FDA Notifications

FDA tentatively approves generic atazanavir

On Feb. 4, 2008, the FDA granted tentative approval for a generic formulation of atazanavir sulfate capsules, 100 mg, 150 mg, and 200 mg, manufactured by Emcure Pharmaceuticals of Pune, India. The application was reviewed under expedited review provisions for the President's Emergency Plan for AIDS Relief (PEPFAR).

Indicated for the treatment of HIV infection in combination with other antiviral medications, atazanavir is a member of the protease inhibitor class of antiretroviral drugs.

As with all generic applications, the 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.

While tentatively approved generic products meet FDA-required standards, they cannot yet be fully approved for sale in the United States because of existing patent protections. However, tentative approval does make the product eligible for purchase under the PEPFAR program for treatment use in nations where PEPFAR is active.

This product is a generic formulation of Reyataz Capsules, 100 mg, 150 mg, and 200 mg, made by Bristol Myers Squibb Co. which remains subject to existing patents as listed in the agency's publication titled "Approved Drug Products with Therapeutic Equivalence Evaluations," also known as the "orange book."

Pediatric formulation of lamivudine approved

The FDA has approved a new formulation of Epivir (lamivudine) designed to facilitate dosing in appropriate pediatric patients who can reliably swallow tablets. Epivir is now available as 150 mg scored tablets. The scored tablets allow for dosing recommendations in pediatric patients. The DOSING AND ADMINISTRATION section of the Epivir label was revised as follows:

• Pediatric Patients

The recommended oral dose of EPIVIR Oral Solution in HIV-1-infected pediatric patients 3 months to 16 years of age is 4 mg/kg twice daily (up to a maximum of 150 mg twice a day), administered in combination with other antiretroviral agents.

EPIVIR is also available as a scored tablet for HIV-1-infected pediatric patients who weigh > 14 kg for whom a solid dosage form is appropriate. Before prescribing EPIVIR Tablets, children should be assessed for the ability to swallow tablets. If a child is unable to reliably swallow EPIVIR Tablets, the oral solution formulation should be prescribed. The recommended oral dosage of EPIVIR Tablets for HIV1-infected pediatric patients is presented in Table 1.

Epivir is a Nucleoside Reverse Transcriptase Inhibitor (NRTI) manufactured by GlaxoSmithKline.

Generic lamivudine tentatively approved

On Jan. 29, 2008, the FDA granted tentative approval for generic lamivudine tablets, 150 mg and 300 mg, manufactured by Hetero Drugs Limited, Hyderabad, India, for use in combination with other antiretrovirals in the treatment of HIV infection.

"Tentative Approval" means that the FDA has concluded that a drug product has met all required quality, safety and efficacy standards, even though it is not yet eligible to be marketed in the United States because of existing patents and/or exclusivity rights. However, this tentative approval does make the product eligible for consideration for purchase under the President's Emergency Plan for AIDS Relief (PEPFAR) program.

This is a generic version of Epivir, manufactured by GlaxoSmithKline, which is subject to existing 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"

As with all generic applications, the 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.

Changes to ART guidelines detailed by the FDA

The following changes have been made to several sections of the Dec. 1, 2007, version of the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents:

What to Start:

Initial Combination Regimens for the Antiretroviral-Naïve Patient?

The Panel revised its recommendations for several "preferred" and "alternative" antiretroviral components for treatment-naïve patients:

  • "Abacavir + lamivudine" has been changed from "alternative" to "preferred" 2-NRTI component in patients who have tested negative for HLA-B*5701 (AII).
  • "Zidovudine + lamivudine" has been changed from "preferred" to "alternative"
  • "Ritonavir-boosted saquinavir" has been changed from a PI-option that was considered as "Acceptable as initial antiretroviral components but inferior to preferred or alternative components" to an "alternative" PI component

The following options are no longer recommended as components for initial therapy in treatment-naïve patients:

  • Nelfinavir as PI component
  • Stavudine + lamivudine as 2-NRTI components
  • Abacavir + zidovudine + lamivudine as a triple-NRTI combination regimen!

A new topic entitled, "Other Treatment Options Under Investigation: Insufficient Data to Recommend" has been added, which includes a review of recent clinical trial data in treatment-naïve patients for ritonavir-boosted darunavir--based regimens, maraviroc-based regimens, and raltegravir-based regimens.

Treatment Interruption

This section has been updated with recent data on short-term and long-term treatment interruption. The Panel reaffirms our recommendation that aside from unplanned or planned short-term interruption due to illnesses precluding oral therapy or toxicities, long-term treatment interruption is not recommended unless in the context of a clinical trial (DI).

Acute HIV Infection

A new table on "Identifying, diagnosing, and managing acute HIV- 1 infection" has replaced the table on "Associated signs and symptoms of acute retroviral syndrome and percentage of expected frequency."

The Panel also recommends that since clinically significant resistance to PIs is less common than resistance to NNRTIs in antiretroviral-naïve persons who harbor drug resistant virus, if therapy is initiated before drug resistance test results are available, consideration should be given to using a PI-based regimen (BIII).

Mycobacterium Tuberculosis Disease or Latent Tuberculosis Infection with HIV Coinfection

This section has been updated with the following information:

  • Discussions and recommendations on the timing of initiation of antiretroviral therapy in patients with active tuberculosis (TB), with emphasis on the risks and benefits of concomitant therapy related to overlapping toxicities, drug interactions, CD4 cell counts, and potential for immune reconstitution inflammatory syndrome.
  • Recommendation for repeat testing to detect latent TB infection in persons who had CD4 count < 200 cells/mm3 and have tested negative prior to antiretroviral therapy and have improved CD4 count to > 200 cells/mm3 (BII).

Table Updates

Various tables have been updated to include information regarding etravirine, updates on various antiretroviral drugs, as well as new atazanavir dosing recommendations when used in combination with proton pump inhibitors or H2 receptor antagonists.

The following tables have been removed from the document:

  • "Antiretroviral components that are acceptable as initial antiretroviral components but are inferior to preferred or alternative components,"
  • "Treatment outcome of selected clinical trials of combination antiretroviral regimens in treatment-naïve patients with 48-week follow-up data."
  • The complete Jan. 29, 2008 version of the adult treatment guidelines is available on the aidsinfo web site at http://aidsinfo.nih.gov.

Changes will display highlighted in yellow.

FDA grants accelerated approval for etravirine

The FDA, on Jan. 18, 2008, granted accelerated approval for etravirine, 100 mg tablets, a non-nucleoside reverse transcriptase inhibitor (NNRTI), an antiviral drug that helps to block reverse transcriptase, an enzyme necessary for HIV virus replication. It is the first NNRTI to demonstrate antiviral activity in patients with NNRTI-resistant virus. Etravirine will be sold under the trade name Intelence.

Etravirine is indicated for use in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV -1) infection in antiretroviral treatment-experienced adult patients who have evidence of viral replication and HIV-1 strains resistant to a non-nucleoside reverse transcriptase inhibitor (NNRTI) and other antiretroviral agents.

Accelerated approval is a regulatory mechanism that allows earlier approval of drugs used to treat serious or life-threatening conditions, based on surrogate endpoints that demonstrate meaningful therapeutic advantage over existing treatment. Accelerated approval is based on evidence of a drug's effect on a surrogate endpoint that reasonably suggests clinical benefit. Accelerated approval requires any necessary studies to establish and define the degree of clinical benefit to patients be completed before traditional approval can be granted.

FDA granted this accelerated approval based on 24 week viral load and CD4 data from 1,203 adults in two randomized, double-blind, placebo-controlled trials (DUET-1 and -2 studies) conducted in clinically advanced, antiretroviral treatment-experienced adults with evidence of resistance to NNRTI(s) and protease inhibitors (PIs). The studies compared 599 patients receiving etravirine 200 mg twice daily plus optimized background regimen with 604 patients receiving optimized background regimen plus placebo. All patients received darunavir/rtv (DRV/rtv) as part of their optimized background regimen.

The 24 week pooled analysis of the DUET studies showed significantly more patients in the etravirine arm as compared to the placebo arm achieved undetectable viral load (less than 50 copies/mL); 59.8 percent vs. 40.2 percent (P < 0.0001), and significantly greater mean increase in CD4+ cell count from baseline of 81 vs. 64 cells/mm3 (P < 0.0022).

The most common adverse events reported were rash (16.9 percent) and nausea (13.9 percent).

In general, rash was mild-to-moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1-2 weeks on continued therapy. Patients developing a rash while taking etravirine should contact their doctor.

Rare cases of serious skin reactions such as Stevens-Johnson syndrome and erythema multiforme have been reported. Treatment with etravirine should be discontinued if severe rash develops.

Elevations in total cholesterol and low density lipoprotein (LDL) and initiation of lipid lowering therapy were more common in etravirine-treated subjects compared with those in the placebo arm.

Etravirine should be used with caution in patients with severe hepatic impairment (Child-Pugh class C) as pharmacokinetics of etravirine have not been studied in these patients.

To avoid drug interactions, patients starting etravirine treatment should tell their doctors about all the medications they take. Information about drug interactions is contained in the etravirine package insert.

The long-term effects of etravirine are not known, and its safety and effectiveness in children ages 16 years and younger has not been studied.

Etravirine also has not been studied in pregnant women. Women who are taking HIV medications when they get pregnant are advised to consult their physician or other health care professional about use of etravirine during pregnancy and about registering with the Antiviral Pregnancy Registry.

Copies of the product label and patient information are attached in pdf format.

Etravirine is distributed by Tibotec Therapeutics, Bridgewater, N.J., a division of Ortho Biotech Products, L.P.

Revised atazanavir package insert

The Reyataz (atazanavir) package insert was revised to include information regarding the administration of atazanavir and/or atazanavir/ritonavir with food, proton pump inhibitors, H2 receptor antagonists, acetaminophen, and fluconazole. Additionally, dosing information in patients with renal impairment was included.

Please refer to www.fda.gov for complete labeling. Below are highlight of the major recent changes.

The Dosage and Administration section and Precautions: Drug Interaction Table 11 were updated to include drug interaction information regarding the use of Reyataz and proton pump inhibitors and H2-Receptor antagonists.

The dose recommendations for therapy-naïve patients receiving H2-receptor antagonists or proton pump inhibitors are the following:

  • H2-receptor antagonist: The H2-receptor antagonist dose should not exceed a 40 mg dose equivalent of famotidine twice daily. Reyataz 300 mg and ritonavir 100 mg should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
  • proton-pump inhibitors: The proton-pump inhibitor dose should not exceed a 20 mg dose equivalent of omeprazole and must be taken approximately 12 hours prior to the Reyataz 300 mg and ritonavir 100 mg dose.

The dose recommendations for therapy-experienced patients receiving H2-receptor antagonists or proton pump inhibitors are the following:

  • Whenever an H2-receptor antagonist is given to a patient receiving Reyataz with ritonavir, the H2-receptor antagonist dose should not exceed a dose equivalent to famotidine 20 mg twice daily, and the Reyataz and ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2-receptor antagonist.
  • Reyataz 300 mg (one 300-mg capsule or two 150-mg capsules) with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2-receptor antagonist.
  • Reyataz 400 mg (two 200-mg capsules) with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir and an H2-receptor antagonist.
  • Proton-pump inhibitors should not be used in treatment-experienced patients receiving Reyataz.

In addition, the Dosage and Administration section was updated to provide dosing information in patients with renal impairment as follows:

  • For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for Reyataz. Treatment-naive patients with end stage renal disease managed with hemodialysis should receive Reyataz 300 mg with ritonavir 100 mg. Reyataz should not be administered to HIV-treatment experienced patients with end stage renal disease managed with hemodialysis.

No dose adjustments are needed when Reyataz is co-administered with acetaminophen or fluconazole.

The Clinical Pharmacology section was updated to include the following information:

  • results of a food effect study with Reyataz 300 mg with ritonavir 100 mg with a light meal and high fat meal (see Clinical Pharmacology: Food Effect).
  • results of a study in adult subjects with severe renal impairment, including those on hemodialysis is presented (see Clinical Pharmacology: Special Populations: Impaired Renal Function).
  • results of drug-drug interaction studies with acetaminophen famotidine, fluconazole, and omeprazole (See Clinical Pharmacology: Table 4: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of C administered Drugs and Table 5: : Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Reyataz.