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Azilect

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Azilect

Azilect

WARNINGS

Included as part of the PRECAUTIONS section.

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 anti depressants) and a non-selective MAOI (e.g., phenelzine, tranylcypromine) or selective M AO-B inhibitors, such as selegiline (Eldepryl) and rasagiline (AZILECT (rasagiline) ). 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 AZILEC T.

The symptoms of serotonin syndrome have included behavioral and cognitive/mental stat us 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 (rasagiline) clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with AZILECT (rasagiline) , but the following antidepressants and doses were allowed in the AZILECT (rasagiline) 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 (rasagiline) with any antidepressant. At least 14 days should elapse between discontinuation of AZILECT (rasagiline) 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 an d 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] .

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, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

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 (rasagiline) should not be used in patients with moderate or severe hepatic impairment [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Risk for Hypertensive Crisis and Nonselective Monoamine Oxidase Inhibition Above The Recommended Doses

AZILECT (rasagiline) is a selective inhibitor of monoamine oxidase (MAO)-B at the recommended doses of 0.5 or 1 mg daily. AZILECT (rasagiline) 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 associate d with nonselective inhibition of MAO [see DOSAGE AND ADMINISTRATION, DRUG INTERACTIONS, and CLINICAL PHARMACOLOGY].

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 (rasagiline) . 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 (rasagiline) 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 (rasagiline) 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 AZI LECT.

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 (rasagiline) 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 (rasagiline) 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 (rasagiline) (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 w as approximately 44 % for AZILECT (rasagiline) vs 33% for placebo for mild to moderate systolic blood pressure decrements ( ≥ 20 mm Hg), 40 % for AZILECT (rasagiline) vs 33 % for placebo for mild to moderate diastolic blood pressure decrements ( ≥ 10 mm Hg), 7 % for AZILECT (rasagiline) vs 3 % for placebo for severe systolic blood pressure decrements ( ≥ 40 mm Hg), and 9 % for AZILECT (rasagiline) 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 (rasagiline) treatment and tends to decrease over time.

Some patients treated with AZILECT (rasagiline) 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 (rasagiline) 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 (rasagiline) 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 (rasagiline) (1 mg/day) was given in conjunction with levodopa, AZIL ECT 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 (rasagiline) (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 (rasagiline) treatment vs placebo.

There was no observed increased risk for in creasing 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 (rasagiline) 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 (rasagiline) , 4% of patients treated with 1 mg/day A ZILECT 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 an d 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 (rasagiline) 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 (rasagiline) .

AZILECT (rasagiline) 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].

Withdrawal emergent hyperpyrexia was not reported in the AZILECT (rasagiline) clinical development program.

Laboratory Tests

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Two year carcinogenicity studies were conducted in CD-1 mice at oral (gavage) doses of 1, 15, and 45 mg/kg and in Sprague-Dawley rats at oral (gavage) doses of 0.3, 1, and 3 mg/kg (males) or 0.5, 2, 5, and 17 mg/kg ( females). In rats, there was no increase in tumors at any dose tested. Plasma exposures at the highest dose tested were approximately 33 and 260 times, in male and female rats, respectively, the expected plasma exposures in humans at the maximum recommended dose (MRD) of 1 mg/day.

In mice, there was an increase in lung tumors (combined adenomas/carcinomas) at 15 and 45 mg/kg males and females. Plasma exposures associated with the no-effect dose (1 mg/kg) were approximately 5 times those expected in humans at the MRD.

The carcinogenic potential of rasagiline administered in combination with levodopa/carbidopa has not been examined.

Mutagenesis

Rasagiline was reproducibly clastogenic in in vitro chromosomal aberration assays in hum an lymphocytes in the presence of metabolic activation and was mutagenic and clastogenic in the in vitro mouse lymphomatic assay in the absence and presence of metabolic activation. Rasagiline was negative in the in vitro bacterial reverse mutation (Ames) assay, the in vivo unscheduled DNA synthesis assay, and the in vivo micronucleus assay in CD-1 mice. Rasagiline was also negative in the in vivo micronucleus assay in CD-1 mice when administered in combination with levodopa/carbidopa.

Impairment of Fertility

Rasagiline had no effect on mating performance or fertility in male rats treated prior to and throughout the mating period, or in female rats treated from prior to mating through day 17 of gestation at oral doses up to 3 mg/kg/day (approximately 30 times the expected plasma rasagiline exposure (AUC) at the maximum recommended human dose [1mg/day]). The effect of rasagiline administered in combination with levodopa/carbidopa on mating and fertility has not been examined.

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) o rally, 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 increase d 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 an d 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 ad ministered 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 MRH D 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 (rasagiline) 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 m ilk 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 (rasagiline) is administered to a nursing woman.

Pediatric Use

The safety and effectiveness of AZILECT (rasagiline) 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, Chi ld-Pugh score 56), moderate (up to 7 fold, Child-Pugh score 7-9), an d severe (Child-Pugh score 10-15) hepatic impairment. Patients with mild hepatic impairment should be given the dose of 0.5 mg/day. AZILECT (rasagiline) should not be used in patients with moderate or severe hepatic impairment [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Renal Impairment

Dose adjustment of AZILECT (rasagiline) is not required for patients with mild or moderate renal impairment because AZILECT (rasagiline) plasma concentrations are not increased in patients with moderate renal impairment. Rasagiline has not been studied in patients with severe renal impairment.

Last reviewed on RxList: 12/29/2009
This monograph has been modified to include the generic and brand name in many instances.

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