FDA Notifications

Maraviroc approved as a CCR5 co-receptor antagonist

On August 6, 2007, the FDA approved maraviroc (Selzentry) 150 mg and 300 mg tablets, a CCR5 co-receptor antagonist used in combination with other antiretroviral products for the treatment of adults infected with CCR5-tropic HIV-1.

Maraviroc received a priority review by the FDA, and is the first drug approved in the new class of anti-HIV medications called CCR5 co-receptor antagonists.

Rather than fighting HIV inside white blood cells, like most antiretrovirals used to treat infection with HIV, maraviroc prevents the virus from entering uninfected cells by blocking the predominant route of entry, the CCR5 co-receptor, and a protein on the surface of immune cells affected by HIV. Among patients who have previously received HIV medications, approximately 50 percent to 60 percent have circulating CCR5-tropic HIV.

Maraviroc, in combination with other antiretroviral agents, is indicated for treatment-experienced adult patients infected only with CCR5-tropic HIV-1 detectable virus, who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

The approval of maraviroc is based on analyses of plasma HIV-1 RNA levels in two controlled studies, each of 24-week duration, with over 1000 clinical trial participants, of which 840 received maraviroc. Both studies were conducted in clinically advanced, 3-class antiretroviral (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitor, protease inhibitors or fusion inhibitor, specifically enfuvirtide) treatment-experienced adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy.

The following points should be considered when initiating therapy with maraviroc:

  • Tropism testing and treatment history should guide the use of maraviroc.
  • Use of maraviroc is not recommended in patients with dual/mixed or CXCR4-tropic HIV-1, as efficacy was not demonstrated in a phase II study of this patient group.
  • The safety and efficacy of maraviroc have not been established in treatment-naïve adult patients or pediatric patients.

The recommended dose of maraviroc differs based on concomitant medications due to drug interactions (see attached pdf label, Section 2, Dosage and Administration). Maraviroc can be taken with or without food.

The product label includes a boxed warning about liver toxicity (hepatoxicity) and a statement in the Warnings/Precautions section about the possibility of increased risk for cardiovascular events such as heart attack or symptomatic postural hypotension (dizziness upon quickly standing). The most common adverse events reported with maraviroc were cough, fever, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness.

Maraviroc has not been tested or studied in pregnant women. The FDA recommends HIV- positive women should not breast feed, whether or not they are on antiretroviral medications.

Maraviroc is distributed by Pfizer Inc., of New York and is available as 150 mg or 300 mg tablets.

FDA revises Baraclude labeling for HIV patients

The FDA approved revised labeling on July 24, 2007, for entecavir (Baraclude) 0.5 mg and 1.0 mg Film-Coated Tablets, and entecavir 0.05 mg/mL oral solution for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases or histologically-active disease. The amended label includes safety information related to the use of entecavir in patients with human immunodeficiency virus (HIV)/hepatitis B virus (HBV) coinfection who are not receiving simultaneous highly active antiretroviral therapy (HAART). Specifically, a recommendation against the use of entecavir in HIV/HBV co-infected patients who are not also receiving adequate therapy for their HIV were added to the Boxed Warnings and the "warnings" sections of the label. Corresponding changes were made to precautions: Information for Patients section, and in the Patient Information (also referred to as the Patient Package Insert).

Added to the Boxed Warning: "Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if Baraclude is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. Therapy with Baraclude is not recommended for HIV/HBV co-infected patients who are not also receiving HAART). See WARNINGS: Co-infection with HIV."

Added to "warnings" section: "Co-infection with HIV: Baraclude has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment. Limited clinical experience suggests there is a potential for the development to resistance HIV nucleoside reverse transcriptase inhibitors if Baraclude is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. (see Microbiology: Antiviral Activity, Antiviral Activity against HIV). Therefore, therapy with Baraclude is not recommended for HIV/HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART). Before initiating Baraclude therapy, HIV antibody testing should be offered to all patients. Baraclude has not been studied as a treatment for HIV infection and is not recommended for this use."

Added to Precautions/Information for Patients: "Patients should be offered HIV antibody testing before starting Baraclude therapy. They should be informed that if they have HIV infection and are not receiving effective HIV treatment, Baraclude may increase the chance of HIV resistance to HIV medication (see Warnings: Co-infection with HIV).

Added to Patient Information: "If you have or get HIV (human immunodeficiency virus) infection be sure to discuss your treatment with your doctor. If you are taking Baraclude to treat chronic hepatitis B and are not taking medicines for your HIV at the same time, some HIV treatments that you take in the future may be less likely to work. You are advised to get an HIV test before you start taking Baraclude and anytime after that when there is a chance you were exposed to HIV. Baraclude will not help your HIV infection."

FDA grants tentative approval of efavirenz

The FDA granted tentative approval on July 12, 2007, for a generic formulation of efavirenz tablets, 600 mg, manufactured by Matrix Laboratories Limited, of Hyderabad, India, under expedited review provisions developed for the President's Emergency Plan for AIDS Relief (PEPFAR).

This is a generic formulation of already approved Sustiva tablets, 600 mg, made by Bristol Myers-Squibb, which is protected by existing patent rights.

"Tentative Approval" means that FDA has concluded that a drug product has met all required quality, safety and efficacy standards, but because of existing patents and/or exclusivity rights, it cannot yet be marketed in the United States. Effective patent dates are listed in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book."

Tentative approval does, however, make the product eligible for consideration for purchase under the PEPFAR program for use outside the United States.

As with all generic applications submitted to the agency, 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 evaluate the ability of the manufacturer to produce a quality product, and to assess the quality of the bioequivalence data supporting the application.

Nevirapine is a Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI) indicated for treatment of HIV infection in combination with other antiretroviral agents.

Tentative approval granted of generic nevirapine

The FDA granted tentative approval on July 10, 2007, for a generic formulation of nevirapine tablets, 200 mg, manufactured by Zhejiang Huahai Pharmaceutical Co. Ltd. of Zhejiang China, under expedited review provisions developed 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, even though it may not yet be marketed in the U.S. because of existing patents and/or exclusivity rights. However, tentative approval does make the product eligible for consideration for purchase under 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 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.

This is a generic formulation of the already approved Viramune tablets, 200 mg, made by Boehringer Ingelheim, which is protected by existing patent and pediatric exclusivity rights. Effective patent dates are listed in the agency's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book."

Nevirapine is a Nonnucleoside Reverse Transcriptase Inhibitors (NNRTI) indicated for treatment of HIV infection in adults and adolescents in combination with other antiretroviral agents.