FDA Notifications

FDA approves generic lamivudine: On Oct. 7, 2008, the FDA granted tentative approval for a generic formulation of lamivudine 150 mg and 300 mg tablets, manufactured by Macleods Pharmaceuticals Limited of Daman, India, indicated for use in combination with other anti-retroviral drugs for the treatment of HIV-1 infection.

"Tentative approval" means that FDA has concluded that a drug product meets all required quality, safety and efficacy standards, but is not eligible for marketing in the U.S. because of existing patents and/or exclusivity rights. Tentative approval, however, does make the product eligible for consideration for purchase outside the United States under the President's Emergency Plan for AIDS Relief (PEPFAR). This product is a generic version of Epivir, manufactured by GlaxoSmithKline, which is still under patent protection.

Effective patent dates can be found in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book."

This application was reviewed under expedited review provisions developed by FDA for the PEPFAR program.

As with all generic applications, 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 prior to granting approval or tentative approval to these applications.

A list of all Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan is available on the FDA website.

Darunavir label has these changes

This FDA message describes the following important changes affecting darunavir (Prezista):

  • Traditional approval of Prezista;
  • New dosing regimen for treatment-naïve patients;
  • New 400 mg tablets;
  • Revised Pregnancy Category.

On Oct. 21, 2008, the FDA granted traditional approval to darunavir 600 mg, co-administered with 100 mg ritonavir and with other antiretroviral agents, for the treatment of HIV-1 infection in treatment-experienced adult patients. Darunavir was granted accelerated approval on June 23, 2006, based on analysis of plasma HIV-1 RNA levels in two controlled studies of 24 weeks duration. The traditional approval is based on a 48 week phase 3 study (TMC114-C214) in treatment-experienced patients and continuation of two controlled trials of 96 weeks duration in clinically advanced, treatment-experienced patients, confirming durability of the virologic response.

In addition to the traditional approval, a new dosing regimen for treatment-naïve patients was approved. The recommended dose for treatment-naïve adult patients is darunavir 800 mg (two 400 mg tablets) taken with ritonavir 100 mg once daily, with food. The type of food does not affect exposure to darunavir.

The dosing regimen for treatment-experienced patients remains unchanged as darunavir 600 mg taken with ritonavir 100 mg twice daily, with food.

The dosing regimen in treatment-naïve patients was based on a randomized, controlled, open-label Phase 3 study (Study TMC114-C211) comparing darunavir/ritonavir 800/100 mg once daily versus lopinavir/ritonavir (Kaletra) 800/200 mg per day (given as twice daily or as once daily regimen). Both arms used a fixed background regimen consisting of tenofovir and emtricitabine. The proportion of patients who were virologic responders (HIV RNA < 50 copies/mL) was 84% for darunavir/ritonavir and 78% for lopinavir/ritonavir.

Additionally, the pregnancy category was changed from B to C (section 8.1). Additional details regarding the supportive animal data for the reproduction studies and juvenile toxicity studies are included. The section now reads:

Pregnancy Category C: Prezista should be used during pregnancy only if the potential benefit justifies the potential risk.

No adequate and well-controlled studies have been conducted in pregnant women. Reproduction studies conducted with darunavir showed no embryotoxicity or teratogenicity in mice, rats and rabbits. However, due to limited bioavailability and/or dosing limitations, animal exposures (based on AUC) were only 50% (mice and rats) and 5% (rabbit) of those obtained in humans at the recommended clinical dose boosted with ritonavir.

In the rat pre- and postnatal development study, a reduction in pup body weight gain was observed with darunavir alone or in combination with ritonavir during lactation. This was due to exposure of pups to drug substances via the milk. Sexual development, fertility and mating performance of offspring were not affected by maternal treatment with darunavir alone or in combination with ritonavir. The maximal plasma exposures achieved in rats were approximately 50% of those obtained in humans at the recommended clinical dose boosted with ritonavir.

In the juvenile toxicity study where rats were directly dosed with darunavir, deaths occurred from post-natal day 5 through 11 at plasma exposure levels ranging from 0.1 to 1.0 of the human exposure levels. In a 4-week rat toxicology study, when dosing initiated on post-natal day 23 (the human equivalent of 2 to 3 years of age), no deaths were observed with a plasma exposure (in combination with ritonavir) of 0.1 of the human plasma exposure levels.

Several other changes were made to the package insert and include the following major revisions. Additionally, the label was converted to Physician Labeling Rule (PLR) format to make product labeling more informative and applicable to clinicians.

Section 6: Adverse Reactions was updated to include safety data from studies TMC114-C211 and TMC114-C214. Additionally serious adverse drug reactions of at least moderate intensity during the Phase 2B and 3 studies were added to section 6.3.

Section 6.6 Postmarketing Experience includes rare events of hypersensitivity including facial edema and rhabdomyolysis associated with coadministration with HMG-CoA reductase inhibitors.

Section 7, Drug Interactions, Table 6: Established and Other Potentially Significant Drug Interactions was updated to include appropriate dosing of carbamazepine and rifabutin in combination with Prezista/ritonavir.