GlaxoSmithKline (GSK) announced the availability of Paxil CR tablets in the United States.6 Paxil CR is approved for the treatment of major depressive disorder, social anxiety disorder, and premenstrual dysphoric disorder.6 The manufacturer anticipates pharmacies and wholesalers will be resupplied with the product by mid-year.6 Paxil CR was voluntarily withdrawn from the market in February 2005 due to manufacturing issues which have been identified and corrected, according to the manufacturer.6

FDA Releases Public Health Advisory Regarding Antidepressant Use in Adults8 On July 1, 2005, the FDA issued a MedWatch Alert to notify health professionals and patients of the newly released public health advisory and FDA talk paper on the use of antidepressant medicines in adults. The FDA is currently reviewing available data to determine if there is an increased risk of suicidal behavior in adults on antidepressant therapy; this review may take more than a year to complete. The FDA advises adults treated with antidepressant medicines (particularly those patients being treated for depression) be monitored for signs of worsening depression and for increased suicidal thinking or behavior. Close observation of patients is important upon antidepressant therapy initiation and/or upon dosage change. The FDA advises patients whose symptoms worsen while on antidepressant therapy (including an increase in suicidal thinking or behavior) be evaluated by a healthcare professional. These recommendations are consistent with the warnings in the approved labeling for antidepressants.

NEW/UPDATED NATIONAL CLINICAL GUIDELINES/RECOMMENDATIONS

American Academy of Neurology (AAN) Releases Essential Tremor Practice Parameter9 The AAN new evidence-based essential tremor guideline reviews the initiation of treatment; the safety, tolerability, and efficacy of certain medications; and the safety and efficacy of surgical treatments for essential tremor. Essential tremor is one of the most common tremor disorders in adults and the incidence and prevalence increases with advancing age. AAN has provided summaries for clinicians and patients on their Web site. For more information, the full practice parameter is available online with subscription and will be published in the June 2005 issue of Neurology.

References 1. U.S. Food and Drug Administration. FDA News: FDA Tentatively Approves First Generic Nevirapine Under the President’s Emergency Plan for AIDS Relief. Available at: http://www.fda.gov/bbs/topics/NEWS/2005/NEW01187.html. Accessed June 22, 2005. 2. U.S. Food and Drug Administration. FDA News: FDA Tentatively Approves Generic Efavirenz – Product Eligible to be Considered Under the President’s Emergency Plan for AIDS Relief. Available at: http://www.fda.gov/bbs/topics/NEWS/2005/NEW01191.html. Accessed June 27, 2005. 3. U.S. Food and Drug Administration. FDA News: FDA Tentatively Approves Another First Time Generic AIDS Drug Associated with the President’s Emergency Plan for AIDS Relief. Available at: http://www.fda.gov/bbs/topics/NEWS/2005/NEW01199.html. Accessed July 1, 2005. 4. Caremark: RxPipeline Insider. Full content available with subscription at: www.rxpipelineinsider.com. Accessed June 24, 2005 and July 1, 2005. 5. U.S. Food and Drug Administration. MedWatch: Iressa (gefinitib). Available at: http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#Iressa. Accessed June 21, 2005. 6. GlaxoSmithKline. Press Release: GlaxoSmithKline Announces Resupply of Paxil CR to U.S. Market. Available at: http://www.gsk.com/index.htm. Accessed June 28, 2005. 7. Avandamet® product information. GlaxoSmithKline, January 2005. 8. U.S. Food and Drug Administration. MedWatch: Public Health Advisory: Suicidality in Adults Being Treated with Antidepressant Medications. Available at: http://www.fda.gov/medwatch/SAFETY/2005/safety05.htm#antidepressant. Accessed July 1, 2005. 9. American Academy of Neurology. AAN Practice Guidelines: Therapies for Essential Tremor. Available at: http://www.aan.com/professionals/practice/guideline/index.cfm#Movement. Accessed June 27, 2005.