Drug Interaction Report

CONTRAINDICATED: Monoamine oxidase inhibitors (MAOIs) markedly potentiate the action of morphine. Coadministration of narcotic analgesics including morphine in patients treated with MAOIs has rarely resulted in hypotension, respiratory depression, or coma. There appear to be two types of interaction, an excitatory and a depressive one. Symptoms of the excitatory reaction may include agitation, headache, diaphoresis, hyperpyrexia, flushing, shivering, myoclonus, rigidity, tremor, diarrhea, hypertension, tachycardia, seizures, and coma. Death has occurred in some cases. The exact mechanism of interaction is unknown, but may involve excessive serotonergic activity in the central nervous system (i.e., serotonin syndrome). The interaction is unpredictable and has been reported primarily with meperidine or fentanyl and various MAOIs including phenelzine, tranylcypromine, linezolid, moclobemide, and selegiline. Fatal hyperpyrexia and hypertension have also been observed in animal studies with meperidine and phenelzine or furazolidone. In contrast, symptoms of the depressive reaction probably stem from potentiation of CNS effects by MAOIs and include respiratory depression, cyanosis, hypotension, and coma. The interaction is also expected to occur with diamorphine.

MANAGEMENT: The use of morphine including liposomal formulations or diamorphine with MAOIs or other agents which possess MAOI activity (e.g., furazolidone, procarbazine, selegiline), together or within 14 days of stopping a MAOI is considered contraindicated.

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.