FDA and Roche has notified about an important drug interaction warning which advises prescribers that rifampin should not be administered to patients also receiving saquinavir/ritonavir (ritonavir boosted saquinavir) as part of combination antiretroviral therapy (ART) for HIV infection.

In a Phase I,randomized,open-label,multiple-dose clinical pharmacology study in healthy volunteers,11/28 (39.3%) subjects exposed to rifampin 600 mg once daily taken together with ritonavir 100 mg / saquinavir 1000 mg given twice daily (ritonavir boosted saquinavir) developed significant hepatocellular toxicity during the 28 day study period.

Among these subjects, transaminase elevations of up to more than 20 times upper limit of normal values were noted and one subject was admitted to the hospital with marked transaminase elevations.For all study participants, dosing of all study medications was immediately terminated and the study was discontinued.Following drug discontinuation,liver function tests in all affected subjects are returning to normal, clinical symptoms have abated and no deaths from this clinical study have been reported.

The current package inserts for both saquinavir mesylate capsules and tablets and saquinavir soft gelatin capsules contraindicate the use of rifampin together with saquinavir.This contraindication is based on a pharmacokinetic interaction between rifampin and saquinavir that results in reduced saquinavir plasma levels.The clinical pharmacology study reported above was undertaken to determine if boosting of saquinavir with ritonavir would overcome the interaction.However, as a result of the high incidence of hepatotoxicity in this study,
Roche now advises prescribers that:

Rifampin SHOULD NOT be administered to patients also receiving saquinavir/ritonavir (ritonavir boosted saquinavir) as part of combination antiretroviral therapy (ART) for HIV infection.

Roche is collaborating closely with the U.S. FDA (Food and Drug Administration) on this issue, and appropriate changes to the package insert will be made as soon as possible.