FDA Nofifications

Generic stavudine and efavirenz are tentatively approved by FDA

On Feb. 29, 2008, the FDA granted tentative approval for two generic formulations of drugs used to treat HIV/AIDS. These are stavudine capsules, 15 mg, 20 mg, 30 mg, and 40 mg., and efavirenz tablets, 600 mg, all manufactured by Hetero Drugs Limited, Hyberdad, India.

They were tentatively approved for use in combination with other antiretrovirals in the treatment of HIV infection. The applications were reviewed under expedited review provisions for the President's Emergency Plan for AIDS Relief (PEPFAR)

"Tentative approval" means that FDA 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. because of existing patents and/or exclusivity rights. Tentative approval, however, does make the product eligible for consideration for purchase under the PEPFAR program.

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."

These tentative approvals are generic versions of Zerit (stavudine) capsules, a Nucleoside Reverse Transcriptase Inhibitor (NRTI), 15 mg, 20 mg, 30 mg, and 40 mg, and Sustiva (efavirenz) tablets, a Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI), 600 mg. Both Zerit and Sustiva are products of Bristol Myers Squibb.

As with all generic applications, FDA conducts an on-site inspection of each manufacturing facility and of the facilities performing the bioequivalence studies prior to granting approval or tentative approval to these applications to evaluate the ability of the manufacturer to produce a quality product and to assess the quality of the bioequivalence data supporting the application.

A list of all Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan (PEPFAR) is available on the FDA website at www.fda.gov.

Pediatric HIV infection guidelines for use of ARTs are revised

The Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection have been revised.

The new version includes updated information on:

- when to initiate therapy;

- change in treatment recommendations for when to initiate therapy in HIV-infected children less than 12 months of age;

- reduction from 4 to 3 age bands for recommendations on when to initiate therapy (less than 12 months, 1 to less than 5 years, and 5 years and older);

- changes in immunologic thresholds for when to start in children 1 year or older;

- timing of diagnostic testing in HIV-exposed infants.

- the pediatric drug appendix and hyperlink on drug preparations, new dosage formulations, and pediatric studies;

- recently approved antiretrovirals: maraviroc (including a new coreceptor tropism assay section), raltegravir, and etravirine

- revised antiretroviral toxicity hyperlink with new tables detailing toxicity management;

- changes are highlighted in yellow throughout the text and tables.

The updated guidelines are available for download from the Pediatric Guidelines section of the AIDSinfo Web site at http://www.aidsinfo.nih.gov/. You can also request to receive them by mail or email from the AIDSinfo Order Publications section.

New 600 mg tablet strength for darunavir is approved by FDA

On Feb. 25, 2008, the FDA approved a new 600 mg tablet strength for darunavir (Prezista), manufactured by Tibotec, Inc., Yardley, PA. The new 600 mg tablet facilitates dosing by reducing pill burden.

The recommended oral dose of darunavir tablets is 600 mg (two 300 mg tablets or one 600 mg tablet) twice daily taken with ritonavir 100 mg twice daily and with food.

The 600 mg formulation will be available in bottles of 60 tablets.

The 300 mg tablet will continue to be available.

Darunavir is a protease inhibitor, which inhibits the formation of mature virus in HIV infected cells.

Tibotec issues Dear Health Care Professional letter

Tibotec Therapeutics, in cooperation with the U.S. Food and Drug Administration, issued a Dear Healthcare Professional letter to relay important, updated prescribing information for darunavir (Prezista) tablets that includes a warning about Hepatotoxicity.

The letter provides, in addition to other information, the following, which has been added to the WARNINGS section of the Prezista label:

Hepatotoxicity — Drug-induced hepatitis (e.g., acute hepatitis, cytolytic hepatitis) has been reported with darunavir (Prezista/rtv). During the clinical development program (N=3063), hepatitis has been reported in 0.5% of patients receiving combination therapy with darunavir (Prezista/rtv). Patients with preexisting liver dysfunction, including chronic active hepatitis B or C, have an increased risk for liver function abnormalities including severe hepatic adverse events.

Postmarketing cases of liver injury, including some fatalities, have been reported. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications, having co-morbidities including hepatitis B or C co-infection, and/or developing immune reconstitution syndrome. A causal relationship with darunavir (Prezista/rtv) therapy has not been established.

Appropriate laboratory testing should be conducted prior to initiating therapy with darunavir (Prezista/rtv) and patients should be monitored during treatment. Increased AST/ALT monitoring should be considered in patients with underlying chronic hepatitis, cirrhosis, or in patients who have pretreatment elevations of transaminases, especially during the first several months of darunavir (Prezista/rtv) treatment.

If there is evidence of new or worsening liver dysfunction (including clinically significant elevation of liver enzymes and/or symptoms such as fatigue, anorexia, nausea, jaundice, dark urine, liver tenderness, hepatomegaly) in patients on darunavir (Prezista/rtv), interruption or discontinuation of treatment must be considered."

In addition, the Adverse Reaction section of the darunavir (Prezista) label and the Patient Package Insert have been updated to include this new information.

The letter, and the new label are available in pdf format from the Tibotec web site.