Side Effects of Azilect (rasagiline)

Azilect (rasagiline) is a monoamine oxidase inhibitor (MAOI) used to treat Parkinson's disease.

Monoamine oxidase is an enzyme that breaks down serotonin, norepinephrine, dopamine, tyramine and similar chemicals that serve as neurotransmitters, chemicals that nerves use to communicate with one another.

There are two types of monoamine oxidase enzymes, MAO-A and MAO-B. Monoamine oxidase inhibitors inhibit one or both enzymes resulting in increased levels of the chemicals normally broken down by MAO-A or MAO-B.

Azilect inhibits MAO-B, but it is not clear if Azilect also inhibits MAO-A. Azilect's exact mechanism of action is not known; however, by inhibiting MAO-B Azilect reduces the breakdown of dopamine resulting in increased levels of dopamine in the brain. Increased dopamine levels alleviate the symptoms of Parkinson's disease. 

Common side effects of Azilect include

• flu-like symptoms,
• headache,
• nausea,
• joint pain,
• upset stomach,
• depression,
• falls,
• constipation,
• dizziness on standing,
• dry mouth,
• rash,
• hallucinations,
• vomiting, and
• difficulty moving.

Serious side effects of Azilect include hypertensive crisis if foods high in tyramine are consumed while taking Azilect.

Drug interactions of Azilect include ciprofloxacin, which inhibits the enzymes in the liver that eliminate Azilect, increasing blood levels and possible side effects of Azilect.

Azilect should not be administered with antidepressants that increase serotonin levels, such as

• selective serotonin uptake inhibitors (SSRIs),
• tricyclic antidepressants,
• serotonin-norepinephrine uptake inhibitors (SNRIs), and
• other monoamine oxidase inhibitors (MAOIs).

Due to a long half-life, fluoxetine, mirtazapine, cyclobenzaprine, dextromethorphan, and St. John's wort should be discontinued at least 5 weeks before starting Azilect due to the risk of serious reactions, including serotonin syndrome.

Azilect should not be used with meperidine, propoxyphene, or tramadol because it may cause serious reactions.

Azilect should not be used with sympathomimetic amine drugs such as amphetamines and products containing vasoconstrictors (blood vessel narrowing drugs, for example, pseudoephedrine, ephedrine, phenylpropanolamine, phenylephrine).

Severe hypertensive reactions have occurred when such drugs were combined with other MAO inhibitors.

Patients taking Azilect should not be given cocaine or local anesthetics containing sympathomimetic vasoconstrictor drugs.

They also should not undergo elective surgery requiring general anesthesia. Azilect should be discontinued at least 14 days before surgery.

Azilect should not be used with other MAO inhibitors because of the risk of a hypertensive crisis.

There are no adequate studies of Azilect in pregnant women. Azilect should only be used in pregnant women if the benefit is felt to justify the unknown risk. It is unknown if Azilect passes into breast milk. Consult your doctor before breastfeeding.

The most common adverse effects of rasagiline are:

• flu like symptoms,
• headache,
• nausea,
• joint pain,
• upset stomach,
• depression,
• falls,
• constipation,
• postural hypotension (a drop in blood pressure when moving from a lying or sitting position to a sitting or standing position, respectively),
• dry mouth,
• rash,
• hallucinations,
• vomiting, and
• difficulty moving.

Rasagiline also may cause low or high blood pressure. A hypertensive crisis may occur if foods high in tyramine are consumed while taking rasagiline.

Tyramine in food usually is broken down in the intestine by MAO-A in the intestinal wall as the tyramine is absorbed into the body. There are no adequate studies in humans to determine whether rasagiline also inhibits MAO-A; however, if MAO-A is inhibited, tyramine ingested in food may enter the body in larger amounts and result in a hypertensive crisis.

Foods high in tyramine include those that are aged, fermented, pickled, or smoked. Examples include aged cheeses, air-dried meats, sauerkraut, soy sauce, tap/draft beers and red wines. As a precaution, foods high in tyramine should be avoided when taking rasagiline.

The following adverse reactions are described in more detail in the product labeling:

• Hypertension
• Serotonin Syndrome
• Falling Asleep During Activities of Daily Living and Somnolence
• Hypotension / Orthostatic Hypotension
• Dyskinesia
• Hallucinations / Psychotic-Like Behavior
• Impulse Control /Compulsive Behaviors
• Withdrawal-Emergent Hyperpyrexia and Confusion
• Melanoma

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.

• During the clinical development of Azilect, Parkinson's disease patients received Azilect as initial monotherapy (Study 1) and as adjunct therapy (Study 2, Study 3, Study 4).
• As the populations in these studies differ, not only in the adjunct use of dopamine agonists or levodopa during Azilect treatment, but also in the severity and duration of their disease, the adverse reactions are presented separately for each study.

Monotherapy Use of Azilect

In Study 1, approximately 5% of the 149 patients treated with Azilect discontinued treatment due to adverse reactions compared to 2% of the 151 patients who received placebo.

• 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 Azilect-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 Azilect as monotherapy and were numerically more frequent than in the placebo group in Study 1.

Table 1: Adverse Reactions* in Study 1

There were no significant differences in the safety profile based on age or gender.

Adjunct Use of Azilect

Azilect was 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).

• In Study 2, approximately 8% of the 162 patients treated with Azilect discontinued treatment due to adverse reactions compared to 4% of the 164 patients who received placebo.
• 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 Azilect-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 Azilect as adjunct therapy without levodopa and numerically more frequent than in the placebo group in Study 2.

Table 2: Adverse Reactions* in Study 2

• There were no significant differences in the safety profile based on age or gender.
• 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.
• In Study 3, approximately 9% of the 164 patients treated with Azilect 0.5 mg/day and 7% of the 149 patients treated with Azilect 1 mg/day discontinued treatment due to adverse reactions, compared to 6% of the 159 patients who received placebo. The adverse reactions that led to discontinuation of more than one Azilect-treated patient were diarrhea, weight loss, hallucination, and rash.
• The most commonly observed adverse reactions in Study 3 (incidence in Azilect-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 lists adverse reactions that occurred in 2% or greater of patients treated with Azilect 1 mg/day and that were numerically more frequent than the placebo group in Study 3.

Table 3: Adverse Reactions* in Study 3

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 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 is contraindicated for use with Azilect.

MAO Inhibitors

• Azilect is 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

• The concomitant use of Azilect and sympathomimetic medications was not allowed in clinical studies. 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 Azilect and sympathomimetic medications.
• Severe hypertension has been reported in patients taking the recommended dose of Azilect and ophthalmic drops containing sympathomimetic medications.
• 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.

Antidepressants

• Concomitant use of Azilect with one of many classes of antidepressants (e.g., SSRIs, SNRIs, triazolopyridine, tricyclic or tetracyclic antidepressants) is not recommended.
• Concomitant use of Azilect 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 Azilect 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 Azilect 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 1 mg daily Azilect 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 Azilect.
• Patients should be advised to avoid foods containing a very large amount of tyramine while taking recommended doses of Azilect.

Dopaminergic Antagonists

• It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of Azilect.

Drug Abuse And Dependence

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.