Drug Interaction Report

ADJUST DOSE: Coadministration with drugs that are potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of tadalafil, which is primarily metabolized by the isoenzyme. According to the product labeling for tadalafil, ketoconazole (400 mg daily), a selective and potent inhibitor of CYP450 3A4, increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of a single 20 mg dose of tadalafil by 22% and 312%, respectively, compared to administration of tadalafil alone. 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), another potent inhibitor of CYP450 3A4, increased the AUC of a single 20 mg dose of tadalafil by 124% with no change in Cmax.

MANAGEMENT: Concomitant use of tadalafil with potent 3A4 inhibitors is not recommended in patients being treated for pulmonary arterial hypertension or for benign prostatic hyperplasia (BPH). In addition, some authorities recommend avoiding concomitant use of tadalafil during and for 2 weeks after treatment with itraconazole in patients with pulmonary arterial hypertension. For erectile dysfunction (ED), tadalafil labeling recommends that the dosage not exceed 10 mg once every 72 hours when taken on an as needed basis in patients treated concomitantly with a potent CYP450 3A4 inhibitor. When taken on a daily basis for BPH or ED, the dose should not exceed 2.5 mg per day. The prescribing information for individual products should be consulted for specific guidance. 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).

MONITOR: Coadministration with nefazodone may increase the plasma concentrations of drugs that are substrates of the CYP450 3A4 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 3A4 activity by nefazodone.

MANAGEMENT: Caution is advised if nefazodone must be used concomitantly with medications that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. A lower initial dosage, as well as clinical and laboratory monitoring, may be appropriate for some drugs.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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.