Drug Interactions between cobicistat and Liqrev

CONTRAINDICATED: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of sildenafil, which is primarily metabolized by the isoenzyme. The possibility of prolonged and/or increased pharmacologic effects of sildenafil should be considered. In 14 healthy volunteers, administration of a single 100 mg dose of sildenafil in combination with the potent CYP450 3A4 inhibitor ritonavir (500 mg twice a day for 7 days) increased mean sildenafil peak plasma concentration (Cmax) and systemic exposure (AUC) by 300% and 1000%, respectively, compared to sildenafil given alone. At 24 hours, sildenafil plasma levels were still approximately 200 ng/mL as opposed to about 5 ng/mL with sildenafil alone. In a parallel study, saquinavir (SGC 1200 mg three times a day for 7 days) increased single-dose sildenafil Cmax and AUC by 140% and 210%, respectively, in 14 healthy volunteers. No change in safety or tolerability of sildenafil was observed with either protease inhibitor. In six HIV-infected patients stabilized on triple antiretroviral therapy containing indinavir (800 mg three times a day), the AUC of a single 25 mg dose of sildenafil was 4.4 times higher than dose-normalized data from historical controls. The patients experienced headache, flushing, dyspepsia and rhinitis, and there was a mean maximal decrease in blood pressure of 14/10 mmHg. The interaction was also suspected in the death of a 47-year-old man who used sildenafil (25 mg) during treatment with ritonavir and saquinavir. Another CYP450 3A4 inhibitor, erythromycin (500 mg twice daily for 5 days), increased single-dose sildenafil AUC by 182%.

MANAGEMENT: A safe and effective dosage of sildenafil has not been established for the treatment of pulmonary arterial hypertension when used in the presence of potent CYP450 3A4 inhibitors. Due to the potential for increased sildenafil-associated adverse events including visual disturbances, hypotension, prolonged erection and syncope, this use is considered contraindicated. When used for erectile dysfunction, the maximum dosage of sildenafil should not exceed a single dose of 25 mg in any given 48-hour period. Patients should be advised to promptly notify their doctor if they experience pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

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