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FDA Approves Generic NRTI Combinations for PEPFAR Program

Drug cost remains a major barrier to access to antiretroviral therapy in resource-limited areas. Several companies produce generic versions of anti-HIV medications under World Trade Organization provisions for low- and middle-income countries. The Food and Drug Administration (FDA), which approves drugs for use in the United States, also evaluates generic versions for use in countries that receive assistance under the President's Emergency Plan for AIDS Relief (PEPFAR).

In recent weeks, the FDA has granted tentative approval for generic versions of 4 antiretroviral drugs and fixed-dose combination pills. "Tentative approval" means the agency has concluded that a drug product has met all required quality, safety, and efficacy standards, but is not eligible for marketing in the U.S. due to existing patent protections.

In evaluating generic applications, the FDA conducts an on-site inspection of each manufacturing facility, and of the facilities performing the bioequivalence studies, to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

On March 30, the FDA approved a generic version of fixed-dose tablets containing 600 mg abacavir plus 300 mg lamivudine (3TC), equivalent to GlaxoSmithKline's brand name Epzicom pill (known as Kivexa outside the U.S.). The generic pill is manufactured by Matrix Laboratories Limited of Hyberdad, India

The agency also tentatively approved a generic version of fixed-dose 300 mg tenofovir plus 200 mg emtricitabine, equivalent to Gilead Science's Truvada pill. This version is also produced by Matrix Laboratories. In this case, the FDA determined that the generic formulation is bioequivalent and, therefore, therapeutically equivalent to Truvada, but existing patent protections and pediatric exclusivity prevent final approval of a generic formulation.

These 2 combinations are equivalent to nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbones widely used in high-income countries. Tenofovir/emtricitabine is listed as a "preferred" component of a regimen for treatment-naive patients in current U.S. and European treatment guidelines. Abacavir/lamivudine was previously considered preferred, but was recently demoted to "alternative" status due to unresolved concerns about cardiovascular risk and suboptimal effectiveness in people with high viral load.

In contrast, several previously approved generic combination pills contain stavudine (d4T, equivalent to Zerit) and/or didanosine (ddI, equivalent to Videx), which are no longer considered standard first-line therapy in wealthy countries due to their side effects.

On February 27, the FDA granted tentative approval of 2 combination pills containing stavudine, lamivudine, and nevirapine, one with 30mg/150mg/200mg and the other with 40mg/150mg/200mg. These generic combination pills, produced by Pharmacare Limited t/a Aspen Pharmacare of South Africa, have no brand-name equivalents (the component drugs are produced by different companies). While stavudine has been linked to a range of side effects, including mitochondrial toxicity, it is commonly used in low-income countries because of its widespread availability and low cost.

Finally, on March 31, the FDA granted tentative approval of a generic formulation of 200 mg nevirapine tablets, equivalent to Boehringer Ingelheim's Viramune, manufactured by MacLeods Pharmaceuticals Limited of Daman, India. Nevirapine is used for prevention of mother-to-child HIV transmission as well as for combination treatment.

The FDA web site provides a complete list of all Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan.

4/03/09

Sources

R Klein (Office of Special Health Issues, Food and Drug Administration) and K Struble (Division of Antiviral Drug Products, Food and Drug Administration). Tentative approval of abacavir sulfate and lamivudine tablets, 600 mg (base)/300 mg. FDA HIV/AIDS Update. March 31, 2009.

R Klein and K Struble. Tentative approval emtricitabine and tenofovir disoproxil fumarate tablets, 200 mg/300 mg. FDA HIV/AIDS Update. March 31, 2009.

R Klein and K Struble. Tentative approval of stavudine, lamivudine and nevirapine fixed dose combination. FDA HIV/AIDS Update. March 3, 2009.

R Klein and K Struble. Tentative approval of generic nevirapine tablets, 200 mg. FDA HIV/AIDS Update. April 1, 2009.