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For Consumers

New Safety Information -Viread co-administration with Videx

9/25/2002

Pharmacokinetic data demonstrate that co-administration of VIREAD (tenofovir disoproxil fumarate) and VIDEX (Didanosine, ddI) resulted in significant increases in didanosine exposures; this information was included in the VIREAD label at the time it was initially approved. Recently the results of an interaction study of VIREAD and VIDEX EC were submitted and reviewed. Based on this new study, it was concluded that the magnitude of the interaction between VIREAD and VIDEX was significant enough to warrant additional precautionary language to be included in both products' labeling.

VIDEX BUFFERED TABLETS

Design
This was a Phase I, open-label, multiple-dose, crossover, and drug interaction study. Eighteen otherwise healthy male and female subjects were randomized to receive the following treatments in a random sequence: VIREAD 300 mg once daily for 7 days, VIREAD 300 mg plus VIDEX TABS 250mg (wt < 60 kg) or 400 mg (wt > 60 kg) once daily for 7 days, VIDEX TABS 250mg (wt < 60 kg) or 400 mg (wt > 60 kg) once daily for 7 days with a 7-day washout between treatments. VIREAD was administered 1 hour following VIDEX TABS, and both were administered under fasted conditions. Samples for assessment of VIREAD and didanosine pharmacokinetics were collected frequently throughout the study period.

Pharmacokinetic Results
The results demonstrated that VIREAD pharmacokinetics were not affected by co-administration of VIDEX TABS. However, following co-administration, there were significant increases in didanosine exposures (see Table 1).

Table 1. Effects of VIREAD on didanosine pharmacokinetics

 didanosine AUC (ng*hr/mL)didanosine Cmax
(ng/mL)
VIDEX TABS alone35602131
VIDEX TABS+ VIREAD5167 (44%)2761 (28%)

VIDEX EC

Design
This was an open-label, fixed-sequence, drug-drug interaction, and drug-food interaction study conducted in 28 healthy volunteers. On day 1, subjects received a single 400-mg dose of VIDEX EC following an overnight fast. On days 2-15 subjects were dosed with VIREAD 300 mg with a light meal. On day 8, subjects took another 400-mg dose of VIDEX EC two hours prior to VIREAD. On day 9, subjects received VIDEX EC and VIREAD simultaneously. Samples for assessment of VIREAD and didanosine pharmacokinetics were collected frequently throughout the 15-day study period.

Pharmacokinetic Results
The results demonstrated that VIDEX EC had no effect on the pharmacokinetics of VIREAD. However, either following simultaneous (fed) or staggered (fasted) administration, there were significant increases in didanosine exposures (see Table 2).

Table 2. Effects of VIREAD on didanosine pharmacokinetics

 didanosine AUC (ng*hr/mL)didanosine Cmax
(ng/mL)
VIDEX EC alone31601050
VIDEX EC + TDF (simultaneous)4990 (60%)1720 (64%)
VIDEX EC
(2 hours prior to TDF)
4660 (48%)1560 (48%)

Based on the results of these two interaction studies, The VIDEX and VIREAD labels have been revised as follows:

The pharmacokinetic results of both interaction studies are being added.
The following precautionary language has been added:
Exposure to didanosine or its active metabolite (dideoxyadenosine 5-triphosphate) is increased when didanosine is co-administered with VIREAD. Increased exposure may cause or worsen didanosine-related clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic acidosis, and peripheral neuropathy. Co-administration of VIREAD with VIDEX should be undertaken with caution, and patients should be monitored closely for didanosine-related toxicities. VIDEX should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactatemia, or lactic acidosis develop (see WARNINGS).


Richard Klein
Office of Special Health Issues
Food and Drug Administration
 

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