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FDA tentatively approves generic efavirenz
On March 26, 2007, FDA granted tentative approval for a generic drug formulation of efavirenz tablets (600 mg), manufactured by Strides Acrolab Ltd., Bangalore, India, under the expedited review provisions created by FDA for the President's Emergency Plan for AIDS Relief (PEPFAR).
The tentatively approved product is a generic version of the nonnucleoside reverse transcriptase inhibitor (NNRTI), Sustiva Tablets, 600 mg, for use in combination with other antiretroviral agents in the treatment of HIV infection. Sustiva, manufactured by Bristol Myers Squibb Co., is currently subject to patent protection.
FDA's tentative approval of this product means that although existing patents and/or exclusivities prevent marketing of this product in the United States, the product has been shown to meet all of FDA's safety, efficacy, and manufacturing quality standards required for marketing in the U.S., and thus qualifies for consideration for purchase under the PEPFAR program for use in qualifying countries.
A complete list of approved and tentatively approved antiretroviral drugs associated with PEPFAR is available at http://www.fda.gov/oia/pepfar.htm.
FDA tentatively approves generic lamivudine
The FDA granted tentative approval on March 19, 2007 for a generic formulation of lamivudine tablets (150 mg), manufactured by Matrix Laboratories, Inc., of Hyderabad, India, under expedited review provisions developed for the President's Emergency Plan for AIDS Relief (PEPFAR). Final approval cannot be granted at this time because the reference drug product, Epivir Tablets, a product of GlaxoSmithKline, is currently subject to patent protection.
Lamivudine is indicated for use in combination with other antiretroviral agents for the treatment of HIV infection.
FDA grants tentative approval to two ART drugs under expedited review
On March 13, 2007, FDA granted tentative approval for two applications for antiretroviral drugs products made by Strides Acrolab Ltd., Bangalore, India, under the expedited review provisions created by FDA for the President's Emergency Plan for AIDS Relief (PEPFAR).
The first is a fixed dose combination of stavudine/lamivudine (40 mg/150 mg) tablets, co-packaged with nevirapine tablets (200 mg) for use in HIV-1 treatment.
The second is a fixed dose combination of stavudine/lamivudine (40 mg/150 mg) tablets for use in HIV-1 treatment in combination with other antiretroviral drugs.
These products represent drug combinations that can significantly decrease pill burden and could result in improved compliance for HIV-infected individuals.
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.
FDA issues public health advisory about ESAs
The FDA has issued a public health advisory outlining new safety information, including revised product labeling about erythropoiesis-stimulating agents (ESAs), widely used drugs for the treatment of anemia in a variety of conditions, including anemia due to zidovudine therapy in HIV patients.
The drugs affected by the safety update are darbepoetin alfa (Aranesp) and epoetin alfa (Epogen and Procrit). (ESAs are genetically engineered forms of the naturally occurring human protein, erythropoietin. Natural erythropoietin is made by the kidney and increases the number of red blood cells).
FDA and the manufacturer of these products have agreed on revised product labeling that includes updated warnings, a new black box warning, and modifications to the dosing instructions. The new black box warning advises physicians to monitor red blood cell levels (hemoglobin) and to adjust the ESA dose to maintain the lowest hemoglobin level needed to avoid the need for blood transfusions. Physicians and patients should carefully weigh the risks of ESAs against transfusion risks.
Recently completed studies describe an increased risk of death, blood clots, strokes, and heart attacks in patients with chronic kidney failure when ESAs were given at higher than recommended doses. In other studies, more rapid tumor growth occurred in patients with head and neck cancer who received these higher doses.
In studies where ESAs were given at recommended doses, an increased risk of death was reported in patients with cancer who were not receiving chemotherapy and an increased risk of blood clots was observed in patients following orthopedic surgery.
"The agency is in the process of re-evaluating the safety of Aranesp, Epogen, and Procrit on the basis of the results of recent clinical studies," said Steven Galson, MD, director of FDA's Center for Drug Evaluation and Research. "The new studies provide significant new information for both prescribers and patients, and the new information applies to all ESAs, which share the same mechanism of action. The safety of these products will be discussed when the Oncologic Drugs Advisory Committee (ODAC) meets in May and further revisions to the labeling may occur after that meeting."
Safety concerns from earlier ESA studies were discussed during a 2004 meeting of the ODAC. Product labeling was previously revised in 1997, 2004, and 2005 to reflect new safety information.
The three drugs are approved to treat anemia in patients with chronic kidney failure and in patients with cancer whose anemia is caused by chemotherapy. Epogen and Procrit are approved for patients scheduled for major surgery to reduce potential blood transfusions and for the treatment of anemia due to zidovudine therapy in HIV patients. ESAs are not approved to treat the symptoms of anemia – including fatigue – in cancer patients, surgical patients, or those with HIV.
All three drugs are manufactured by Amgen, Inc., of Thousand Oaks, California. Procrit is marketed and distributed by Ortho Biotech LP, a subsidiary of Johnson & Johnson.
FDA grants approval for generic didanosine for oral solution
On March 8, 2007, the FDA granted approval for generic didanosine for oral solution (Pediatric Powder), 10 mg/mL, packaged in 2-gram and 4-gram containers, manufactured by Aurobindo Pharma Limited, of Hyderabad, India, allowing marketing in United States.
This is a generic version of the already FDA-approved Videx Pediatric Powder for Oral Solution, 10 mg/mL, manufactured by Bristol Myers Squibb.
FDA granted tentative approval for this product on Oct. 5, 2006, permitting purchase of this generic formulation of didanosine by the President's Emergency Plan for AIDS Relief, or PEPFAR. A tentative approval means that a drug product has met FDA's safety, efficacy and quality standards, but is ineligible for marketing in the U.S. until patent and/or exclusivity restrictions expire.
However, because patents and exclusivity for Videx For Oral Solution have expired (see FDA's publication titled Approved Drug Products with Therapeutic Equivalence Evaluations, also known as the "Orange Book"), the generic formulation can be granted approval, allowing it to be marketed in the United States.
Didanosine for oral solution is approved for use in combination with other antiretroviral agents in the treatment of HIV infection.
The PEPFAR program was created to provide government funding to treat, and reduce transmission of HIV in 15 focus countries, mostly in Sub-Saharan Africa, but including Haiti, Guyana, and Vietnam.
Because drugs that do not conform to standards of potency, purity, stability, or good manufacturing procedures may pose a threat by increasing chance of substandard performance, treatment failure, and emergence of resistant virus, PEPFAR limits funding to acquire only products that have undergone stringent regulatory review.
While FDA does not approve drugs for use in other countries, the agency has expedited review procedures in place (and conducts inspections of the manufacture and testing sites) to determine whether the drug products meet FDA safety, efficacy, and manufacturing quality standards, thus making them eligible for purchase using PEPFAR funds.
When the determination is made that a product meets the required criteria and standards, FDA may issue a "tentative approval," even though the product cannot yet be marketed in the U.S. because of legal restrictions related to existing exclusivity rights held by the original drug manufacturer. Once marketing exclusivities expire, FDA can grant marketing approval of the generic formulation in the U.S. market.
Since the time didanosine for oral solution received a tentative approval in October, 2006, allowing it to be purchased through PEPFAR (for use in PEPFAR-affected countries), expiration of patents has resulted in an approval that now allows marketing of this generic formulation of didanosine for oral solution in the United States.