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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].
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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.
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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.
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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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