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FDA approves first three-drug fixed-dose tablet for PEPFAR use
Keith Alcorn, Wednesday, July 05, 2006
The US Food and Drug Administration (FDA) this week issued the first tentative approval for a three drug, fixed dose tablet for use as a stand-alone antiretroviral treatment for HIV infection in adults. The product (lamivudine-zidovudine-nevirapine tablet) contains the active ingredients in the widely used antiretroviral drugs Epivir (lamivudine), Retrovir (zidovudine), and Viramune (nevirapine).

The agency’s tentative approval means that although existing patents and/or exclusivity prevent approval of this product in the United States, it meets all of FDA’s manufacturing quality and clinical safety and efficacy standards required for marketing in the United States. The fixed-dose combination tablet, manufactured by Aurobindo Pharma Ltd. in Hyderabad, India, will be available for purchase and distribution in 15 other countries under the President’s Emergency Plan for AIDS Relief (PEPFAR).

“Today’s approval marks a significant step forward in our commitment to clearing the way to quickly deliver quality, life-saving HIV/AIDS drugs to people who desperately need them in developing countries. Fixed-dose combination products are an important tool in President Bush’s PEPFAR program, which seeks to combat the AIDS epidemic in the worst affected countries,” said Michael O. Leavitt, Secretary of Health and Human Service.

“This new option, a fixed dose combination tablet containing lamivudine, zidovudine, and nevirapine, simplifies the treatment of HIV-1, which is a stumbling block for many individuals who find it difficult to maintain a regimen requiring the use of several drugs.”

In 2004, FDA issued a guidance encouraging manufacturers to develop fixed dose combination and co packaged products consisting of previously approved antiretroviral therapies for the treatment of HIV infection. FDA has already approved several co-packaged combinations in which three antiretroviral drugs are packaged together in a way that makes it clear how the drugs should be taken.

“Using fixed dose combinations in developing countries may provide an added advantage by improving the patient’s ability to better adhere to treatment regimens that will help minimize the development of viral resistance and result in long-term effective control of the disease,” said Dr. Scott Gottlieb, FDA Deputy Commissioner for Medical and Scientific Affairs.

The recommended regimen for the lamivudine-zidovudine-nevirapine tablet is one pill twice a day following an initial two week treatment with the individual components taken individually. This dosing pattern is necessary because nevirapine must be taken at half dose for the first two weeks of treatment until blood levels stabilise, in order to reduce the risk of serious toxicity.

Zidovudine-containing fixed dose combinations were initially considered to be less attractive in developing countries owing to the higher risk of anaemia associated with zidovudine, together with the lower price of stavudine (d4T). In the past year however it has become clear that stavudine is causing lactic acidosis (high levels of lactate in the blood, a life-threatening side effect) at a higher frequency than expected, and is also beginning to cause lipoatrophy. The lower risk of lactic acidosis associated with zidovudine has led to greater interest in using combinations that contain the drug.