Rasagiline Drug Information

Rasagiline tablets are indicated for the treatment of Parkinson's disease (PD). Rasagiline Tablets, a monoamine oxidase (MAO)-B inhibitor (MAOI), is indicated for the treatment of Parkinson's disease

General Dosing Recommendations

When rasagiline tablets are prescribed as monotherapy or as adjunct therapy in patients not taking levodopa, patients may start rasagiline tablets at the recommended dose of 1 mg administered orally once daily. In patients taking levodopa, with or without other PD drugs (e.g., dopamine agonist, amantadine, anticholinergics), the recommended initial dose of rasagiline tablet is 0.5 mg once daily. If the patient tolerates the daily 0.5 mg dose, but a sufficient clinical response is not achieved, the dose may be increased to 1 mg once daily.

When rasagiline tablets are used in combination with levodopa, a reduction of the levodopa dose may be considered, based upon individual response. The recommended doses of rasagiline tablets should not be exceeded because of risk of hypertension.

Patients Taking Ciprofloxacin or Other CYP1A2 Inhibitors

Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of rasagiline tablet 0.5 mg once daily.

Patients with Hepatic Impairment Patients with mild hepatic impairment should not exceed a dose of rasagiline tablet 0.5 mg once daily. Rasagiline tablets should not be used in patients with moderate or severe hepatic impairment.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the incidence of adverse reactions in the clinical trials of another drug and may not reflect the rates of adverse reactions observed in practice. As the populations in these studies differ, not only in the adjunct use of dopamine agonists or levodopa during rasagiline treatment, but also in the severity and duration of their disease, the adverse reactions are presented separately for each study. The only adverse reaction that led to the discontinuation of more than one patient was hallucinations.

The most commonly observed adverse reactions in Study 1 (incidence in rasagiline tablets -treated patients 3% or greater than the incidence in placebo-treated patients) included flu syndrome, arthralgia, depression, and dyspepsia. Table 1 lists adverse reactions that occurred in 2% or greater of patients receiving rasagiline tablets as monotherapy and were numerically more frequent than in the placebo group in Study 1. Adjunct Use of Rasagiline Tablets Rasagiline tablets were studied as an adjunct therapy without levodopa (Study 2), or as an adjunct therapy to levodopa, with some patients also taking dopamine agonists, COMT inhibitors, anticholinergics, or amantadine (Study 3 and Study 4).

Adverse reactions that led to the discontinuation of more than one patient were nausea and dizziness. The most commonly observed adverse reactions in Study 2 (incidence in rasagiline tablets -treated patients 3% or greater than incidence in placebo-treated patients) included peripheral edema, fall, arthralgia, cough, and insomnia. Table 2 lists adverse reactions that occurred in 2% or greater in patients receiving rasagiline tablets as adjunct therapy without levodopa and numerically more frequent than in the placebo group in Study 2.

In Study 3, adverse event reporting was considered more reliable than Study 4; therefore, only the adverse event data from Study 3 are presented below. The adverse reactions that led to discontinuation of more than one rasagiline tablets -treated patient were diarrhea, weight loss, hallucination, and rash. The most commonly observed adverse reactions in Study 3 (incidence in rasagiline tablets -treated patients 3% or greater than the incidence in placebo-treated patients) included dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, abnormal dreams, fall, and tenosynovitis.

Table 3: Adverse Reactions* in Study Several of the more common adverse reactions seemed dose-related, including weight loss, postural hypotension, and dry mouth. There were no significant differences in the safety profile based on age or gender. During all Parkinson's disease phase 2/3 clinical trials, the long-term safety profile was similar to that observed with shorter duration exposure.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of rasagiline tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Skin and Subcutaneous Tissue Disorders: Melanoma

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.

Dextromethorphan

The concomitant use of rasagiline tablets 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 tablets.

MAO Inhibitors

Rasagiline tablets are contraindicated for use with other MAO inhibitors because of the increased risk of nonselective MAO inhibition that may lead to a hypertensive crisis.

Sympathomimetic Medications

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 tablets and sympathomimetic medications. Severe hypertension has been reported in patients taking the recommended dose of rasagiline tablets 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 tablets with any sympathomimetic medications including nasal, oral, and ophthalmic decongestants and cold remedies.

Antidepressants

Concomitant use of rasagiline tablets with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic, or tetracyclic antidepressants) is not recommended. Concomitant use of rasagiline and MAO inhibitors is contraindicated.

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 tablets 0.5 mg once daily.

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 tablets 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 1mg daily rasagiline tablet 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 tablets. Patients should be advised to avoid foods containing a very large amount of tyramine while taking recommended doses of rasagiline tablets.

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

Rasagiline is contraindicated for use with meperidine, tramadol, methadone, propoxyphene and MAO inhibitors (MAOIs), including other selective MAO-B inhibitors, because of risk of serotonin syndrome. At least 14 days should elapse between discontinuation of rasagiline and initiation of treatment with these medications. Rasagiline is contraindicated for use with St.

John's wort and with cyclobenzaprine. Rasagiline is contraindicated for use with dextromethorphan because of risk of episode of psychosis or bizarre behavior. Concomitant use of meperidine, tramadol, methadone, propoxyphene dextromethorphan, St.

John's wort, cyclobenzaprine, or another (selective or non-selective) MAO inhibitor

In a dose escalation study in patients on chronic levodopa therapy treated with 10 mg of rasagiline there were three reports of cardiovascular side effects (including hypertension and postural hypotension) which resolved following treatment discontinuation. Although no cases of overdose have been observed with rasagiline during the clinical development program, the following description of presenting symptoms and clinical course is based upon overdose descriptions of nonselective MAO inhibitors. The signs and symptoms of nonselective MAOI overdose may not appear immediately.

Delays of up to 12 hours after ingestion of drug and the appearance of signs may occur. The peak intensity of the syndrome may not be reached until for a day following the overdose. Death has been reported following overdose; therefore, immediate hospitalization, with continuous patient observation and monitoring for at least two days following the ingestion of such drugs in overdose, is strongly recommended.

The severity of the clinical signs and symptoms of MAOI overdose varies and may be related to the amount of drug consumed. The central nervous and cardiovascular systems are prominently involved. Signs and symptoms of MAOI overdose may include: 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.

There is no specific antidote for rasagiline overdose. The following suggestions are offered based upon the assumption that rasagiline overdose may be modeled after nonselective MAO inhibitor poisoning. Treatment of overdose with nonselective MAO inhibitors is symptomatic and supportive.

Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required. Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required.

Maintenance of fluid and electrolyte balance is essential. For this reason, in cases of overdose with rasagiline, dietary tyramine restriction should be observed for several weeks to reduce the risk of hypertensive tyramine reaction. A poison control center should be called for the most current treatment guidelines.

A postmarketing report described a single patient who developed a nonfatal serotonin syndrome after ingesting 100 mg of rasagiline in a suicide attempt. Another patient who was treated in error with 4 mg rasagiline daily and tramadol also developed a serotonin syndrome. One patient who was treated in error with 3 mg rasagiline daily experienced alternating episodes of vascular fluctuations consisting of hypertension and orthostatic hypotension.