Pharmacy & Therapeutics - March 2008 - (Page 157) Pharmaceutical Approval Update continued from page 151 4. The risks and benefits of etravirine have not been established in children or in treatment-naive adults. Drug Class: Etravirine, in the class of NNRTIs, is a diarylpyrimidine derivative with potent in vitro activity against HIV. Uniqueness of Drug: Etravirine is the first NNRTI to show antiviral activity in treatment-experienced adults with HIV resistance to NNRTIs and other antiretroviral agents. In vitro, etravirine has equipotent activity against wild-type HIV and NNRTI-resistant variants that encode L100I, K103N, Y181C, Y188L, and G190A/S mutations. Warnings and Precautions: Severe Skin Reactions: Severe and potentially life-threatening skin reactions have occurred in fewer than 0.1% of patients taking etravirine, including Stevens–Johnson syndrome, hypersensitivity reaction, and erythema multiforme. If a severe rash develops, it should be discontinued and appropriate therapy initiated. In clinical trials, rash was generally mild to moderate. It occurred primarily in the second week of therapy, was infrequent after the fourth week, and usually resolved within one to two weeks with continued therapy. A total of 2% of HIV-1–infected subjects receiving etravirine withdrew from phase 3 trials because of rash. Fat Redistribution: Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and a cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are unclear. A causal relationship between the drug and fat redistribution has not been established. Immune Reconstitution Syndrome: This syndrome has been reported in patients receiving combination antiretroviral therapy, including etravirine. During the initial phase of combined antiretroviral treatment, patients whose immune system benefits from therapy may have an inflammatory response to indolent or residual opportunistic infections, which may necessitate further evaluation and treatment. Examples of such infections include Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, and tuberculosis. Dosage and Administration: The recommended oral dose of etravirine is 200 mg (two 100-mg) tablets taken twice daily following a meal. The type of food does not affect the exposure to etravirine. Patients who cannot swallow etravirine tablets whole may disperse the tablets in a glass of water. Once the tablet is dispersed, patients should stir the mixture well and drink it immediately. The glass should be rinsed with water several times. Patients should swallow each rinse completely to ensure that the entire dose is consumed. Commentary: Etravirine is the first new NNRTI to be introduced in nearly 10 years, and it is the first one to show antiviral activity in patients with NNRTI-resistant virus. NNRTIs block reverse transcriptase, a key enzyme used by HIV to replicate. Resistance to NNRTIs occurs when HIV develops mutations that partially or completely stop the NNRTI from binding to the reverse transcriptase enzyme, causing the drug to lose effectiveness. As with other HIV medications, patients can develop resistance to etravirine. Source: www.fda.gov/cder/foi/label/2008/022187lbl.pdf Colesevelam HCl (Welchol) Manufacturer: Daiichi Sankyo, Inc., Parsippany, N.J. Indication: Colesevelam, a bile acid sequestrant, is indicated as an adjunct to diet and exercise to reduce elevated lowdensity lipoprotein cholesterol (LDL-C) levels in patients with primary hyperlipidemia as monotherapy or in combination with a statin drug. In January 2008, it was also approved to improve glycemic control in adults with type-2 diabetes mellitus. Important Limitations of Use: This drug is not indicated for improving glycemic control in type-1 diabetes or for treating diabetic ketoacidosis. It has not been studied in type-2 diabetes as monotherapy; in combination with a dipeptidyl peptidase 4 (DPP-4) inhibitor; in combination with thiazolidinediones; or in Fredrickson type I, III, IV, and V dyslipidemias. Drug Class: Colesevelam HCl is a an oral, non-absorbed, polymeric agent that lowers lipid and glucose levels. It is poly(allyl-amine HCl) cross-linked with epichlorohydrin and alkylated with 1-bromodecane and (6-bromohexyl)-trimethyl ammonium bromide. The chemical name is allyl-amine polymer with 1-chloro-2,3-epoxypropane,[6-(allyl-amino)-hexyl] trimethylammonium chloride and N-allyl-decylamine HCl. Uniqueness of Product: Colesevelam binds bile acids in the intestine, impeding their reabsorption. As the bile acid pool becomes depleted, the hepatic enzyme, cholesterol 7αhydroxylase, is up-regulated, which increases the conversion of cholesterol to bile acids. This causes an increased demand for cholesterol in the liver cells, resulting in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, HMG-CoA reductase (or statin), and increasing the number of hepatic LDL receptors. These compensatory effects result in increased clearance of LDL-C from the blood, resulting in lower LDL-C levels. Serum triglyceride levels may increase or remain unchanged. Warnings and Precautions: The drug’s effect on cardiovascular morbidity and mortality has not been determined. Serum Triglycerides: Like other bile acid sequestrants, this agent can increase triglyceride concentrations. In patients with primary hyperlipidemia, colesevelam had small effects on serum triglycerides, with a median increase of 5% when compared with placebo. In trials in type-2 diabetic patients, greater increases in triglycerides occurred with colesevelam/sulfonylurea combinations, showing a median increase of 18%, compared with placebo plus a sulfonylurea agent. Colesevelam plus insulin produced a median increase of 22%, compared with placebo plus insulin. Hypertriglyceridemia of sufficient severity can cause acute pancreatitis. The long-term effect of elevated triglyceride levels on the risk of coronary artery disease is uncertain. In type2 diabetes, the effect of colesevelam on LDL-C levels may be attenuated by the drug’s effects on triglycerides and by a smaller reduction in non–HDL-C levels, compared with the reduction in LDL-C. Caution should be exercised if triglyceride levels exceed 300 mg/dL. Because most patients in the colesevelam clinical trials had baseline triglyceride values below 300 mg/dL, it is unknown whether patients with more uncontrolled hypertriglyceridemia at baseline would have greater increases in serum triglyceride levels with colesevelam. continued on page 181 Vol. 33 No. 3 • March 2008 • P&T® 157 http://www.fda.gov/cder/foi/label/2008/022187lbl.pdf
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