Data from FDA - Curated by EPG Health - Last updated 12 July 2018

Indication(s)

1 INDICATIONS AND USAGE AZILECT (rasagiline tablets) is indicated for the treatment of Parkinson’s disease (PD). AZILECT, a monoamine oxidase (MAO)-B inhibitor (MAOI), is indicated for the treatment of Parkinson’s disease (1)

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Advisory information

contraindications
4 CONTRAINDICATIONS AZILECT is contraindicated for use with meperidine, tramadol, methadone, propoxyphene, and MAO inhibitors (MAOIs), including other selective MAO-B inhibitors, because of risk of serotonin syndrome [see Warnings and Precautions (5.2)]. At least 14 days should elapse between discontinuation of AZILECT and initiation of treatment with these medications. AZILECT is contraindicated for use with St. John’s wort and with cyclobenzaprine. AZILECT is contraindicated for use with dextromethorphan because of risk of episode of psychosis or bizarre behavior. Concomitant use of meperidine, tramadol, methadone, propoxyphene dextromethorphan, St. John’s wort, cyclobenzaprine, or another (selective or non-selective) MAO inhibitor (4)
Adverse reactions
6 ADVERSE REACTIONS The following adverse reactions are described in more detail in the Warnings and Precautions section of the label: Hypertension [see Warnings and Precautions (5.1)] Serotonin Syndrome [see Warnings and Precautions (5.2)] Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.3)] Hypotension / Orthostatic Hypotension [see Warnings and Precautions (5.6)] Dyskinesia [see Warnings and Precautions (5.7)] Hallucinations / Psychotic-Like Behavior [see Warnings and Precautions (5.8)] Impulse Control /Compulsive Behaviors [see Warnings and Precautions (5.9)] Withdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.10)] Melanoma [see Warnings and Precautions (5.11)] Most common adverse reactions (incidence 3% or greater than placebo): AZILECT monotherapy: flu syndrome, arthralgia, depression, dyspepsia (6.1) AZILECT used as adjunct without levodopa: peripheral edema, fall, arthralgia, cough, and insomnia (6.1) AZILECT used as adjunct to levodopa: dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, abnormal dreams, fall, and tenosynovitis (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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 AZILECT 1 mg (N=149) Placebo (N=151) % of Patients % of Patients Headache 14 12 Arthralgia 7 4 Dyspepsia 7 4 Depression 5 2 Fall 5 3 Flu syndrome 5 1 Conjunctivitis 3 1 Fever 3 1 Gastroenteritis 3 1 Rhinitis 3 1 Arthritis 2 1 Ecchymosis 2 0 Malaise 2 0 Neck Pain 2 0 Paresthesia 2 1 Vertigo 2 1 *Incidence 2% or greater in AZILECT 1 mg group and numerically more frequent than in placebo group 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 AZILECT 1 mg (N=162) Placebo (N=164) % of Patients % of Patients Dizziness 7 6 Peripheral edema 7 4 Headache 6 4 Nausea 6 4 Fall 6 1 Arthralgia 5 2 Back pain 4 3 Cough 4 1 Insomnia 4 1 Upper respiratory tract infection 4 2 Orthostatic hypotension 3 1 *Incidence 2% or greater in AZILECT 1 mg group and numerically more frequent than in placebo group 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 AZILECT 1 mg (N=149) AZILECT 0.5 mg (N=164) Placebo (N=159) % of Patients % of Patients % of Patients Dyskinesia 18 18 10 Accidental injury 12 8 5 Nausea 12 10 8 Headache 11 8 10 Fall 11 12 8 Weight loss 9 2 3 Constipation 9 4 5 Postural hypotension 9 6 3 Arthralgia 8 6 4 Vomiting 7 4 1 Dry mouth 6 2 3 Rash 6 3 3 Somnolence 6 4 4 Abdominal pain 5 2 1 Anorexia 5 2 1 Diarrhea 5 7 4 Ecchymosis 5 2 3 Dyspepsia 5 4 4 Paresthesia 5 2 3 Abnormal dreams 4 1 1 Hallucinations 4 5 3 Ataxia 3 6 1 Dyspnea 3 5 2 Infection 3 2 2 Neck pain 3 1 1 Sweating 3 2 1 Tenosynovitis 3 1 0 Dystonia 3 2 1 Gingivitis 2 1 1 Hemorrhage 2 1 1 Hernia 2 1 1 Myasthenia 2 2 1 *Incidence 2% or greater in AZILECT 1 mg group and numerically more frequent than in placebo group Several of the more common adverse reactions seemed dose-related, including weight loss, postural hypotension, and dry mouth. There were no significant differences in the safety profile based on age or gender. During all Parkinson’s disease phase 2/3 clinical trials, the long-term safety profile was similar to that observed with shorter duration exposure.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Monotherapy: AZILECT 1 mg once daily (2.1) As adjunct without levodopa: AZILECT 1 mg once daily (2.1) As adjunct to levodopa: AZILECT 0.5 mg once daily. Increase dose to 1 mg daily as needed for sufficient clinical response (2.1) Patients taking ciprofloxacin or other CYP1A2 inhibitors: AZILECT 0.5 mg once daily (2.2, 5.4) Patients with mild hepatic impairment: AZILECT 0.5 mg once daily. AZILECT should not be used in patients with moderate or severe hepatic impairment (2.3, 5.5) 2.1 General Dosing Recommendations When AZILECT is prescribed as monotherapy or as adjunct therapy in patients not taking levodopa, patients may start AZILECT at the recommended dose of 1 mg administered orally once daily. In patients taking levodopa, with or without other PD drugs (e.g., dopamine agonist, amantadine, anticholinergics), the recommended initial dose of AZILECT is 0.5 mg once daily. If the patient tolerates the daily 0.5 mg dose, but a sufficient clinical response is not achieved, the dose may be increased to 1 mg once daily. When AZILECT is used in combination with levodopa, a reduction of the levodopa dose may be considered, based upon individual response. The recommended doses of AZILECT should not be exceeded because of risk of hypertension [see Warnings and Precautions ( 5.1 )]. 2.2 Patients Taking Ciprofloxacin or Other CYP1A2 Inhibitors Patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should not exceed a dose of AZILECT 0.5 mg once daily [see Warnings and Precautions (5.4), Drug Interactions (7.6), and Clinical Pharmacology (12.3)]. 2.3 Patients with Hepatic Impairment Patients with mild hepatic impairment should not exceed a dose of AZILECT 0.5 mg once daily. AZILECT should not be used in patients with moderate or severe hepatic impairment [see Warnings and Precautions (5.5), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. Do not use AZILECT unless the potential benefit justifies the potential risk to the fetus (8.1) 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of rasagiline in pregnant women. AZILECT should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In a combined mating/fertility and embryo-fetal development study in pregnant rats, no effect on embryo-fetal development was observed at oral doses up to 3 mg/kg/day (approximately 30 times the plasma exposure (AUC) in humans at the maximum recommended human dose [MRHD, 1 mg/day]). In pregnant rabbits administered rasagiline throughout the period of organogenesis at oral doses of up to 36 mg/kg/day, no developmental toxicity was observed. At the highest dose tested, the plasma AUC was approximately 800 times that in humans at the MRHD. In pregnant rats administered rasagiline (0.1, 0.3, 1 mg/kg/day) orally during gestation and lactation, offspring survival was decreased and offspring body weight was reduced at 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the plasma AUC in humans at the MRHD). No plasma data were available at the no-effect dose (0.1 mg/kg); however, that dose is similar to the MRHD on a mg/m2 basis. The effect of rasagiline on physical and behavioral development was not adequately assessed in this study. Rasagiline may be given as an adjunct therapy to levodopa/carbidopa treatment. In pregnant rats administered rasagiline (0.1, 0.3, 1 mg/kg/day) and levodopa/carbidopa (80/20 mg/kg/day) (alone and in combination) orally throughout the period of organogenesis, there was an increased incidence of wavy ribs in fetuses from rats treated with rasagiline in combination with levodopa/carbidopa at 1/80/20 mg/kg/day (approximately 8 times the rasagiline plasma AUC in humans at the MRHD and similar to the MRHD of levodopa/carbidopa [800/200 mg/day] on a mg/m2 basis). In pregnant rabbits dosed orally throughout the period of organogenesis with rasagiline alone (3 mg/kg) or in combination with levodopa/carbidopa (rasagiline: 0.1, 0.6, 1.2 mg/kg, levodopa/carbidopa: 80/20 mg/kg/day), an increase in embryo-fetal death was noted at rasagiline doses of 0.6 and 1.2 mg/kg/day when administered in combination with levodopa/carbidopa (approximately 7 and 13 times, respectively, the rasagiline plasma AUC in humans at the MRHD). There was an increase in cardiovascular abnormalities with levodopa/carbidopa alone (similar to the MRHD on a mg/m2 basis) and to a greater extent when rasagiline (at all doses; 1-13 times the rasagiline plasma AUC in humans at the MRHD) was administered in combination with levodopa/carbidopa. 8.3 Nursing Mothers In rats rasagiline was shown to inhibit prolactin secretion and it may inhibit milk secretion in humans. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when AZILECT is administered to a nursing woman. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Approximately half of patients in clinical trials were 65 years and over. There were no significant differences in the safety profile of the geriatric and nongeriatric patients. 8.6 Hepatic Impairment Rasagiline plasma concentration may be increased in patients with mild (up to 2 fold, Child-Pugh score 5-6), moderate (up to 7 fold, Child-Pugh score 7-9), and severe (Child-Pugh score 10-15) hepatic impairment. Patients with mild hepatic impairment should not exceed a dose of 0.5 mg/day. AZILECT should not be used in patients with moderate or severe hepatic impairment [see Dosage and Administration (2.3), Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)]. 8.7 Renal Impairment Dose adjustment of AZILECT is not required for patients with mild or moderate renal impairment because AZILECT plasma concentrations are not increased in patients with moderate renal impairment. Rasagiline has not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)].
Pregnancy and lactation
8.3 Nursing Mothers In rats rasagiline was shown to inhibit prolactin secretion and it may inhibit milk secretion in humans. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when AZILECT is administered to a nursing woman.

Interactions

7 DRUG INTERACTIONS Meperidine: Risk of serotonin syndrome (4, 7.1) Dextromethorphan: Risk of psychosis or bizarre behavior (4, 7.2) MAO inhibitors: Risk of non-selective MAO inhibition and hypertensive crisis (4, 7.3) 7.1 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 (4)]. 7.2 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 [see Contraindications (4)]. 7.3 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 [see Contraindications (4)]. 7.4 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. 7.5 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 (5.2) and Clinical Pharmacology (12.3)]. Concomitant use of AZILECT and MAO inhibitors is contraindicated [see Contraindications (4)]. 7.6 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 [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)]. 7.7 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 [see Warnings and Precautions (5.1)]. 7.8 Dopaminergic Antagonists It is possible that dopamine antagonists, such as antipsychotics or metoclopramide, could diminish the effectiveness of AZILECT.

More information

Category Value
Authorisation number NDA021641
Agency product number LH8C2JI290
Orphan designation No
Product NDC 68546-142,68546-229
Date Last Revised 07-06-2018
Type HUMAN PRESCRIPTION DRUG
Marketing authorisation holder Teva Neuroscience, Inc.