(See WARNINGS , PRECAUTIONS-Information for Patients , OVERDOSE , and DOSAGE AND ADMINISTRATION).
Data from population pharmacokinetic studies comparing rasagiline clearance in the presence and absence of levodopa have given conflicting results. Although there may be some increase in rasagiline blood levels in the presence of levodopa, the effect is modest and rasagiline dosing need not be modified in the presence of levodopa.
Effect of Other Drugs on the Metabolism of AZILECT
In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of rasagiline. There is the potential for inhibitors of this enzyme to alter AZILECT clearance when coadministered. (See WARNINGS, Ciprofloxacin and Other CYP1A2 Inhibitors and DOSAGE AND ADMINISTRATION, Patients Taking Ciprofloxacin and Other CYP1A2 Inhibitors).
When ciprofloxacin, an inhibitor of CYP1A2, was administered to healthy volunteers (n=12) at 500 mg (BID) with rasagiline at 2 mg/day, the AUC of rasagiline increased by 83% and there was no change in the elimination half life. (See WARNINGS, Ciprofloxacin and Other CYP1A2 Inhibitors and DOSAGE AND ADMINISTRATION, Patients Taking Ciprofloxacin and Other CYP1A2 Inhibitors ).
Coadministration of rasagiline 1 mg/day and theophylline, a substrate of CYP1A2, up to 500 mg twice daily to healthy subjects (n=24) did not affect the pharmacokinetics of either drug.
Severe CNS toxicity associated with hyperpyrexia and death has been reported with the combination of tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), or serotonin-norepinephrine reuptake inhibitors (SNRIs) and non-selective MAOIs or selective MAO-B inhibitors. (See WARNINGS, Coadministration with Antidepressants).
Effect of AZILECT on Other Drugs
No additional in vivo trials have investigated the effect of AZILECT on other drugs metabolized by the cytochrome P450 enzyme system. In vitro studies showed that rasagiline at a concentration of 1 ug/ml (equivalent to a level that is 160 times the average Cmax ~ 5.9-8.5 ng/mL in Parkinson's disease patients after 1 mg rasagiline multiple dosing) did not inhibit cytochrome P450 isoenzymes, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A. These results indicate that rasagiline is unlikely to cause any clinically significant interference with substrates of these enzymes.
Symptoms reported following overdose of AZILECT in doses ranging from 3 mg to 100 mg include dysphoria, hypomania, hypertensive crisis, and serotonin syndrome.
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.
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.
A poison control center should be called for the most current treatment guidelines.
Meperidine and Other Analgesics
AZILECT is contraindicated for use with meperidine. Serious reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors including selective MAO-B inhibitors. These reactions have been characterized by coma, severe hypertension or hypotension, severe respiratory depression, convulsions, malignant hyperpyrexia, excitation, peripheral vascular collapse and death. 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.
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, mirtazapine (a tetracyclic antidepressant), and cyclobenzaprine (a tricyclic muscle relaxant).
Like other MAOIs, AZILECT is contraindicated for use with sympathomimetic amines, including amphetamines as well as cold products and weight-reducing preparations that contain vasoconstrictors (e.g., pseudoephedrine, phenylephrine, phenylpropanolamine, and ephedrine). Severe hypertensive reactions have followed the administrations of sympathomimetics and non-selective MAO inhibitors. At least one case of hypertensive crisis has been reported in a patient taking the recommended doses of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine).
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. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with MAO inhibitors.
As with other MAOIs, patients taking AZILECT should not undergo elective surgery requiring general anesthesia. Also, they should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. AZILECT should be discontinued at least 14 days prior to elective surgery. If surgery is necessary sooner, benzodiazepines, mivacurium, rapacuronium, fentanyl, morphine, and codeine may be used cautiously.
As with other MAOIs, AZILECT is contraindicated in patients with pheochromocytoma.
DRUG ABUSE AND DEPENDENCE
AZILECT is not a controlled substance.
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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