Drug Interactions between amprenavir and macitentan / tadalafil

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of macitentan, which is primarily metabolized by the isoenzyme. In ten healthy subjects, administration of a single 10 mg oral dose of macitentan on day 5 of treatment with the potent CYP450 3A4 inhibitor ketoconazole (400 mg daily for 24 days) resulted in an approximately 2-fold increase in macitentan systemic exposure (AUC) compared to administration alone. Additionally, there was a 26% reduction in the AUC of the active metabolite, which has been reported to be approximately 5-fold less potent than macitentan in vitro, but whose systemic exposure in human is 2.5-fold higher than that of macitentan. The clinical significance of these changes has not been established. Macitentan was well tolerated with or without ketoconazole in the study, and there were no relevant differences in safety parameters between the treatments.

MANAGEMENT: According to the product labeling, concomitant use of macitentan with potent CYP450 3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, conivaptan, nefazodone, cobicistat, delavirdine, protease inhibitors, and ketolide and certain macrolide antibiotics should generally be avoided. Alternative treatment options for pulmonary arterial hypertension are recommended when potent CYP450 3A4 inhibitors are needed as part of HIV treatment.

ADJUST DOSE: Coadministration with protease inhibitors (PIs) may increase the plasma concentrations of tadalafil. The mechanism is PI inhibition of tadalafil metabolism via CYP450 3A4. In study subjects, administration of a single 20 mg dose of tadalafil during treatment with ritonavir 500 mg or 600 mg twice daily at steady state resulted in a 30% reduction in tadalafil peak plasma concentration (Cmax) and 32% increase in systemic exposure (AUC) compared to tadalafil administered alone. Administration of the same dose of tadalafil in combination with ritonavir 200 mg twice a day was associated with a 124% increase in tadalafil AUC and no change in Cmax. The pharmacokinetics of tadalafil in the treatment of pulmonary arterial hypertension (PAH) have been studied in the presence of tipranavir/ritonavir. Tadalafil concentrations increased when coadministered with the first dose of tipranavir/ritonavir, but not with tipranavir/ritonavir at steady-state. This would suggest that the initial inhibitory effect of ritonavir on CYP450 3A4 may be mitigated by a more slowly evolving induction effect so that after about one week of ritonavir administered twice daily, the exposure to tadalafil is similar in the presence and absence of ritonavir. Although not specifically studied, other HIV protease inhibitors are expected to increase tadalafil exposure.

MANAGEMENT: Caution is advised if tadalafil is administered in combination with protease inhibitors. For the treatment of erectile dysfunction, the dosage of tadalafil should not exceed 10 mg once every 72 hours when used on an as-needed basis in patients receiving PI therapy. When given for once-daily use in the treatment of erectile dysfunction or benign prostatic hyperplasia, the maximum recommended dose is 2.5 mg. For the treatment of pulmonary arterial hypertension, tadalafil should be started at 20 mg once daily in patients who have been receiving ritonavir-boosted PI therapy for at least one week. The dosage may be increased to 40 mg once daily based upon individual tolerability. The use of tadalafil for PAH should be avoided during the initiation of ritonavir-boosted PI therapy. The manufacturers recommend that tadalafil be discontinued at least 24 hours prior to initiating the PIs. After at least one week, tadalafil may be resumed at 20 mg once daily, and the dosage increased to 40 mg once daily based upon individual tolerability. There is no need to discontinue tadalafil when initiating PI therapy that does not contain ritonavir as a pharmacokinetic booster, nor wait at least one week after PI therapy to start tadalafil. The tadalafil dosage should be initiated at or adjusted to 20 mg once daily when coadministered with nonritonavir-boosted PI regimens, then increased to 40 mg as tolerated. All patients treated with tadalafil 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).