FDA Notifications
Raltegravir indication extended for treatment-naïve patients
On July 8, 2009, FDA granted approval to raltegravir (ISENTRESS) for the treatment of HIV-1 infection in treatment-naïve patients. An integrase inhibitor made by Merck & Co, the recommended dose for treatment-naïve adult patients is raltegravir 400 mg twice daily, with or without food.
The use of raltegravir in treatment-naïve patients is based on a 48-week randomized, double-blind, active control trial to evaluate the safety and efficacy of raltegravir 400 mg twice daily + emtricitabine + tenofovir versus efavirenz 600 mg + emtricitabine + tenofovir. The proportion of patients with HIV RNA < 50 copies/mL was 87% for the raltegravir group compared to 82% for the efavirenz group. The difference between raltegravir and efavirenz with respect to HIV RNA < 50 copies/mL and the 95% confidence intervals is 4.7% (-1.3%, 10.6%).
Several other changes were made to the package insert and include the following major revisions:
A drug interactions heading was included along with a warning about use with UGT (UDP-glucuronosyltransferases) inducers other than rifampin, specifically, "Coadministration of raltegravir with drugs that are strong inducers of UGT1A1 may result in reduced plasma concentrations of raltegravir"
Indications and usage was changed to incorporate use in treatment-naïve patients: "Raltegravir is indicated in combination with other anti-retroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients. This indication is based on analyses of plasma HIV-1 RNA levels up through 48 weeks in three double-blind controlled studies of raltegravir. Two of these studies were conducted in clinically advanced, 3-class antiretroviral (NNRTI, NRTI, PI) treatment-experienced adults and one was conducted in treatment-naïve adults. The use of other active agents with raltegravir is associated with a greater likelihood of treatment response."
- Section 6.1: Clinical trials experience, treatment-naive studies: This section now includes 48-week safety and laboratory data from Protocol 021.
- Section 6.2: Postmarketing experience: addition of paranoia and anxiety.
- Section 7.1 Effect of raltegravir on the pharmacokinetics of other agents adds information for CYP1A2, CYP2B6 and methadone.
- Section 12.4 Microbiology was updated to include the following headings and information: Antiviral Activity in Cell Culture
In addition, 5 clinical isolates of HIV-1 subtype B had EC95 values ranging from 9 to 19 nM in cultures of mitogen-activated human peripheral blood mononuclear cells.
Resistance: Treatment-naïve subjects: By Week 48 in the STARTMRK trial, the primary raltegravir resistance-associated substitutions were observed in 3 (1 with Y143R and 2 with Q148H/R) of the 6 virologic failure subjects with evaluable paired genotypic data.
Tentative approval for lamivudine
On June 22, 2009, FDA granted tentative approval for lamivudine tablets, 150 mg and 300 mg, manufactured by Matrix Laboratories Ltd of Hyberdad, India, for use in combination with other antiretrovirals in the treatment of HIV-1 infection in adults. The application was reviewed under expedited review provisions for the President's Emergency Plan for AIDS Relief (PEPFAR).
The FDA originally granted tentative approval for the Matrix Laboratories formulation of lamivudine 150 mg on March 19, 2007. The current tentative approval adds lamivudine tablets 300 mg, and also addresses scoring issues associated with the 150 mg tablet.
"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 patent protections applied to Epivir Tablets, 150 mg and 300 mg, made by GlaxoSmithKline,. Tentative approval does, however, make the product eligible for consideration for purchase outside the United States under the PEPFAR program.
Effective patent dates for all approved drugs 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, 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 Approved and Tentatively Approved Antiretrovirals in Association with the President's Emergency Plan is available on the FDA website.
New labeling for Videx pediatric powder
The FDA recently approved new labeling for didanosine (Videx pediatric powder and Videx EC capsules). The revisions to the Dosage and Administration, Contraindications, Warnings and Precautions, and Drug Interactions sections in both package inserts are outlined below. Other minor changes to the package inserts were made for consistency. In addition the Videx pediatric powder package insert was converted to Physician Labeling Rule (PLR) format.
Summary of Revisions:
I. Section 2.3 Dosage Adjustment was modified to remove statements for dose reductions for adverse events such as pancreatitis or peripheral neuropathy. Dose reductions for didanosine other than for weight have not been established.
In the Videx pediatric powder package insert, Section 2.3 Dosage Adjustment was revised to state that no didanosine dosage adjustment is required with hepatic impairment. This information has already been incorporated into the package insert for Videx EC capsules.
II. Two contraindications were added to both package inserts as shown below. The changes reflect re-interpretation of previously known drug information in the current setting of HIV infection and available antiretroviral therapy. The rational for the change are summarized below.
These recommendations are based on either drug interaction studies or observed clinical toxicities.
Coadministration of didanosine and allopurinol is contraindicated because systemic exposures of didanosine are increased, which may increase didanosine-associated toxicity [see Clinical Pharmacology (12.3)].
Coadministration of didanosine and ribavirin is contraindicated because exposures of the active metabolite of didanosine (dideoxyadenosine 5'-triphosphate) are increased. Fatal hepatic failure, as well as peripheral neuropathy, pancreatitis, and symptomatic hyperlactatemia/lactic acidosis have been reported in patients receiving both didanosine and ribavirin.
Rationale: Contraindicating Use of Didanosine with Allopurinol:
Previously the coadministration of didanosine and allopurinol was 'not recommended', however, the potential for didanosine toxicity was re-evaluated in the current context of other available NRTIs and other available drugs for gout therapy. Coadministration of allopurinol with didanosine increases didanosine AUC by 113% and Cmax by 69% in healthy subjects. Contraindicating administration of didanosine with allopurinol is recommended based on the increase potential for didanosine-associated toxicity due to increase in didanosine levels.
Contraindicating Use of Didanosine with Ribavirin:
Previously the combination of didanosine and ribavirin was 'not recommended' due to serious adverse events including fatal hepatic failure. Given availability of other NRTIs and the concern for potential didanosine-induced hepatotoxicity in patients with underlying liver disease (those receiving ribavirin as part of Hepatitis C treatment), the coadministration of ribavirin and didanosine is now contraindicated.
III. Hyperuricemia was removed from Warnings and Precautions section of the package inserts.
A review of postmarketing cases indicated hyperuricemia was listed along with multiple medical issues reported, usually in the context of serious conditions like lactic acidosis, hypersensitivity, general advancement of AIDS. A few cases of only gout were identified; none of the cases were compelling.
IV. Section 7 Drug Interactions was updated to provide information regarding drug-drug interactions with ganciclovir and methadone, as presented below.
A dosing recommendation for administration of nelfinavir with didanosine was added to the enteric coated capsule package insert. This information is already included in the pediatric powder package insert.
The clinical comment for ganciclovir was revised to state: If there is no suitable alternative to ganciclovir, then use in combination with didanosine with caution. Monitor for didanosine-associated toxicity.
The rationale for this change includes the following: Coadministration of didanosine with ganciclovir increases didanosine AUC by 111% (data for didanosine Cmax is not available). A similar magnitude of increase in didanosine levels is noted with both allopurinol (increase in AUC of 113% and Cmax of 69%) and ganciclovir, and consideration was given to contraindicating concomitant use of didanosine and ganciclovir. Use of didanosine with ganciclovir is not contraindicated for the following reason: ganciclovir is used for treatment of serious and life-threatening CMV infection and in certain clinical scenarios ganciclovir may be the only agent available for treatment of CMV infection. Therefore, in contrast to allopurinol, concurrent administration of didanosine with ganciclovir is allowed when no suitable alternative to ganciclovir is available and with monitoring for didanosine toxicity.
Information regarding methadone was also included as follows: Do not co-administer methadone with Videx pediatric powder due to significant decreases in didanosine concentrations. If coadministration of methadone and didanosine is necessary, the recommended formulation of didanosine is Videx EC. Patients should be closely monitored for adequate clinical response when Videx EC is coadministered with methadone, including monitoring for changes in HIV RNA viral load.
The rationale for this recommendation is as follows: An analysis evaluated methadone's effect on didanosine exposure which was separately evaluated for the enteric coated capsules and buffered tablets compared to combined or pooled historical pharmacokinetic data from healthy subjects. The results indicated that while the average didanosine exposure was decreased less than 20% for both Cmax and AUC(0-inf) with the enteric coated capsules, greater decreases in didanosine exposure were observed with the buffered tablets. The buffered tablet average Cmax and AUC(0-inf) decreased by approximately 40% and 30%, respectively.
The clinical relevance of the observed decrease in didanosine AUC and Cmax for both formulations are unknown. In the absence of exposure-response data, it can not be determined whether the decreases in didanosine exposure require a dosage adjustment for didanosine with concurrent administration of methadone.
Videx is a Nucleoside Reverse Transcriptase Inhibitor (NRTI) manufactured by Bristol Myers-Squibb.
On July 8, 2009, FDA granted approval to raltegravir (ISENTRESS) for the treatment of HIV-1 infection in treatment-naïve patients. An integrase inhibitor made by Merck & Co, the recommended dose for treatment-naïve adult patients is raltegravir 400 mg twice daily, with or without food.Subscribe Now for Access
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