indication

For the treatment of the signs and symptoms of idiopathic Parkinsons disease as initial monotherapy and as adjunct therapy to levodopa.

pharmacology

Rasagiline is a propargylamine and an irreversible inhibitor of monoamine oxidase (MAO). MAO, a flavin-containing enzyme, regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. It is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO-A is found predominantly in the GI tract and liver, and regulates the metabolic degradation of circulating catecholamines and dietary amines. MAO-B is the major form in the human brain and is responsible for the regulation of the metabolic degradation of dopamine and phenylethylamine. In ex vivo animal studies in brain, liver and intestinal tissues rasagiline was shown to be a potent,selective, and irreversible monoamine oxidase type B (MAO-B) inhibitor. At the recommended therapeutic doses, Rasagiline was also shown to be a potent and irreversible inhibitor of MAO-B in platelets. The selectivity of rasagiline for inhibiting only MAO-B (and not MAO-A) in humans and the sensitivity to tyramine during rasagiline treatment at any dose has not been sufficiently characterized to avoid restriction of dietary tyramine and amines contained in medications.

mechanism of action

The precise mechanisms of action of rasagiline is unknown. One mechanism is believed to be related to its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline's beneficial effects seen in models of dopaminergic motor dysfunction.

toxicity

Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.

biotransformation

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP 1A2 being the major isoenzyme involved in rasagiline metabolism.

absorption

Rasagiline is rapidly absorbed following oral administration. The absolute bioavailability of rasagiline is about 36%.

half life

Rasagiline has a mean steady-state half life of 3 hours but there is no correlation of pharmacokinetics with its pharmacological effect because of its irreversible inhibition of MAO-B.

route of elimination

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway. After oral administration of 14C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.

drug interactions

Altretamine: Risk of severe hypotension

Amitriptyline: Possibility of severe adverse effects

Amoxapine: Possibility of severe adverse effects

Amphetamine: Possible hypertensive crisis

Atomoxetine: Possible severe adverse reaction with this combination

Benzphetamine: MAO Inhibitors may enhance the hypertensive effect of Amphetamines. Concomitant use of amphetamines and monoamine oxidase inhibitors (MAOI) should be avoided. If used concomitantly, careful monitoring of blood pressure must occur. It may take up to 2 weeks after the discontinuation of an MAOI for the effects to dissipate enough to afford safety to the administration of interacting agents.

Bezafibrate: MAO Inhibitors may enhance the adverse/toxic effect of Bezafibrate. Avoid concomitant use of bezafibrate with monoamine oxidase inhibitors (MAOIs) rasagiline.

Brimonidine: MAO Inhibitors like rasagiline may enhance the hypertensive effect of Alpha2-Agonists (Ophthalmic). The concomitant use of monoamine oxidase inhibitors and ophthalmic alpha2 agonists is contraindicated.

Buprenorphine: Buprenorphine may enhance the adverse/toxic effect of MAO Inhibitors like rasagiline. When possible, avoid use of buprenorphine in patients who have used a monoamine oxidase inhibitor within the past 14 days due to possible severe adverse effects.

Bupropion: Possible severe adverse reaction with this combination

Buspirone: Possible blood pressure elevation

Ciprofloxacin: Ciprofloxacin, a strong CYP1A2 inhibitor, may decrease the metabolism of rasagiline. Monitor for changes in the therapeutic and adverse effects of rasagiline if ciprofloxacin is initiated or discontinued.

Citalopram: Possible severe adverse reaction with this combination

Clomipramine: Possibility of severe adverse effects

Cyclobenzaprine: Increased risk of toxicity with this association

Desipramine: Possibility of severe adverse effects

Desvenlafaxine: Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.

Dexfenfluramine: Possible hypertensive crisis

Dextroamphetamine: Possible hypertensive crisis

Dextromethorphan: Possible severe adverse reaction

Diethylpropion: Possible hypertensive crisis

Dobutamine: Increased arterial pressure

Dopamine: Increased arterial pressure

Doxepin: Possibility of severe adverse effects

Duloxetine: Possible severe adverse reaction with this combination

Ephedra: Increased arterial pressure

Ephedrine: Increased arterial pressure

Epinephrine: Increased arterial pressure

Escitalopram: Possible severe adverse reaction with this combination

Fenfluramine: Possible hypertensive crisis

Fenoterol: Increased arterial pressure

Fluoxetine: Possible severe adverse reaction with this combination

Fluvoxamine: Possible severe adverse reaction with this combination

Imipramine: Possibility of severe adverse effects

Isoproterenol: Increased arterial pressure

Mazindol: Possible hypertensive crisis

Meperidine: Increased risk of serotonin syndrome. Concomitant use should be avoided.

Mephentermine: Increased arterial pressure

Metaraminol: Increased arterial pressure

Methamphetamine: Possible hypertensive crisis

Methoxamine: Increased arterial pressure

Methylphenidate: Possible hypertensive crisis with this combination.

Midodrine: Risk of hypertensive crisis.

Mirtazapine: Possible severe adverse reaction with this combination

Nefazodone: Possible severe adverse reaction with this combination

Norepinephrine: Increased arterial pressure

Nortriptyline: Possibility of severe adverse effects

Orciprenaline: Increased arterial pressure

Paroxetine: Possible severe adverse reaction with this combination

Phendimetrazine: Possible hypertensive crisis

Phenmetrazine: Possible hypertensive crisis

Phentermine: Possible hypertensive crisis

Phenylephrine: Increased arterial pressure

Phenylpropanolamine: Increased arterial pressure

Pirbuterol: Increased arterial pressure

Procaterol: Increased arterial pressure

Protriptyline: Possibility of severe adverse effects

Pseudoephedrine: Increased arterial pressure

Salbutamol: Increased arterial pressure

Sertraline: Possible severe adverse reaction with this combination

Sibutramine: Possible serotoninergic syndrome with this combination

St. John's Wort: Increased risk of toxicity with this association

Terbutaline: Increased arterial pressure

Tetrabenazine: Tetrabenazine may increase the adverse/toxic effects of Rasagiline. Concomitant therapy is contraindicated.

Tolcapone: Tolcapone and Rasagiline decrease the metabolism of endogenous catecholamines. Concomitant therapy may result in increased catecholamine effects. Consider alternate therapy or use cautiously and monitor for increased catecholamine effects.

Tramadol: Tramadol may increase the risk of serotonin syndrome and seizure induction by the MAO inhibitor, rasagiline.

Tranylcypromine: Increased risk of serotonin syndrome. Use caution during concomitant therapy and monitor for symptoms of serotonin syndrome.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Trimipramine: Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Avoid combination or monitor for symptoms of serotonin syndrome and/or hypertensive crisis.

Venlafaxine: Increased risk of serotonin syndrome. Ensure adequate washout period between therapies to avoid toxicity. Concurrent therapy should be avoided.

Zolmitriptan: The MAO inhibitor, rasagiline, may increase the serum concentration of zolmitriptan by decreasing its metabolism. Concomitant therapy and use of zolmitriptan within two weeks of discontinuing rasagiline are contraindicated.