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Azilect (Rasagiline Mesylate) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

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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].

Dextromethorphan

The concomitant use of AZILECT 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 AZILECT's MAO inhibitory activity, dextromethorphan should not be used concomitantly with AZILECT [see Contraindications].

Sympathomimetic Medications

The concomitant use of AZILECT and sympathomimetic medications was not allowed in clinical studies. Severe hypertensive reactions have followed the administration of sympathomimetics and non-selective MAO inhibitors. One case of hypertensive crisis has been reported in a patient taking the recommended dose of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine). Elevated blood pressure was reported in another patient taking the recommended dose of AZILECT and ophthalmic drops with a sympathomimetic medication (tetrahydrozoline).

Because AZILECT 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 AZILECT with any sympathomimetic medications including nasal, oral, and ophthalmic decongestants and cold remedies.

MAO Inhibitors

AZILECT should not be administered along with other MAO inhibitors because of the increased risk of non-selective MAO inhibition that may lead to a hypertensive crisis [see Contraindications].

Antidepressants

Concomitant use of AZILECT with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommended [see Warnings and Precautions].

Levodopa/Carbidopa

[see Warnings and Precautions and Clinical Pharmacology].

Ciprofloxacin and 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 [see Warnings and Precautions and Clinical Pharmacology].

Theophylline

[see Clinical Pharmacology].

Tyramine/Rasagiline Interaction

MAO in the gastrointestinal tract and liver (primarily type A) is thought to provide vital protection from exogenous amines (e.g., tyramine) that have the capacity, if absorbed intact, to cause a "hypertensive crisis," the so-called "cheese reaction". If large amounts of certain exogenous amines (e.g., from fermented cheese, herring, over-the-counter cough/cold medications) gain access to the systemic circulation because MAO-A has been inhibited, they cause release of norepinephrine which may result in a rise in systemic blood pressure. MAOIs that selectively inhibit MAO-B are largely devoid of the potential to cause tyramine-induced hypertensive crisis.

Results of a special tyramine challenge study indicate that rasagiline is selective for MAO-B at recommended doses and can ordinarily be used without dietary tyramine restriction. However, certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts (i.e., > 150 mg) of tyramine and could potentially cause a hypertensive cheese reaction in patients taking AZILECT due to mild increased sensitivity to tyramine. Patients should be advised to avoid foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of AZILECT because of the potential for large increases in blood pressure. 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.

Despite the selective inhibition of MAO-B at recommended doses of AZILECT, there have been post-marketing 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 AZILECT [see Dosing and Administration (2), and Warnings and Precautions].

OVERDOSAGE

No cases of AZILECT overdose were reported in clinical trials.

Rasagiline was well tolerated in a single-dose study in healthy volunteers receiving 20 mg/day and in a ten-day study in healthy volunteers receiving 10 mg/day. Adverse events were mild or moderate. 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.

Symptoms of overdosage, although not observed with rasagiline during clinical development, may resemble those observed with non-selective MAO inhibitors (MAOIs).

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 non-selective MAO inhibitors.

Characteristically, signs and symptoms of non-selective MAOI overdose may not appear immediately. Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur. Importantly, the peak intensity of the syndrome may not be reached for upwards of a day following the overdose. Death has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring for a period of at least two days following the ingestion of such drugs in overdose, is strongly recommended.

The clinical picture of MAOI overdose varies considerably; its severity may be a function of the amount of drug consumed. The central nervous and cardiovascular systems are prominently involved.

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.

There is no specific antidote for rasagiline overdose. The following suggestions are offered based upon the assumption that rasagiline overdose may be modeled after non-selective MAO inhibitor poisoning. Treatment of overdose with non-selective 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 AZILECT, dietary tyramine restriction should be observed for several weeks to avoid the risk of a hypertensive/cheese reaction.

A poison control center should be called for the most current treatment guidelines.

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

CONTRAINDICATIONS

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Meperidine and Certain Other Analgesics

AZILECT is contraindicated for use with meperidine. Serious adverse reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors (MAOIs) including selective MAO-B inhibitors. These adverse reactions are often described as "serotonin syndrome", a potentially serious condition, which can result in death. Typical clinical signs and symptoms include behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, hypotension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor). At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with meperidine.
For similar reasons, AZILECT should not be administered with the analgesic agents tramadol, methadone, and propoxyphene.
In the post-marketing period, serotonin syndrome has been reported in a patient erroneously treated with a higher than recommended dose of AZILECT (4 mg daily) and tramadol.

Other Drugs

AZILECT should not be used with the antitussive agent dextromethorphan. The combination of MAO inhibitors and dextromethorphan has been reported to cause brief episodes of psychosis or bizarre behavior. AZILECT is also contraindicated for use with St. John's wort, and cyclobenzaprine (a tricyclic muscle relaxant).

MAO Inhibitors

AZILECT should not be administered along with any other MAO inhibitor (selective or non-selective) because of the increased risk of non-selective MAO inhibition that may lead to a hypertensive crisis. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with any MAO inhibitor.

DRUG ABUSE AND DEPENDENCE

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Controlled Substance

AZILECT is not a controlled substance.

Abuse

Studies conducted in mice and rats did not reveal any potential for drug abuse and dependence. Clinical trials have not revealed any evidence of the potential for abuse, tolerance or physical dependence; however, systematic studies in humans designed to evaluate these effects have not been performed.

Dependence

Studies conducted in mice and rats did not reveal any potential for drug abuse and dependence. Clinical trials have not revealed any evidence of the potential for abuse, tolerance or physical dependence; however, systematic studies in humans designed to evaluate these effects have not been performed.

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