Drug Interactions between ceritinib and Revatio

ADJUST DOSE: 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, the potent CYP450 3A4 inhibitor ritonavir (500 mg twice a day for 7 days) increased mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of sildenafil (100 mg single dose) 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: Caution is advised if sildenafil is coadministered with potent CYP450 3A4 inhibitors. Dosage adjustments may be appropriate for sildenafil whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy based on efficacy and side effects. For the treatment of erectile dysfunction, an initial sildenafil dosage of 25 mg should be considered in patients treated concomitantly with potent CYP450 3A4 inhibitors. Patients should be advised to promptly notify their physician 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). For the treatment of pulmonary arterial hypertension, a dosage adjustment for sildenafil should be considered during coadministration with some CYP450 3A4 inhibitors such as erythromycin, saquinavir, telithromycin, and nefazodone. However, use with more potent CYP450 3A4 inhibitors such as ritonavir, ketoconazole, itraconazole, or clarithromycin is not recommended. Some authorities consider the use of very potent CYP450 3A4 inhibitors with sildenafil to be contraindicated in patients with pulmonary arterial hypertension. When sildenafil is used for the treatment of pulmonary hypertension, the manufacturer of itraconazole recommends avoiding concomitant use during and for 2 weeks after treatment with itraconazole.

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