Azilect (rasagiline tablets) is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa.
The effectiveness of Azilect was demonstrated in patients with early Parkinson's disease who were receiving Azilect as monotherapy and who were not receiving any concomitant dopaminergic therapy. The effectiveness of Azilect as adjunct therapy was demonstrated in patients with Parkinson's disease who were treated with levodopa.
Azilect Dosage and Administration
Azilect is a selective inhibitor of monoamine oxidase (MAO)-B at recommended doses of 0.5 or 1 mg daily. Dietary tyramine restriction is not ordinarily required with recommended doses of Azilect. 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 even at the recommended dose due to mild increased sensitivity to tyramine. The selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily dose [see Warnings and Precautions (5.4), Clinical Pharmacology (12.3, and Information for Patients (17.3))].
Monotherapy
The recommended Azilect dose for the treatment of Parkinson's disease patients is 1 mg administered orally once daily.
Adjunctive Therapy
The recommended initial dose is 0.5 mg administered orally once daily. If a sufficient clinical response is not achieved, the dose may be increased to 1 mg administered once daily.
Change of Levodopa Dose in Adjunct Therapy
When Azilect is used in combination with levodopa, a reduction of the levodopa dosage may be considered based upon individual response. During the controlled trials of Azilect as adjunct therapy to levodopa, levodopa dosage was reduced in some patients. In clinical studies, dosage reduction of levodopa was allowed within the first 6 weeks if dopaminergic side effects, including dyskinesia and hallucinations, emerged. In Study 1, levodopa dosage reduction occurred in 8% of patients in the placebo group and in 16% and 17% of patients in the 0.5 mg/day and 1 mg/day rasagiline groups, respectively. In those patients who had levodopa dosage reduced, the dose was reduced on average by about 7%, 9%, and 13% in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively. In Study 2, levodopa dosage reduction occurred in 6% of patients in the placebo group and in 9% in the rasagiline 1 mg/day group. In patients who had their levodopa dosage reduced, the dose was reduced on average by about 13% and 11% in the placebo and the rasagiline groups, respectively.
Patients with Hepatic Impairment
Azilect plasma concentrations will increase in patients with hepatic impairment. Patients with mild hepatic impairment should use 0.5 mg daily of Azilect. Azilect should not be used in patients with moderate or severe hepatic impairment [see Warnings and Precautions (5.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Patients with 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.
Patients Taking Ciprofloxacin or Other CYP1A2 Inhibitors
Rasagiline plasma concentrations are expected to double in patients taking concomitant ciprofloxacin and other CYP1A2 inhibitors. Therefore, patients taking concomitant ciprofloxacin or other CYP1A2 inhibitors should use 0.5 mg daily of Azilect [see Warnings and Precautions (5.2), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].
Dosage Forms and Strengths
Azilect 0.5 mg Tablets: White to off-white, round, flat, beveled tablets, debossed with "GIL 0.5" on one side and plain on the other side containing, as the active ingredient, rasagiline mesylate equivalent to 0.5 mg of rasagiline base.
Azilect 1 mg Tablets: White to off-white, round, flat, beveled tablets, debossed with "GIL 1" on one side and plain on the other side containing, as the active ingredient, rasagiline mesylate equivalent to 1 mg of rasagiline base.
Contraindications
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.
Warnings and Precautions
Coadministration with Antidepressants
Severe CNS toxicity associated with hyperpyrexia has been reported with the combined treatment of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a non-selective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (Eldepryl) and rasagiline (Azilect). These adverse reactions are often described as "serotonin syndrome" which can result in death. In the post-marketing period, non-fatal cases of serotonin syndrome have been reported in patients treated with antidepressants concomitantly with Azilect.
The symptoms of serotonin syndrome have included 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, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor).
Azilect clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with Azilect, but the following antidepressants and doses were allowed in the Azilect trials: amitriptyline ≤ 50 mg/daily, trazodone ≤ 100 mg/daily, citalopram ≤ 20 mg/daily, sertraline ≤ 100 mg/daily and paroxetine ≤ 30 mg/daily.
Although a small number of rasagiline-treated patients were concomitantly exposed to antidepressants (tricyclics n=115; SSRIs n=141), the exposure, both in dose and number of subjects, was not adequate to rule out the possibility of an untoward reaction from combining these agents. Furthermore, because the mechanisms of these reactions are not fully understood, it seems prudent, in general, to avoid the combination of Azilect with any antidepressant. At least 14 days should elapse between discontinuation of Azilect and initiation of treatment with a SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant. Because of the long half lives of certain antidepressants (e.g., fluoxetine and its active metabolite), at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of Azilect [see Drug Interactions (7.5)].
Ciprofloxacin and Other CYP1A2 Inhibitors
Rasagiline plasma concentrations may increase up to 2 fold in patients using concomitant ciprofloxacin and other CYP1A2 inhibitors [see Dosage and Administration (2.5), Drug Interactions (7.7), and Clinical Pharmacology (12.3)].
Hepatic Impairment
Rasagiline plasma concentration may increase 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 be given the 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) and Clinical Pharmacology (12.3)].
Risk for Hypertensive Crisis and Nonselective Monoamine Oxidase Inhibition Above The Recommended Doses
Azilect is a selective inhibitor of monoamine oxidase (MAO)-B at the recommended doses of 0.5 or 1 mg daily. Azilect should not be used at daily doses exceeding 1 mg/day (or 0.5 mg/day for patients with mild hepatic impairment or in patients using concomitant ciprofloxacin or another CYP1A2 inhibitor) because of the risks of hypertensive crisis and other adverse reactions associated with nonselective inhibition of MAO [see Dosage and Administration (2), Drug Interactions (7.9), and Clinical Pharmacology (12.3)].
Dietary tyramine restriction is not ordinarily required with ingestion of most foods and beverages that may contain tyramine, during treatment with recommended doses of Azilect. 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 even at the recommended doses 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.
Rare cases of hypertensive crisis have been reported in the post-marketing period in patients after ingesting unknown amounts of tyramine-rich foods while taking recommended doses of Azilect.
Melanoma
Epidemiological studies have shown that patients with Parkinson's disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.
For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).
Dyskinesia
When used as an adjunct to levodopa, Azilect may cause dyskinesia or potentiate dopaminergic side effects and exacerbate pre-existing dyskinesia (treatment-emergent dyskinesia occurred in about 18% of patients treated with 0.5 mg or 1 mg rasagiline as an adjunct to levodopa, and 10% of patients who received placebo as an adjunct to levodopa). Decreasing the dose of levodopa may ameliorate this side effect.
Lowering of Blood Pressure and Postural/Orthostatic Hypotension
In placebo controlled studies of Azilect given in combination with levodopa, the incidence of postural hypotension consisting of a systolic blood pressure decrease (≥ 30 mm Hg) or a diastolic blood pressure decrease (≥ 20 mm Hg) after standing was 13.4 % with Azilect (1 mg/day) compared to 8.5 % with placebo.
At the 1 mg dose, the frequency of orthostatic hypotension at any time during the study was approximately 44 % for Azilect vs 33% for placebo for mild to moderate systolic blood pressure decrements (≥ 20 mm Hg), 40 % for Azilect vs 33 % for placebo for mild to moderate diastolic blood pressure decrements (≥ 10 mm Hg), 7 % for Azilect vs 3 % for placebo for severe systolic blood pressure decrements (≥ 40 mm Hg), and 9 % for Azilect vs 6 % for placebo for severe diastolic blood pressure decrements (≥ 20 mm Hg). There was also an increased risk for some of these abnormalities at the lower 0.5 mg daily dose and for an individual patient having mild to moderate or severe postural hypotension for both systolic and diastolic blood pressure.
Clinical trial data further suggest that postural hypotension occurs most frequently in the first two months of Azilect treatment and tends to decrease over time.
Some patients treated with Azilect experienced a mildly increased risk for significant decreases in blood pressure unrelated to standing but while supine.
The risk for post-treatment hypotension (e.g., systolic < 90 or diastolic < 50 mm Hg) combined with a significant decrease from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for Azilect 1 mg (3.2 %) compared to placebo (1.3 %).
There was no clear increased risk for lowering of blood pressure or postural hypotension associated with Azilect 1 mg/day as monotherapy.
When used as an adjunct to levodopa, postural hypotension was also reported as an adverse reaction in approximately 6% of patients treated with 0.5 mg rasagiline, 9% of patients treated with 1 mg rasagiline and 3% of patients treated with placebo. Postural hypotension led to drug discontinuation and premature withdrawal from clinical trials in one (0.7%) patient treated with rasagiline 1 mg/day, no patients treated with rasagiline 0.5 mg/day and no placebo-treated patients.
Elevation of Blood Pressure
In studies in which Azilect (1 mg/day) was given in conjunction with levodopa, Azilect produced an increased incidence of a significant, high blood pressure (e.g., systolic > 180 or diastolic > 100 mm Hg) of 4% compared to 3% for placebo.
The risk for developing post-treatment high blood pressure (e.g., systolic > 180 or diastolic >100 mm Hg) combined with a significant increase from baseline (e.g., systolic > 30 or diastolic > 20 mm Hg) was higher for Azilect (2 %) compared to placebo (1 %).
There was no increased frequency of the incidence of hypertension as an adverse reaction in the adjunctive treatment pivotal trials for Azilect treatment vs placebo.
There was no observed increased risk for increasing blood pressure or high blood pressure (based upon various measurements and analyses) or for the development of hypertension as an adverse reaction in the monotherapy study for 1 mg daily Azilect treatment (vs placebo).
Hallucinations / Psychotic-Like Behavior
In the monotherapy study, hallucinations were reported as an adverse event in 1.3% of patients treated with 1 mg rasagiline and in 0.7% of patients treated with placebo. In the monotherapy trial, hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 1.3% of the 1 mg rasagiline-treated patients and in none of the placebo-treated patients.
When used as an adjunct to levodopa, hallucinations were reported as an adverse reaction in approximately 5% of patients treated with 0.5 mg/day Azilect, 4% of patients treated with 1 mg/day Azilect and 3% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of patients treated with 0.5 mg/day or 1 mg/day rasagiline and none of the placebo-treated patients.
Patients should be informed of the possibility of developing hallucinations and instructed to report them to their health care provider promptly should they develop.
Patients with a major psychotic disorder should ordinarily not be treated with Azilect because of the risk of exacerbating the psychosis with an increase in central dopaminergic tone. In addition, many treatments for psychosis that decrease in central dopaminergic tone may decrease the effectiveness of Azilect.
Azilect administration may cause or exacerbate psychotic-like behavior based upon post-marketing reports. This adverse reaction has been reported with many anti-Parkinsonian drugs that increase central dopaminergic tone. This abnormal behavior has been exhibited by one or more of a variety of manifestations including paranoia, confusional state/confusion, psychotic disorder, agitation, delusion, and hallucinations.
Withdrawal-Emergent Hyperpyrexia and Confusion
A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone. [see Dosage and Administration (2.2)].
Withdrawal emergent hyperpyrexia was not reported in the Azilect clinical development program.
Laboratory Tests
No specific laboratory tests are required for the treatment of patients on Azilect.
Adverse Reactions
Clinical Studies Experience
During the clinical development of Azilect, 1361 Parkinson's 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 reactions. Therefore, most of the adverse reactions data in this section are presented separately for each population.
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 rates in the clinical trials of another drug and may not reflect the rates of adverse reactions observed in practice.
Patients Receiving Azilect as Initial Monotherapy Treatment
Adverse Reactions 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 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.
Adverse Reaction Incidence in Controlled Clinical Studies
The most commonly observed adverse reactions were those in which the treatment difference for the incidence in Azilect-treated patients was ≥ 3 % greater than the incidence in the placebo-treated patients and included flu syndrome, arthralgia, depression, and dyspepsia. Table 1 lists treatment-emergent adverse reactions 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.
| Placebo-Controlled Studies Without Levodopa Treatment | 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 |
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.
Patients Receiving Azilect as Adjunct to Levodopa Therapy
Adverse Reactions Leading to Discontinuation in Controlled Clinical Studies
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 reactions compared to 6% of the 159 patients who received placebo. The adverse reactions 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.
Adverse Reactions: Incidence in Controlled Clinical Studies
The most commonly observed adverse reactions were those in which the treatment difference for the incidence in Azilect-treated patients (n=149) was ≥ 3 % greater than the incidence in the placebo-treated patients (n=159) and included dyskinesia, accidental injury, weight loss, postural hypotension, vomiting, anorexia, arthralgia, abdominal pain, nausea, constipation, dry mouth, rash, abnormal dreams, and fall.
Table 2 lists treatment-emergent adverse reactions that occurred in ≥ 2% of patients treated with Azilect 1 mg/day as 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.
| Azilect 1 mg + Levodopa (N=149) | Azilect 0.5 mg + Levodopa (N=164) | Placebo + Levodopa (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 |
Several of the more common adverse reactions seemed dose-related, including weight loss, postural hypotension, and dry mouth.
Other adverse reactions 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.
Other Adverse Reactions Observed During All Phase 2/3 Clinical Trials
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: Infrequent: eczema, urticaria Rare: exfoliative dermatitis, leukoderma
Special senses: 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
Post-marketing Experience
The following adverse events not described in sections 4 and 5 have been identified during the post-marketing/post-approval use of Azilect. Because these adverse events are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency nor to establish unequivocally a causal relationship to drug exposure: Increased libido including hypersexuality, impulse control symptoms, pathological gambling [see Patient Counseling Information (17.11)]
Drug Interactions
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 (4.1)].
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 (4.2)].
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 (4.3)].
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 (5.1)].
Levodopa/Carbidopa
[see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].
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 (5.2) and Clinical Pharmacology (12.3)].
Theophylline
[see Clinical Pharmacology (12.3)].
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 (5.4)].
USE IN SPECIFIC POPULATIONS
Pregnancy
Category C
No effect on embryo-fetal development was observed in a combined mating/fertility and embryo-fetal development study in female rats at doses up to 3 mg/kg/day (approximately 30 times the expected plasma rasagiline exposure (AUC) at the maximum recommended human dose [MRHD, 1 mg/day]). Effects on embryo-fetal development in rabbit have not been adequately assessed.
In a study in which pregnant rats were dosed with rasagiline (0.1, 0.3, 1 mg/kg/day) orally, from the beginning of organogenesis to day 20 post-partum, offspring survival was decreased and offspring body weight was reduced at doses of 0.3 mg/kg/day and 1 mg/kg/day (10 and 16 times the expected plasma rasagiline exposure [AUC] at the MRHD). No plasma data were available at the no-effect dose (0.1 mg/kg); however, that dose is 1 times the MRHD on a mg/m2 basis. Rasagiline's effect 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 a study in which pregnant rats were dosed with rasagiline (0.1, 0.3, 1 mg/kg/day) and levodopa/carbidopa (80/20 mg/kg/day) (alone and in combination) 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 plasma AUC expected in humans at the MRHD and 1/1 times the MRHD of levodopa/carbidopa [800/200 mg/day] on a mg/m2 basis). In a study in which pregnant rabbits were dosed 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 plasma rasagiline AUC at the MRHD). There was an increase in cardiovascular abnormalities with levodopa/carbidopa alone (1/1 times the MRHD on a mg/m2 basis) and to a greater extent when rasagiline (at all doses; 1-13 times the plasma rasagiline AUC at the MRHD) was administered in combination with levodopa/carbidopa.
There are no adequate and well-controlled studies of rasagiline in pregnant women. Therefore, Azilect should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
In rats rasagiline was shown to inhibit prolactin secretion and it may inhibit milk secretion in females.
It is not known whether rasagiline 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.
Pediatric Use
The safety and effectiveness of Azilect in the pediatric population have not been studied.
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 non-geriatric patients.
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 be given the 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 (5.3) and Clinical Pharmacology (12.3)].
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.
Drug Abuse and Dependence
Controlled Substance
Azilect is not a controlled substance.
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