Drug Interaction Report

CONTRAINDICATED: Coadministration with the hepatitis C virus (HCV) NS3/4A protease inhibitors, boceprevir and telaprevir, may significantly increase the plasma concentrations of tadalafil. The mechanism involves inhibition of CYP450 3A4, the isoenzyme primarily responsible for the metabolic clearance of tadalafil. The interaction has not been specifically studied with either boceprevir or telaprevir, but has been reported with other potent CYP450 3A4 inhibitors such as ketoconazole or ritonavir. According to the product labeling for tadalafil, administration of a single 20 mg dose during treatment with ketoconazole (400 mg daily) increased the tadalafil peak plasma concentration (Cmax) and systemic exposure (AUC) by 22% and 312%, respectively, compared to administration alone. A lower dosage of ketoconazole (200 mg daily) increased the Cmax and AUC of a single 10 mg dose of tadalafil by 15% and 107%, respectively. Ritonavir (200 mg twice a day) increased the AUC of a single 20 mg dose of tadalafil by 124% without changing the Cmax.

MANAGEMENT: A safe and effective dosage of tadalafil has not been established for the treatment of pulmonary arterial hypertension when used in the presence of HCV NS3/4A protease inhibitors. Due to the potential for increased tadalafil-associated adverse events including visual disturbances, hypotension, prolonged erection and syncope, this use is considered contraindicated. 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 boceprevir or telaprevir. When given for once-daily use in the treatment of erectile dysfunction or benign prostatic hyperplasia, the maximum recommended dose is 2.5 mg. 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).

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.

ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of telaprevir. When given with a meal containing 533 kcal and 21 g fat, telaprevir systemic exposure (AUC) increased by 237% compared to administration under fasting conditions. The type of meal also affects the exposure to telaprevir. Relative to fasting, telaprevir AUC increased by approximately 117% with a low-fat meal (249 kcal; 3.6 g fat) and 330% with a high-fat meal (928 kcal; 56 g fat). In Phase 3 clinical trials, telaprevir doses were administered within 30 minutes of completing a meal or snack containing approximately 20 grams of fat.

MANAGEMENT: Telaprevir should be administered with food containing approximately 20 grams of fat. Patients should be advised that the fat content of the meal or snack is critical to the absorption of telaprevir. Food taken with telaprevir should be ingested within 30 minutes prior to each dose. Examples of some foods that could be taken with telaprevir include: bagel with cream cheese; half cup of nuts; 3 tablespoons of peanut butter; 1 cup of ice cream; 2 ounces of American or cheddar cheese; 2 ounces of potato chips; or half cup of trail mix.