Pharmacology

Rasagiline is N-propargyl-1-®aminoindan. Its main metabolite, aminoindan, improves motor and cognitive functions in experimental models and may, thus, contribute to the overall beneficial pharmacological profile of the drug.

Pharmacodynamics. Rasagiline completely, selectively, and irreversibly inhibits MAO-B with a potency 5 to 10 times greater than selegiline. MAO-B inhibition lasts at least 1 week after last dose. In clinical trials with patients with Parkinson disease, 25% to 35% MAO-B inhibition was achieved after a single rasagiline dose of 1 mg/day and multiple doses of rasagiline of 0.5, 1, and 2 mg per day resulted in complete MAO-B inhibition.

Rasagiline has the potential for a disease-modifying effect in Parkinson disease, in addition to its well-established symptomatic effect. It reduces the predominant levodopa-associated wearing-off phenomena, and complimentary combination with entacapone may support the concept of continuous nigrostriatal dopaminergic stimulation (18). The aminoindan metabolite of rasagiline has neuroprotective properties (01). The results of a study on a cell-line model indicate that rasagiline protects dopaminergic cells against free radical-mediated damage and apoptosis in the presence of alpha-synuclein over-expression (06). The mechanism of neuroprotective effect of rasagiline in Parkinson disease models was shown to be by prevention of the formation of reactive oxygen species derived from oxidation of dopamine by MAO-B and via an antiapoptotic action, which appears to be independent of MAO-B inhibition and related to its embedded N-propargyl moiety (32). Whether rasagiline is associated with clinically significant neuroprotection is the subject of ongoing clinical trials.

Pharmacokinetics. Rasagiline is absorbed from the gastrointestinal tract following oral administration and is presumed to cross the blood-brain barrier. The pharmacokinetic profile is as follows.

Rasagiline is primarily metabolized to an active metabolite, 1-®-aminoindan, which shares some of the pharmacological actions of the parent compound.

A simple, rapid, and sensitive reverse-phase liquid chromatographic method has been developed and validated for estimation of rasagiline mesylate in different plasma matrices (26). This method can be used for determining pharmacokinetic parameters of rasagiline by noncompartmental analysis after oral dosing.

Transdermal rasagiline. In an open-label, randomized, parallel-group study on Chinese patients, a single-dose transdermal application of rasagiline prolonged t 1/2, increased AUC, and provided a more stable plasma drug concentration (34). Rasagiline patch may allow a longer dosing interval compared to the oral tablet.

Clinical trials

Results of well-designed clinical studies indicate that rasagiline is effective as initial monotherapy and improves symptomatology in patients with early Parkinson disease.

Table 1. Clinical Trials of Rasagiline

The disease-modifying or neuroprotective effect of rasagiline is difficult to assess in late-start clinical trials because of its symptomatic effect on Parkinson disease.

Rasagiline, when used as adjunct therapy with levodopa in patients with moderate-to-advanced Parkinson disease in the phase 3 PRESTO and LARGO studies, was found to be safe as well as effective and benefited patients with signs of early wearing-off phenomenon (08). Data from clinical trials as well as review of literature suggest that rasagiline at an oral dose of 1 mg daily, used as monotherapy as well as adjunctive therapy, is effective for reducing tremor severity in patients with Parkinson disease (15). A single-blind study to evaluate the rapidity of onset effect of rasagiline on motor symptoms showed therapeutic effect from the first week of therapy, which further improved at 4 weeks without the need of a dose titration (33). A single-center, prospective, observational, 12-week study has concluded that addition of rasagiline to levodopa improves sleep outcomes and may be an option for patients with Parkinson disease experiencing sleep disorders (27).

A head-to-head, 3-year retrospective case-control study found that rasagiline and selegiline were equally efficient in controlling motor symptoms of patients with Parkinson disease on optimized therapy (03). A metaanalysis of various studies has concluded that rasagiline treatment is associated with significant improvement of UPDRS scores, which is not dose-dependent (04).

Indications

Rasagiline is indicated in the treatment of Parkinson disease, both as initial monotherapy in patients with early Parkinson disease and as adjunct to levodopa treatment in moderate-to-advanced Parkinson disease.

Off-label uses

Contraindications

None have been identified by the manufacturer or published in the literature.

Goals and duration of treatment

The aim of rasagiline is neuroprotection and to slow the progression of Parkinson disease. Compared to delayed start, early initiation of rasagiline provided long-term clinical benefit due to neuroprotection (11). The pharmacology and safety data indicate that the drug may be safely continued for an indefinite period. As adjunctive therapy to levodopa in patients with advanced Parkinson disease, rasagiline 0.5 or 1 mg/day significantly reduces the total daily “off” time (14; 19).

Dosing

One mg per day orally with or without food.

Special considerations

Rasagiline should not be taken by patients with moderate to severe hepatic impairment or pheochromocytoma.

Pediatric. Not indicated for use in children.

Geriatric. In clinical trials, older patients were more prone to serious adverse effects than younger patients, but no statistically significant interaction between age and rasagiline exposure has been reported. Therefore, no special precautions are required for use of rasagiline in the elderly.

Pregnancy. No information is available in the literature or from the manufacturer.

Anesthesia. No interaction has been reported.

Interactions

Rasagiline does not interact with cabergoline. It may interact with fluoxetine, meperidine, and tricyclic antidepressants. It is generally advisable to avoid the combination of rasagiline with antidepressants. Caution should be used when rasagiline is used concurrently with CYP1A2 inhibitors such as ciprofloxacin. It is metabolized by CYP 3A4 and CYP 2D6. Ciprofloxacin-rasagiline drug interaction has been reported to lead to dopaminergic effects (05).

Adverse effects

Rasagiline was generally well tolerated and was like placebo groups in case of monotherapy trials. Results of a double-blind, placebo-controlled study to determine the tyramine sensitivity factor and degree of MAO-A inhibition in healthy volunteers showed that rasagiline selectively inhibits MAO-B and is not associated with increased tyramine sensitivity at the dose of 1 mg/d, leading to the deletion of dietary tyramine restriction from labeling of rasagiline in the United States (10). Dopaminergic events were reported in patients who received rasagiline as adjuvant to levodopa and included weight loss, anorexia, vomiting, ataxia, and postural hypotension. There was no increase of dyskinesias. The adverse events disappeared spontaneously and did not require discontinuation of the medication. Pisa syndrome has been reported as a complication of rasagiline therapy in a patient with Parkinson disease (30).

Because of a low incidence of cognitive and behavioral adverse events, oral rasagiline as monotherapy or as adjunctive therapy to levodopa provides a useful option in the treatment of adult patients with Parkinson disease (13).