US FDA issues new safety information for tenofovir co-administration with ddI
13 November 2002. Related: Treatment alerts, Antiretrovirals.
Pharmacokinetic data demonstrate that co-administration of tenofovir (disoproxil fumarate, Viread) and ddI (didanosine, Videx) resulted in significant increases in ddI exposures; this information was included in the tenofovir label at the time it was initially approved.
Recently the results of an interaction study of tenofovir and ddI EC were submitted and reviewed. Based on this new study, it was concluded that the magnitude of the interaction between tenofovir and ddI was significant enough to warrant additional precautionary language to be included in both products’ labelling.
ddI 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 randomised to receive the following treatments in a random sequence: tenofovir 300 mg once daily for seven days, tenofovir 300 mg plus ddI Tabs 250mg (wt < 60 kg) or 400 mg (wt > 60 kg) once daily for seven days, ddI Tabs 250mg (wt < 60 kg) or 400 mg (wt > 60 kg) once daily for seven days with a seven -day washout between treatments. Tenofovir was administered one hour following ddI Tabs, and both were administered under fasted conditions. Samples for assessment of tenofovir and didanosine pharmacokinetics were collected frequently throughout the study period.
Pharmacokinetic results
The results demonstrated that tenofovir pharmacokinetics were not affected by co-administration of ddI Tabs. However, following co-administration, there were significant increases in ddI exposures.
Effects of tenofovir on ddI pharmacokinetics:
- DdI Tabs alone resulted in ddI Area Under the Curve (AUC) of 3560 ng*hr/mL and ddI maximum concentration (Cmax) of 2131 ng/mL.
- DdI Tabs + tenofovir resulted in a ddI AUC of 5167 (44% increase) and ddI Cmax of 2761 (28% increase).
DdI EC
Design
This was an open-label, fixed-sequence, drug-drug interaction, and drug-food interaction study conducted in 28 healthy volunteers. On day one, subjects received a single 400-mg dose of ddI EC following an overnight fast. On day two, 15 subjects were dosed with tenofovir 300 mg with a light meal. On day eight, subjects took another 400-mg dose of ddI EC two hours prior to tenofovir. On day nine, subjects received ddI EC and tenofovir simultaneously. Samples for assessment of tenofovir and ddI pharmacokinetics were collected frequently throughout the 15-day study period.
Pharmacokinetic results
The results demonstrated that ddI EC had no effect on the pharmacokinetics of tenofovir. However, either following simultaneous (fed) or staggered (fasted) administration, there were significant increases in ddI exposures.
Effects of tenofovir on ddI pharmacokinetics:
- DdI EC alone resulted in ddI AUC of 3160 ng*hr/mL, and ddI Cmax of 1050 ng/mL.
- DdI EC + tenofovir (simultaneous) resulted in ddI AUC of 4990 (* 60% increase) and ddI Cmax of 1720 (* 64% increase).
- DdI EC (two hours prior to tenofovir) resulted in ddI AUC of 4660 ng*hr/mL (* 48% increase) and ddI Cmax of 1560 (* 48% increase).
Based on the results of these two interaction studies, the ddI and tenofovir 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 ddI or its active metabolite (dideoxyadenosine 5′-triphosphate) is increased when ddI is co-administered with tenofovir. Increased exposure may cause or worsen ddI -related clinical toxicities, including pancreatitis, symptomatic hyperlactataemia/lactic acidosis, and peripheral neuropathy. Co-administration of tenofovir with ddI should be undertaken with caution, and patients should be monitored closely for ddI-related toxicities. DdI should be suspended if signs or symptoms of pancreatitis, symptomatic hyperlactataemia, or lactic acidosis develop.
This document was provided by the U.S. Food and Drug Administration.
Link:
http://www.fda.gov/