FDA recently approved new labeling for 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.
4 Contraindications
These recommendations are based on either drug interaction studies or observed clinical toxicities.
4.1 Allopurinol
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)].
4.2 Ribavirin
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:
1. 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.
2. 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 the 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 VIDEX EC 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 coadminister 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.
The comment that didanosine pediatric powder and methadone should not be coadministered is based on the following:
a) The formulation characteristics for the pediatric powder and the buffered tablet are similar.
b) The buffered tablets demonstrated significant decreases in didanosine exposure [Cmax and AUC(0-inf)] which were greater than the decreases in didanosine
exposure observed with the enteric coated capsules.
Videx is a Nucleoside Reverse Transcriptase Inhibitor (NRTI) manufactured by Bristol Myers-Squibb.
Richard Klein
Office of Special Health Issues
Food and Drug Administration
Kimberly Struble
Division of Antiviral Drug Products
Food and Drug Administration
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