Coadministration of clopidogrel and ritonavir-boosted regimens has been evaluated in clinical studies. Clopidogrel is a prodrug and is converted to its active metabolite via CYPs 3A4, 2B6, 2C19 and 1A2. The interaction between clopidogrel (300 mg loading dose followed by 75 mg once daily) and ritonavir (100 mg twice daily) was investigated in 12 HCV-negative subjects in the presence of dasabuvir (250 mg single dose). The AUC and Cmax of clopidogrel’s active metabolite decreased by 51% and 48% in the presence of ritonavir, with the average inhibition of platelet aggregation decreasing from 51% in the clopidogrel/dasabuvir phase to 31% in the clopidogrel/dasabuvir/ritonavir phase. In HIV-positive subjects, the presence of a pharmacoenhancer (ritonavir n=8; cobicistat n=1) decreased the AUC and Cmax of clopidogrel’s active metabolite both by 69% when compared to values obtained in HIV-negative subjects (n=12). Subjects showed a comparable decrease in prasugrel’s active metabolite AUC (52% decrease), however this decrease did not impair prasugrel’s antiplatelet effect. Given the risk of diminished clopidogrel response, prasugrel should be preferred in presence of ritonavir-boosted regimens, unless the patient has a clinical condition which contraindicates its use in which case an alternative antiplatelet agent should be considered. [Note, the European SmPC for clopidogrel contraindicates its use in severe hepatic impairment but the US Prescribing Information states no dose alteration.]

Coadministration with Viekirax alone has not been studied but a similar effect to that with Viekirax + dasabuvir is expected due to inhibition of CYP3A4 by ritonavir. Coadministration of amlodipine (5 mg single dose) with Viekirax + dasabuvir increased amlodipine AUC by 2.57-fold, with no change in ombitasvir AUC and a 22% decrease in paritaprevir AUC. Decrease amlodipine dose by 50%. Caution is warranted and close monitoring of patients is recommended.

Coadministration has not been studied. Tramadol is metabolized by CYPs 3A4, 2B6, and 2D6. Metabolism by CYP2D6 is to a metabolite more potent than the parent compound. Ritonavir may increase tramadol exposure but also reduce the conversion to the more potent active metabolite. Monitoring for tramadol related side effects and for the analgesic effect may be required as clinically indicated. Adjust tramadol dosage if needed.

Coadministration has not been studied. Pantoprazole exposure may decrease when administered with by ombitasvir/paritaprevir/ritonavir. Pantoprazole is a substrate of CYP2C19, CYP3A4 and CYP2C9, and is also metabolised by sulfotranseferases. Exposure of omeprazole, a model CYP2C19 substrate, decreased by 50% when administered with ombitasvir/paritaprevir/ritonavir, but exposure of the DAA was not affected. An interaction of similar magnitude is expected with other CYP2C19 substrates. Use higher doses of pantoprazole only if clinically indicated.

Duloxetine can be administered with ombitasvir/paritaprevir/ritonavir and no dose alteration is required. Duloxetine is metabolized by CYP2D6 and CYP1A2. There was no interaction between duloxetine and ombitasvir/paritaprevir/ritonavir. Coadministration with duloxetine (60 mg single dose) increased paritaprevir Cmax by 7% and decreased AUC and Cmin by 4% and 7%. [Note, duloxetine is contraindicated in patients with hepatic impairment as concentrations may increase due to decreased clearance of duloxetine.]