Drug Interaction Report

MONITOR: Coadministration with safinamide may increase the plasma concentrations of drugs that are substrates of the breast cancer resistance protein (BCRP) transporter. The proposed mechanism is decreased clearance due to intestinal BCRP-inhibition by safinamide.

MANAGEMENT: Caution is advised when safinamide is prescribed with drugs that are BCRP substrates, particularly those with a narrow therapeutic range such as methotrexate, topotecan, and irinotecan. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever safinamide is added to or withdrawn from therapy.

GENERALLY AVOID: Foods that contain large amounts of tyramine may precipitate a hypertensive crisis in patients treated with safinamide. The proposed mechanism involves potentiation of the tyramine pressor effect due to inhibition of monoamine oxidase (MAO) by safinamide. Monoamine oxidase in the gastrointestinal tract and liver, primarily type A (MAO-A), is the enzyme responsible for metabolizing exogenous amines such as tyramine and preventing them from being absorbed intact. Once absorbed, tyramine is metabolized to octopamine, a substance that is believed to displace norepinephrine from storage granules causing a rise in blood pressure. In vitro, safinamide inhibits MAO-B with greater than 1000-fold selectivity over MAO-A, and neither safinamide nor its major metabolites inhibit MAO-A at clinically relevant concentrations. Results from an oral tyramine challenge study also suggest that safinamide is a selective inhibitor of MAO-B at the recommended dosages of 50 or 100 mg/day. However, this selectivity is not absolute and may diminish in a dose-related manner above the maximum recommended daily dosage. In clinical trials, the incidence of hypertension was 7% and 5% for safinamide 50 mg and 100 mg, respectively, versus 4% for placebo. There were no reported cases of hypertensive crisis.

Administration of safinamide following intake of a high-fat, high-caloric breakfast resulted in a slight delay in the absorption of safinamide, but had no effects on safinamide peak plasma concentration (Cmax) and systemic exposure (AUC) compared to administration under fasted conditions.

MANAGEMENT: Dietary restriction is not ordinarily required during safinamide treatment with respect to most foods and beverages that contain tyramine, which usually include aged, fermented, cured, smoked, or pickled foods (e.g., air-dried and fermented meats or fish, aged cheeses, most soybean products, yeast extracts, red wine, beer, sauerkraut). However, certain foods like some of the aged cheeses (e.g., Boursault, Liederkrantz, Mycella, Stilton) and pickled herring may contain very high amounts of tyramine and could potentially cause a hypertensive reaction in patients taking safinamide, even at recommended dosages, due to increased sensitivity to tyramine. Patients should be advised to avoid the intake of very high levels of tyramine (e.g., greater than 150 mg) and to promptly seek medical attention if they experience potential signs and symptoms of a hypertensive crisis such as severe headache, visual disturbances, confusion, stupor, seizures, chest pain, unexplained nausea or vomiting, and stroke-like symptoms. Blood pressure should be regularly monitored and managed accordingly. Medication adjustment may be necessary if blood pressure elevations are sustained or not adequately controlled. Safinamide should not be used at dosages exceeding 100 mg/day, or 50 mg/day in patients with moderate hepatic impairment (Child-Pugh B, 7-9), as it may increase the risk of hypertensive crisis and other adverse reactions associated with nonselective inhibition of MAO. Safinamide can be administered with or without food.

Food enhances the oral absorption and bioavailability of tenofovir, the active entity of tenofovir disoproxil fumarate. According to the product labeling, administration of the drug following a high-fat meal increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of tenofovir by approximately 14% and 40%, respectively, compared to administration in the fasting state. However, administration with a light meal did not significantly affect the pharmacokinetics of tenofovir compared to administration in the fasting state. Food delays the time to reach tenofovir Cmax by approximately 1 hour. Tenofovir disoproxil fumarate may be administered without regard to meals.