Drug Interaction Report

MONITOR: Coadministration with inhibitors of CYP450 3A4 may increase the plasma concentrations of tadalafil, which is primarily metabolized by the isoenzyme. Ketoconazole (400 mg daily), a potent CYP450 3A4 inhibitor, increased the single-dose systemic exposure (AUC) of tadalafil (20 mg) by 312% and its peak plasma concentration (Cmax) by 22%. Similarly, ketoconazole (200 mg daily) increased the single-dose AUC of tadalafil (10 mg) (AUC) by 107% and its Cmax by 15% relative to the AUC and Cmax values for tadalafil alone. The possibility of prolonged and/or increased pharmacologic effects of tadalafil should be considered. Clinical data with other less potent inhibitors of CYP450 3A4 are not available.

MANAGEMENT: Caution is advised if tadalafil is prescribed with weak to moderate CYP450 3A4 inhibitors. In general, dosage adjustments may be appropriate for tadalafil whenever a CYP450 3A4 inhibitor is added to or withdrawn from therapy based on efficacy and side effects. However, recommendations vary according to the intended indication of tadalafil. The prescribing information for individual products should be consulted for specific guidance. Patients should be advised to promptly notify their doctor if they experience potential symptoms of PDE5 inhibitor toxicity such as pain or tightness in the chest or jaw, irregular heartbeat, nausea, shortness of breath, visual disturbances, syncope, or prolonged erection (greater than 4 hours).

GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4 or moderate dual or combined inhibitors of CYP450 3A4 and CYP450 2C9 may increase the plasma concentrations of macitentan. Macitentan is primarily metabolized by CYP450 3A4 and to a minor extent by CYP450 2C8, CYP450 2C9 and CYP450 2C19. 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. In addition, physiologically based pharmacokinetic modeling in poor metabolizers of CYP450 2C9 showed that a 400 mg daily dose of fluconazole, a moderate dual CYP450 3A4 and CYP450 2C9 inhibitor, may increase macitentan exposure by approximately 3.8-fold. However, there was no clinically relevant change in exposure to the active metabolite of macitentan. The clinical significance of these findings is not known.

MANAGEMENT: Caution is advisable if macitentan is used with inhibitors of CYP450 3A4 and/or moderate dual or combined inhibitors of CYP450 3A4 and CYP450 2C9. The product labeling recommends avoiding concomitant use with potent inhibitors (e.g., protease inhibitors, clarithromycin, cobicistat, conivaptan, delavirdine, itraconazole, ketoconazole, nefazodone, posaconazole, voriconazole). The manufacturer of macitentan also recommends avoiding concomitant use with moderate dual inhibitors of CYP450 3A4 and 2C9 (e.g., fluconazole, amiodarone) or in combination with both a moderate CYP450 3A4 inhibitor and a moderate CYP450 2C9 inhibitor.

Based on their pharmacology, phosphodiesterase-5 (PDE5) inhibitors may conceivably potentiate the hypotensive effect of antihypertensive medications or effects of agents with hypotensive properties. These agents inhibit PDE5-mediated degradation of cyclic guanosine monophosphate (cGMP), which in vascular smooth muscles can cause peripheral vasodilation. However, clinical pharmacology studies of tadalafil (administered as a 10 mg dose except in studies with angiotensin II receptor (AR) blockers and amlodipine, which used a dose of 20 mg) have demonstrated no clinically significant interaction with various antihypertensive drugs from major classes including calcium channel blockers, ACE inhibitors, beta blockers, thiazide diuretics, and AR blockers. Tadalafil 10 mg and 20 mg also had no clinically significant effect on blood pressure changes due to tamsulosin, an alpha-1a blocker. In addition, analysis of data from Phase 3 clinical trials showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medications. In patients receiving concomitant antihypertensive medications, tadalafil 20 mg may induce a blood pressure decrease that is, in general, minor and not likely to be clinically relevant. In a clinical study of healthy male subjects 45 to 78 years of age, administration of silodosin with a single 20 mg dose of tadalafil resulted in increased frequency of positive orthostatic test results during a 12-hour period following concomitant dosing compared to administration with placebo. No events of symptomatic orthostasis or dizziness were reported in subjects receiving silodosin with tadalafil. Nevertheless, patients should be advised of the potential for interaction and to contact their doctor if they experience symptoms of hypotension such as dizziness, lightheadedness, or fainting.

GENERALLY AVOID: Coadministration with grapefruit juice is likely to increase the plasma concentrations of tadalafil, which is primarily metabolized by CYP450 3A4. However, the interaction has not been studied. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

MONITOR: Additive hypotensive effects may occur when phosphodiesterase-5 (PDE5) inhibitors such as tadalafil are used with alcohol, as both are mild systemic vasodilators. In clinical pharmacology studies, more subjects administered alcohol at a dose of 0.7 g/kg (equivalent to approximately 6 ounces of 80-proof vodka in an 80-kg male; consumed within 10 minutes in study subjects, providing blood alcohol levels of 0.08%) in combination with tadalafil 10 or 20 mg single doses had clinically significant decreases in blood pressure than with alcohol alone. There were reports of postural dizziness, and orthostatic hypotension was observed in some. When tadalafil 20 mg was administered with alcohol at a lower dose of 0.6 g/kg (equivalent to approximately 4 ounces of 80-proof vodka in an 80-kg male), orthostatic hypotension was not observed, dizziness occurred with similar frequency relative to alcohol alone, and the hypotensive effects of alcohol were not potentiated. Neither tadalafil nor alcohol affected the plasma concentrations of the other.

MANAGEMENT: Caution is recommended with concurrent consumption of large amounts of alcohol in patients taking tadalafil as it may increase the potential for orthostatic signs and symptoms, such as increase in heart rate, decrease in standing blood pressure, dizziness, and headache. It may also be appropriate to avoid consuming large amounts of grapefruit juice.

GENERALLY AVOID: Coadministration with grapefruit juice may increase the plasma concentrations of macitentan, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. The interaction has not been studied with grapefruit juice but has been reported for ketoconazole, a potent CYP450 3A4 inhibitor. In ten healthy subjects, coadministration of a single 10 mg oral dose of macitentan on day 5 of treatment with ketoconazole (400 mg daily for 24 days) resulted in an approximately 2-fold increase in macitentan systemic exposure compared to administration alone. However, the clinical significance of the interaction is unclear. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Until further information is available, patients receiving macitentan therapy should avoid the consumption of grapefruit or grapefruit juice.