Drug Interactions between Azilect and Cuprimine

ADJUST DOSING INTERVAL: Food may interfere with the gastrointestinal absorption of penicillamine. In a study of six healthy volunteers, administration of penicillamine (500 mg) following a standard breakfast reduced the mean peak plasma concentrations of penicillamine by 48% compared to administration in the fasting state.

MANAGEMENT: Penicillamine should be administered on an empty stomach, at least one hour before or two hours after meals, and at least one hour apart from any other drug, food, or milk. This permits maximum absorption and reduces the likelihood of inactivation by metal binding in the gastrointestinal tract.

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.

ADJUST DOSING INTERVAL: Oral administration of aluminum, copper, iron, zinc, magnesium, and possibly other minerals such as calcium may decrease the gastrointestinal absorption of penicillamine, and vice versa. The proposed mechanism involves chelation of penicillamine to polyvalent cations, which leads to formation of a nonabsorbable complex. In a study of six healthy volunteers, administration of penicillamine (500 mg) following a single dose of ferrous sulfate (300 mg) or antacid (Maalox Plus 30 mL) reduced the mean peak plasma concentration of penicillamine by 65% and 34%, respectively, compared to administration in the fasting state. In addition to chelation, some investigators suggest that antacids may also reduce penicillamine bioavailability by increasing gastric pH, which favors the oxidation of penicillamine to its poorly absorbed disulfide form. These changes could result in diminished therapeutic effects of penicillamine.

MANAGEMENT: Mineral supplements or other products containing polyvalent cations (e.g., antacids or preparations containing antacids such as didanosine buffered tablets or pediatric oral solution) should be administered at least two hours before or two hours after the penicillamine dose. In addition, pharmacologic response to penicillamine should be monitored more closely whenever these products are added to or withdrawn from therapy, and the penicillamine dosage adjusted as necessary. When penicillamine is coadministered with Suprep Bowel Prep (magnesium/potassium/sodium sulfates), the manufacturer recommends administering penicillamine at least 2 hours before and not less than 6 hours after Suprep Bowel Prep to avoid chelation with magnesium.