Drug Interactions between rasagiline and Sinemet CR

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

MONITOR: Limited clinical data suggest that high protein content in the diet may reduce or cause fluctuations in the clinical response to oral and enteral formulations of levodopa in patients with Parkinson's disease. Proposed mechanisms include delayed gastric emptying, decreased levodopa absorption when taken with a protein rich diet, and competition with certain amino acids for transport across the gut wall and/or the blood brain barrier. Data have been conflicting. Clinical studies have variously reported no effect, reduced levodopa absorption with low-protein meals, reduced effects of oral and enteral formulations of levodopa with high daily protein intake, and no differences compared to fasting with high-protein meals. Neuroleptic malignant-like symptoms were reported in a patient with Parkinson's disease who was receiving pramipexole, entacapone, and immediate-release levodopa/carbidopa, after the protein content of his enteral feedings via nasogastric tube was increased from 0.88 g/kg/day to 1.8 g/kg/day; symptoms improved after the protein was reduced to 1 g/kg/day and bromocriptine was administered. Another patient receiving immediate-release carbidopa/levodopa, pramipexole, and entacapone experienced severe rigidity after initiation of continuous enteral nutrition via oral gastric tube containing 1.4 g/kg/day of protein; his Parkinsonian symptoms improved after the protein content was reduced to 0.9 g/kg/day, the feeding was changed to bolus feedings, and the levodopa was administered between boluses.

MANAGEMENT: In general, alcohol consumption should be avoided or limited during treatment with CNS-depressant agents. Until more data are available, it is advisable to avoid large fluctuations in daily protein intake and to monitor patients for altered effects of oral and enteral levodopa formulations if the protein content of the diet is increased.

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GENERALLY AVOID: Foods that contain large amounts of tyramine may precipitate a hypertensive crisis in patients treated with monoamine oxidase (MAO) inhibitors. The mechanism involves inhibition of MAO-A, the enzyme responsible for metabolizing exogenous amines such as tyramine in the gut 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. Although rasagiline is a selective inhibitor of MAO-B at the recommended dosages of 0.5 or 1 mg/day, selectivity is not absolute and may diminish with increasing dosage. There were no cases of hypertensive crisis in the clinical development program associated with rasagiline treatment at 1 mg/day, in which most patients did not follow dietary tyramine restriction. However, rare cases of hypertensive crisis have been reported during the postmarketing period in patients who ingested unknown amounts of tyramine-rich foods while taking recommended dosages of rasagiline or selegiline, another MAO-B inhibitor.

Rasagiline peak plasma concentration (Cmax) and systemic exposure (AUC ) are decreased by approximately 60% and 20%, respectively, during coadministration with a high-fat meal. The time to peak concentration (Tmax) is not affected by food.

MANAGEMENT: Dietary restriction is not ordinarily required during rasagiline treatment with respect to most foods and beverages that may contain tyramine such as air-dried and fermented meats or fish, aged cheeses, most soybean products, yeast extracts, red wine, beer, and sauerkraut. However, certain foods like some of the aged cheeses (e.g., Boursault, Liederkrantz, Mycella, Stilton) may contain very high amounts of tyramine and could potentially cause a hypertensive reaction in patients taking rasagiline even at recommended dosages due to increased sensitivity to tyramine. Patients should be advised to avoid ingesting 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 or coma, seizures, chest pain, unexplained nausea or vomiting, and stroke-like symptoms. Rasagiline should not be used at dosages exceeding 1 mg/day (0.5 mg/day for patients with mild hepatic impairment or concomitant use of ciprofloxacin or other CYP450 1A2 inhibitors), as it can increase the risk of hypertensive crisis and other adverse reactions associated with nonselective inhibition of MAO. Rasagiline can be administered with or without food.

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ADJUST DOSING INTERVAL: The oral bioavailability and pharmacologic effects of levodopa and carbidopa may be decreased during concurrent administration with iron-containing products. The proposed mechanism is chelation of levodopa and carbidopa by the iron cation, forming an insoluble complex that is poorly absorbed from the gastrointestinal tract. In nine patients with Parkinson's disease, administration of levodopa-carbidopa 100 mg-25 mg with ferrous sulfate 325 mg decreased levodopa peak plasma concentration (Cmax) and systemic exposure (AUC) by 47% and 30%, respectively, and carbidopa Cmax and AUC by 77% and 82%, respectively, compared to administration with placebo. There was also evidence of reduced efficacy of levodopa in some patients. In another study consisting of eight healthy subjects, coadministration of levodopa 250 mg with ferrous sulfate 325 mg resulted in greater than 50% reductions in the Cmax and AUC of levodopa compared to administration of levodopa alone. The magnitude of the interaction was the greatest in patients whose plasma levels of levodopa were the highest following administration of levodopa alone.

MANAGEMENT: Until more information is available, patients receiving levodopa and/or carbidopa in combination with iron-containing products should be advised to separate the times of administration by as much as possible. Patients should be monitored for reduced efficacy of levodopa, and the dosage adjusted as necessary.

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