Drug-induced hepatitis in healthy volunteers receiving rifampicin 600mg daily in combination with ritonavir 100mg and saquinavir 1000mg twice daily (boosted saquinavir)
18 April 2005. Related: Treatment alerts.
Roche Laboratories issued a “Dear Health Care Provider” letter to ID/GUM and HIV physicians, nurses and pharmacists to communicate an important drug interaction warning for saquinavir/ritonavir, used as part of combination therapy for treatment of HIV infection.
Roche has been conducting PK studies into the interactions of boosted saquinavir. One of these studies looking at the interaction of boosted saquinavir with rifampicin, produced the adverse side effect below.
In this PK study in healthy volunteers, 11/28 (39.3%) subjects exposed to rifampicin 600 mg daily taken together with ritonavir 100 mg and saquinavir 1000 mg given twice daily (ritonavir boosted saquinavir) developed significant hepatocellular toxicity. One subject was admitted to hospital with mild liver failure. Dosing was immediately interrupted and the study discontinued immediately. Liver function tests in all affected subjects are returning to normal following drugs discontinuation.
As a result of these findings, Roche advises that Rifampicin SHOULD NOT be used in patients also receiving saquinavir/ritonavir as part of combination antiretroviral therapy (ART). This affects all formulations of saquinavir (Fortovase, Invirase 200mg and Invirase 500mg).
Roche advises that patients currently taking rifampicin with boosted saquinavir should contact their healthcare professional for advice. The combination of rifampicin with unboosted saquinavir is already contraindicated as rifampicin is a known inducer of CYP 3A4 and accelerates the metabolism of saquinavir, leading to sub therapeutic saquinavir levels. The new findings however result in a contraindication for the combined use of rifampicin with saquinavir and ritonavir, because of hepatotoxicity. This finding is unlikely to have a large impact on clinical practice within the UK.
For further information in the UK contact Dr Cham Herath Medical Advisor HIV on 01707 367515 or Roche Drug Information on 0800 3281629.
Source: FDA listserve