Rasagiline

Meperidine: Risk of serotonin syndrome ( 4 , 7.1 ) Dextromethorphan: Risk of psychosis or bizarre behavior ( 4 , 7.2 ) MAO inhibitors: Risk of non-selective MAO inhibition and hypertensive crisis ( 4 , 7.3 )

7.1 Meperidine Serious, sometimes fatal reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors including selective MAO-B inhibitors [see Contraindications ( 4 )] .

7.2 Dextromethorphan The concomitant use of rasagiline and dextromethorphan was not allowed in clinical studies. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. Therefore, in view of rasagiline’s MAO inhibitory activity, dextromethorphan is contraindicated for use with rasagiline [see Contraindications ( 4 )] .

7.3 MAO Inhibitors Rasagiline is contraindicated for use with other MAO inhibitors because of the increased risk of nonselective MAO inhibition that may lead to a hypertensive crisis [see Contraindications ( 4 )] .

7.4 Sympathomimetic Medications The concomitant use of rasagiline and sympathomimetic medications was not allowed in clinical studies. Severe hypertensive reactions have followed the administration of sympathomimetics and nonselective MAO inhibitors. Hypertensive crisis has been reported in patients taking the recommended dose of rasagiline and sympathomimetic medications. Severe hypertension has been reported in patients taking the recommended dose of rasagiline and ophthalmic drops containing sympathomimetic medications. Because rasagiline is a selective MAOI, hypertensive reactions are not ordinarily expected with the concomitant use of sympathomimetic medications.

Nevertheless, caution should be exercised when concomitantly using recommended doses of rasagiline with any sympathomimetic medications including nasal, oral, and ophthalmic decongestants and cold remedies.

7.5 Antidepressants Concomitant use of rasagiline with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic, or tetracyclic antidepressants) is not recommended [see Warnings and Precautions ( 5.2 ) and Clinical Pharmacology ( 12.3 )] . Concomitant use of rasagiline and MAO inhibitors is contraindicated [see Contraindications ( 4 )].

7.6 Ciprofloxacin or Other CYP1A2 Inhibitors Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors. This could result in increased adverse events. Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of rasagiline 0.5 mg once daily [see Warnings and Precautions ( 5.4 ) and Clinical Pharmacology ( 12.3 )] .

7.7 Tyramine/Rasagiline Interaction MAO in the gastrointestinal tract and liver (primarily type A) provides protection from exogenous amines (e.g., tyramine) that have the capacity, if absorbed intact, to cause a tyramine reaction with hypertension including clinical syndromes referred to as hypertensive urgency, crisis, or emergency. Foods and medications containing large amounts of exogenous amines (e.g., from fermented cheese, herring, over-the-counter cough/cold medications) may cause release of norepinephrine resulting in a rise in systemic blood pressure.

Results of a special tyramine challenge study indicate that rasagiline is selective for MAO-B at recommended doses and can be used without dietary tyramine restriction. However, certain foods may contain very high amounts (i.e., 150 mg or greater) of tyramine and could potentially cause a hypertensive reaction in individual patients taking rasagiline due to increased sensitivity to tyramine. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses.

There were no cases of hypertensive crisis in the clinical development program associated with 1 mg daily rasagiline treatment, in which most patients did not follow dietary tyramine restriction. There have been postmarketing reports of patients who experienced significantly elevated blood pressure (including rare cases of hypertensive crisis) after ingestion of unknown amounts of tyramine-rich foods while taking recommended doses of rasagiline. Patients should be advised to avoid foods containing a very large amount of tyramine while taking recommended doses of rasagiline [see Warnings and Precautions ( 5.1 )].

7.8 Dopaminergic Antagonists It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of rasagiline.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risks associated with the use of rasagiline in pregnant women. In animal studies, oral administration of rasagiline to rats during gestation and lactation resulted in decreased survival and reduced body weight in the offspring at doses similar to those used clinically. When administered to pregnant animals in combination with levodopa/carbidopa, there were increased incidences of fetal skeletal variations in rats and increases in embryofetal death and cardiovascular abnormalities in rabbits [see Data] .

In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risks of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data In a combined mating/fertility and embryofetal development study in pregnant rats, no effect on embryofetal development was observed at oral doses up to 3 mg/kg/day (approximately 30 times the plasma exposure (AUC) in humans at the maximum recommended human dose [MRHD, 1 mg/day]).

In pregnant rabbits administered rasagiline throughout the period of organogenesis at oral doses of up to 36 mg/kg/day, no developmental toxicity was observed. At the highest dose tested, the plasma AUC was approximately 800 times that in humans at the MRHD. In pregnant rats administered rasagiline (0, 0.1, 0.3, 1 mg/kg/day) orally during gestation and lactation, offspring survival was decreased and offspring body weight was reduced at 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the plasma AUC in humans at the MRHD). The no-effect dose (0.1 mg/kg) for adverse developmental effects is similar to the MRHD on a body surface area (mg/m 2 ) basis.

The effect of rasagiline on physical and behavioral development was not adequately assessed in this study. Rasagiline may be given as an adjunct therapy to levodopa/carbidopa treatment. In pregnant rats administered rasagiline (0, 0.1, 0.3, 1 mg/kg/day) and levodopa/carbidopa (80/20 mg/kg/day) (alone and in combination) orally throughout the period of organogenesis, there was an increased incidence of fetal skeletal variations in fetuses from rats treated with rasagiline in combination with levodopa/carbidopa at 1/80/20 mg/kg/day (approximately 8 times the rasagiline plasma AUC in humans at the MRHD and similar to the MRHD of levodopa/carbidopa [800/200 mg/day] on a mg/m 2 basis).

In pregnant rabbits dosed orally throughout the period of organogenesis with rasagiline alone…