During the clinical development of AZILECT, 1361 Parkinsons disease patients received rasagiline as initial monotherapy or as adjunct therapy to levodopa. As these two populations differ, not only in the adjunct use of levodopa during rasagiline treatment, but also in the severity and duration of their disease, they may have differential risks for various adverse events. Therefore, most of the adverse events data in this section are presented separately for each population.

Patients receiving AZILECT as initial monotherapy treatment

Adverse events leading to discontinuation in controlled clinical studies:

In the double-blind, placebo-controlled trials conducted in patients receiving AZILECT as monotherapy, approximately 5% of the 149 patients treated with rasagiline discontinued treatment due to adverse events compared to 2% of the 151 patients who received placebo.

The only adverse event that led to the discontinuation of more than one patient was hallucinations.

The most commonly observed adverse events that occurred in ≥ 5% of patients receiving AZILECT 1 mg as monotherapy (n=149) participating in the double-blind, placebo-controlled trial and that were at least 1.5 times the incidence in the placebo group (n=151), were flu syndrome, arthralgia, depression, dyspepsia, and fall.

Table 6 lists treatment emergent adverse events that occurred in ≥ 2% of patients receiving AZILECT as monotherapy participating in the double-blind, placebo-controlled trial and were numerically more frequent than in the placebo group.

Table 6. Treatment Emergent* Adverse Events in AZILECT 1 mg-Treated Monotherapy Patients

*Incidence ≥ 2% in AZILECT 1 mg group and numerically more frequent than in placebo group

Other events of potential clinical importance reported by 1% or more of patients receiving AZILECT as monotherapy, and at least as frequent as in the placebo group, in descending order of frequency include: dizziness, diarrhea, chest pain, albuminuria, allergic reaction, alopecia, angina pectoris, anorexia, asthma, hallucinations, impotence, leukopenia, libido decreased, liver function tests abnormal, skin carcinoma, syncope, vesiculobullous rash, vomiting.

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

In a double-blind, placebo-controlled trial (Study 1) conducted in patients treated with AZILECT as adjunct to levodopa therapy, 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 events compared to 6% of the 159 patients who received placebo. The AEs that led to discontinuation of more than one rasagiline treated patient were: diarrhea, weight loss, hallucination, and rash. Adverse event reporting was considered more reliable for Study 1 than for the second controlled trial (Study 2); therefore only the adverse event data from Study 1 are presented in this section of labeling.

The most commonly observed adverse events that occurred in ≥ 5% of patients receiving AZILECT 1 mg (n=149) as adjunct to levodopa therapy participating in the double-blind, placebo-controlled trial (Study 1) and that were at least 1.5 times the incidence in the placebo group (n=159) in descending order of difference in incidence were dyskinesia, accidental injury , weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, ecchymosis, somnolence and paresthesia.

Table 8 lists treatment emergent adverse events that occurred in ≥ 2% of patients treated with AZILECT1 mg/dayas adjunct to levodopa therapy participating in the double-blind, placebo-controlled trial (Study 1) and that were numerically more frequent than the placebo group. The table also shows the rates for the 0.5 mg group in Study 1.

Table 8. Incidence of Treatment Emergent* Adverse Events in Patients Receiving AZILECT as Adjunct to Levodopa Therapy in Study 1

*Incidence ≥ 2% in AZILECT 1 mg group and numerically more frequent than in placebo group

Several of the more common adverse events seemed dose-related, including weight loss, postural hypotension, and dry mouth.

Other events of potential clinical importance reported in Study 1 by 1% or more of patients treated with rasagiline 1 mg/day as adjunct to levodopa therapy, and at least as frequent as in the placebo group, in descending order of frequency include: skin carcinoma, anemia, albuminuria, amnesia, arthritis, bursitis, cerebrovascular accident, confusion, dysphagia, epistaxis, leg cramps, pruritus, skin ulcer.

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

Rasagiline was administered to approximately 1361 patients during all PD phase 2/3 clinical trials. About 283 patients received rasagiline for at least one year, approximately 410 patients received rasagiline for at least two years, 116 patients received rasagiline for at least 3 years, and 245 patients received rasagiline for more than 3 years, with some patients treated for more than 5 years. The long-term safety profile was similar to that observed with shorter duration exposure. The frequencies listed below represent the proportion of the 1361 individuals exposed to rasagiline who experienced events of the type cited.

All events that occurred at least twice (or once for serious or potentially serious events), except those already listed above, trivial events, terms too vague to be meaningful, adverse events with no plausible relation to treatment, and events that would be expected in patients of the age studied were reported without regard to determination of a causal relationship to rasagiline.

Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients, infrequent adverse events are defined as those occurring in at least 1/100 to 1/1000 patients and rare adverse events are defined as those occurring in fewer than 1/1000 patients.

Body as a whole: Frequent:asthenia, Infrequent: chills, face edema, flank pain, photosensitivity reaction

Cardiovascular system: Frequent: bundle branch block, Infrequent: deep thrombophlebitis, heart failure, migraine, myocardial infarct, phlebitis, ventricular tachycardia Rare: arterial thrombosis, atrial arrhythmia, AV block complete, AV block second degree, bigeminy, cerebral hemorrhage, cerebral ischemia, ventricular fibrillation

Digestive system: Frequent: gastrointestinal hemorrhage Infrequent: colitis, esophageal ulcer, esophagitis, fecal incontinence, intestinal obstruction, mouth ulceration, stomach ulcer, stomatitis, tongue edema, Rare: hematemesis, hemorrhagic gastritis, intestinal perforation, intestinal stenosis, jaundice, large intestine perforation, megacolon, melena,

Hemic and Lymphatic system: Infrequent: macrocytic anemia Rare: purpura, thrombocythemia

Metabolic and Nutritional disorders: Infrequent: hypocalcemia

Musculoskeletal system: Infrequent: bone necrosis, muscle atrophy Rare: arthrosis

Nervous system: Frequent: abnormal gait, anxiety, hyperkinesia, hypertonia, neuropathy, tremor Infrequent: agitation, aphasia, circumoral paresthesia, convulsion, delusions, dementia, dysarthria, dysautonomia, dysesthesia, emotional lability, facial paralysis, foot drop, hemiplegia, hypesthesia, incoordination, manic reaction, myoclonus, neuritis, neurosis, paranoid reaction, personality disorder, psychosis, wrist drop Rare: apathy, delirium, hostility, manic depressive reaction, myelitis, neuralgia, psychotic depression, stupor

Respiratory system: Frequent: cough increased, Infrequent: apnea, emphysema, laryngismus, pleural effusion, pneumothorax, Rare: interstitial pneumonia, larynx edema, lung fibrosis

Skin and Appendages: Frequent: Infrequent: eczema, urticaria Rare: exfoliative dermatitis, leukoderma

Special senses: Frequent: Infrequent: blepharitis, deafness, diplopia, eye hemorrhage, eye pain, glaucoma, keratitis, ptosis, retinal degeneration, taste perversion, visual field defect, Rare: blindness, parosmia, photophobia, retinal detachment, retinal hemorrhage, strabismus, taste loss, vestibular disorder

Urogenital system: Frequent: hematuria, urinary incontinence Infrequent: acute kidney failure, dysmenorrhea, dysuria, kidney calculus, nocturia, polyuria, scrotal edema, sexual function abnormal, urinary retention, urination impaired, vaginal hemorrhage, vaginal moniliasis, vaginitis Rare: abnormal ejaculation, amenorrhea, anuria, epididymitis, gynecomastia, hydroureter, leukorrhea, priapism

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.

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 AZILECTs 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 doses of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine). Therefore, in view of AZILECTs MAO inhibitory activity, AZILECT should not be used concomitantly with sympathomimetics including nasal and oral decongestants and cold remedies. (See CONTRAINDICATIONS AND WARNINGS, Need for restriction of dietary tyramine and amines contained in medications.)

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.)

Selective serotonin reuptake inhibitors (SSRIs), tricyclic and tetracyclic antidepressants: Concomitant use of SSRI, tricyclic, and tetracyclic antidepressants with AZILECT is not recommended (See WARNINGS.)

Levodopa/carbidopa: (See CLINICAL PHARMACOLOGY, Drug-Drug Interactions; PRECAUTIONS, General, Dyskinesias Due to Levodopa Treatment.)

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 CLINICAL PHARMACOLOGY, Drug-Drug Interactions and WARNINGS, Ciprofloxacin and Other CYP1A2 Inhibitors.)

Theophylline: (See CLINICAL PHARMACOLOGY, Drug-Drug Interactions.)

No specific laboratory tests are required for the treatment of patients on AZILECT.

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