Azilect

Name: Azilect

Side effects

The following adverse reactions are described in more detail in the WARNINGS AND PRECAUTIONS section of the label:

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

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
  AZILECT 1 mg (N=149) Placebo (N=151)
  % of Patients % of Patients
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
  AZILECT 1 mg (N=149) AZILECT 0.5 mg (N=164) Placebo
(N=159)
  % of patients % of patients % of patients
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.

Clinical pharmacology

Mechanism Of Action

AZILECT is a selective, irreversible MAO-B inhibitor indicated for the treatment of idiopathic Parkinson's disease. The results of a clinical trial designed to examine the effects of AZILECT on blood pressure when it is administered with increasing doses of tyramine indicates the functional selectivity can be incomplete when healthy subjects ingest large amounts of tyramine while receiving recommended doses of AZILECT. The selectivity for inhibiting MAO-B diminishes in a dose-related manner.

MAO, a flavin-containing enzyme, is classified into two major molecular species, A and B, and is localized in mitochondrial membranes throughout the body in nerve terminals, brain, liver and intestinal mucosa. MAO regulates the metabolic degradation of catecholamines and serotonin in the CNS and peripheral tissues. MAO-B is the major form in the human brain. In ex vivo animal studies in brain, liver, and intestinal tissues, rasagiline was shown to be a potent, irreversible monoamine oxidase type B (MAO-B) selective inhibitor. Rasagiline at the recommended therapeutic dose was also shown to be a potent and irreversible inhibitor of MAO-B in platelets. The precise mechanisms of action of rasagiline are unknown. One mechanism is believed to be related to its MAO-B inhibitory activity, which causes an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline's beneficial effects seen in models of dopaminergic motor dysfunction.

Pharmacodynamics

Tyramine Challenge Test

Results of a tyramine challenge study indicate that rasagiline at recommended doses is relatively selective for inhibiting MAO-B and can be used without dietary tyramine restriction. However, certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts of tyramine (i.e., 150 mg or greater) and could potentially cause severe hypertension caused by tyramine interaction in patients taking AZILECT due to mild increased sensitivity to tyramine at recommended doses. Relative selectivity of AZILECT for inhibiting MAO-B diminished in a dose-related manner as the dose progressively increased above the highest recommended daily dose (1 mg) [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

Platelet MAO Activity in Clinical Studies

Studies in healthy subjects and in Parkinson's disease patients have shown that rasagiline inhibits platelet MAO-B irreversibly. The inhibition lasts at least 1 week after last dose. Almost 25-35% MAO-B inhibition was achieved after a single rasagiline dose of 1 mg/day and more than 55% of MAO-B inhibition was achieved after a single rasagiline dose of 2 mg/day. Over 90% inhibition was achieved 3 days after rasagiline daily dosing at 2 mg/day and this inhibition level was maintained 3 days postdose. Multiple doses of rasagiline of 0.5, 1 and 2 mg per day resulted in complete MAO-B inhibition.

Pharmacokinetics

Rasagiline in the range of 1-6 mg demonstrated a more than proportional increase in AUC, while Cmax was dose proportional. Rasagiline mean steady-state half life is 3 hours but there is no correlation of pharmacokinetics with its pharmacological effect because of its irreversible inhibition of MAO-B.

Absorption

Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 1 hour. The absolute bioavailability of rasagiline is about 36%.

Food does not affect the Tmax of rasagiline, although Cmax and exposure (AUC) are decreased by approximately 60% and 20%, respectively, when the drug is taken with a high fat meal. Because AUC is not significantly affected, AZILECT can be administered with or without food.

Distribution

The mean volume of distribution at steady-state is 87 L, indicating that the tissue binding of rasagiline is in excess of plasma protein binding. Plasma protein binding ranges from 88-94% with mean extent of binding of 61-63% to human albumin over the concentration range of 1-100 ng/mL.

Metabolism and Elimination

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. The metabolism of rasagiline proceeds through two main pathways: N-dealkylation and/or hydroxylation to yield 1-aminoindan (AI), 3-hydroxy-N-propargyl-1 aminoindan (3-OH-PAI) and 3-hydroxy-1-aminoindan (3-OH-AI). In vitro experiments indicate that both routes of rasagiline metabolism are dependent on the cytochrome P450 (CYP) system, with CYP1A2 being the major isoenzyme involved in rasagiline metabolism. Glucuronide conjugation of rasagiline and its metabolites, with subsequent urinary excretion, is the major elimination pathway.

After oral administration of 14C-labeled rasagiline, elimination occurred primarily via urine and secondarily via feces (62% of total dose in urine and 7% of total dose in feces over 7 days), with a total calculated recovery of 84% of the dose over a period of 38 days. Less than 1% of rasagiline was excreted as unchanged drug in urine.

Special Populations

Hepatic Impairment

Following repeat dose administration (7 days) of rasagiline (1 mg/day) in subjects with mild hepatic impairment (Child-Pugh score 5-6), AUC and Cmax were increased by 2 fold and 1.4 fold, respectively, compared to healthy subjects. In subjects with moderate hepatic impairment (Child-Pugh score 7-9), AUC and Cmax were increased by 7 fold and 2 fold, respectively, compared to healthy subjects [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Renal Impairment

Following repeat dose administration (8 days) of rasagiline (1 mg/day) in subjects with moderate renal impairment, rasagiline exposure (AUC) was similar to rasagiline exposure in healthy subjects, while the major metabolite 1-AI exposure (AUC) was increased 1.5-fold in subjects with moderate renal impairment, compared to healthy subjects. Because 1-AI is not an MAO inhibitor, no dose adjustment is needed for patients with mild and moderate renal impairment. Data are not available for patients with severe renal impairment.

Elderly

Since age has little influence on rasagiline pharmacokinetics, it can be administered at the recommended dose in the elderly (≥ 65 years).

Pediatric

AZILECT has not been investigated in patients below 18 years of age.

Gender

The pharmacokinetic profile of rasagiline is similar in men and women.

Drug-Drug Interactions

Levodopa

A study in Parkinson's disease patients, in which the effect of levodopa/carbidopa (LD/CD) on rasagiline pharmacokinetics at steady state was investigated, showed that the pharmacokinetics of rasagiline were not affected by concomitant administration of LD/CD.

Effect of Other Drugs on the Metabolism of AZILECT

In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of rasagiline. There is the potential for inhibitors of this enzyme to alter AZILECT clearance when coadministered [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Ciprofloxacin: When ciprofloxacin, an inhibitor of CYP1A2, was administered to healthy volunteers (n=12) at 500 mg (BID) with rasagiline at 2 mg/day, the AUC of rasagiline increased by 83% and there was no change in the elimination half life [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Theophylline: Coadministration of rasagiline 1 mg/day and theophylline, a substrate of CYP1A2, up to 500 mg twice daily to healthy subjects (n=24) did not affect the pharmacokinetics of either drug.

Antidepressants: Severe CNS toxicity (occasionally fatal) associated with hyperpyrexia as part of a serotonin syndrome, has been reported with combined treatment of an antidepressant (e.g., from one of many classes including tricyclic or tetracyclic antidepressants, SSRIs, SNRIs, triazolopyridine antidepressants) and nonselective MAOI or a selective MAO-B inhibitor [see WARNINGS AND PRECAUTIONS].

Effect of AZILECT on Other Drugs

No additional in vivo trials have investigated the effect of AZILECT on other drugs metabolized by the cytochrome P450 enzyme system. In vitro studies showed that rasagiline at a concentration of 1 mcg/ml (equivalent to a level that is 160 times the average Cmax ~ 5.9-8.5 ng/mL in Parkinson's disease patients after 1 mg rasagiline multiple dosing) did not inhibit cytochrome P450 isoenzymes, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A. These results indicate that rasagiline is unlikely to cause any clinically significant interference with substrates of these enzymes.

Clinical Studies

The effectiveness of AZILECT for the treatment of Parkinson's disease was established in four 18-to 26-week, randomized, placebo-controlled trials, as initial monotherapy or adjunct therapy.

Monotherapy Use Of AZILECT

Study 1 was a double-blind, randomized, fixed-dose parallel group, 26-week study in early Parkinson's disease patients not receiving any concomitant dopaminergic therapy at the start of the study. The majority of the patients were not treated with medications for Parkinson's disease before receiving AZILECT.

In Study 1, 404 patients were randomly assigned to receive placebo (138 patients), AZILECT 1 mg/day (134 patients) or AZILECT 2 mg/day (132 patients). Patients were not allowed to take levodopa, dopamine agonists, selegiline or amantadine, but could take stable doses of anticholinergic medication, if necessary. The average Parkinson's disease duration was approximately 1 year (range 0 to 11 years).

The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS), [mentation (Part I) + activities of daily living (ADL) (Part II) + motor function (Part III)]. The UPDRS is a multi-item rating scale that measures the ability of a patient to perform mental and motor tasks as well as activities of daily living. A reduction in the score represents improvement and a beneficial change from baseline appears as a negative number.

AZILECT (1 or 2 mg once daily) was superior to placebo on the primary measure of effectiveness in patients receiving six months of treatment and not on dopaminergic therapy. The effectiveness of AZILECT 1 mg and 2 mg was comparable. Table 4 shows the results of Study 1. There were no differences in effectiveness based on age or gender between AZILECT 1 mg/day and placebo.

Table 4: Change in Total UPDRS Score in Study 1

  Baseline score Change from baseline to termination score p-value vs. placebo
Placebo 24.5 3.9
AZILECT 1 mg 24.7 0.1 0.0001
AZILECT 2 mg 25.9 0.7 0.0001

Adjunct Use Of AZILECT

Study 2 was a double-blind, randomized, placebo-controlled, parallel group, 18-week study, investigating AZILECT 1 mg as adjunct therapy to dopamine agonists without levodopa. Patients were on a stable dose of dopamine agonist (ropinirole, mean 8 mg/day or pramipexole, mean 1.5 mg/day) therapy for ≥ 30 days, but at doses not sufficient to control Parkinson's disease symptoms.

In Study 2, 321 patients randomly received placebo (162 patients) or AZILECT 1 mg/day (159 patients) and had a post-baseline assessment. The average Parkinson's disease duration was approximately 2 years (range 0.1 to 14.5 years).

The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS) [mentation (Part I) + activities of daily living (ADL) (Part II) + motor function (Part III)].

In Study 2, AZILECT 1 mg was superior to placebo on the primary measure of effectiveness (see Table 5).

Table 5: Change in Total UPDRS Score in Study 2

  Baseline score Change from baseline to termination score* p-value vs. placebo
Placebo 29.8 -1.2
AZILECT1 mg 32.1 -3.6 0.012
*A negative change from baseline indicates improvement in the UPDRS

Secondary outcome assessment of the individual subscales of the UPDRS indicates that the UPDRS Part III motor subscale was primarily responsible for the overall AZILECT effect on the UPDRS score (see Table 6).

Table 6: Secondary Measures of Effectiveness in Study 2

  Baseline (score) Change from baseline to termination score
UPDRS Part IIADL (Activities of Daily Living) subscale score
Placebo 7.9 0.4
AZILECT 1 mg 8.6 -0.3
UPDRS Part III Motor subscale score
Placebo 20.4 -1.2
AZILECT 1 mg 22.2 -3.7

Study 3 and Study 4 were randomized, multinational trials conducted in more advanced Parkinson's disease patients treated chronically with levodopa and experiencing motor fluctuations (including but not limited to, end of dose “wearing off,” sudden or random “off,” etc.). Study 3 was conducted in North America (U.S. and Canada) and compared AZILECT 0.5 mg and 1 mg daily to placebo. Study 4 was conducted outside of North America in Europe, Argentina and Israel, and compared AZILECT 1 mg daily to placebo.

Patients had Parkinson's disease for an average of 9 years (range 5 months to 33 years), had taken levodopa for an average of 8 years (range 5 months to 32 years), and had motor fluctuations for approximately 3 to 4 years (range 1 month to 23 years). Patients kept home Parkinson's disease diaries just prior to baseline and at specified intervals during the trial. Diaries recorded one of the following four conditions for each half-hour interval over a 24-hour period: “ON” (period of relatively good function and mobility) as either “ON” with no dyskinesia or without troublesome dyskinesia, or “ON” with troublesome dyskinesia, “OFF” (period of relatively poor function and mobility) or asleep. “Troublesome” dyskinesia is defined as dyskinesia that interferes with the patient's daily activity. All patients had inadequate control of their motor symptoms with motor fluctuations typical of advanced stage disease despite receiving levodopa/decarboxylase inhibitor. The average dose of levodopa taken with a decarboxylase inhibitor was approximately 700 to 800 mg (range 150 to 3000 mg/day). Patients continued their stable doses of additional anti-PD medications at entry into the trials. Approximately 65% of patients in both studies were also taking a dopamine agonist. In the North American study (Study 3), approximately 35% of patients took entacapone with levodopa/decarboxylase inhibitor. The majority of patients taking entacapone were also taking a dopamine agonist.

In Study 3 and Study 4, the primary measure of effectiveness was the change in the mean number of hours spent in the “OFF” state at baseline compared to the mean number of hours spent in the “OFF” state during the treatment period.

In Study 3, patients were randomly assigned to receive placebo (159 patients), AZILECT 0.5 mg/day (164 patients), or AZILECT 1 mg/day (149 patients) for 26 weeks. Patients averaged 6 hours daily in the “OFF” state at baseline as confirmed by home diaries.

In Study 4, patients were randomly assigned to receive placebo (229 patients), AZILECT 1 mg/day (231 patients) or a COMT inhibitor (active comparator), taken along with scheduled doses of levodopa/decarboxylase inhibitor (227 patients) for 18 weeks. Patients averaged 5.6 hours daily in the “OFF” state at baseline as confirmed by home diaries.

In Study 3 and Study 4, AZILECT 1 mg once daily reduced “OFF” time compared to placebo when added to levodopa in patients experiencing motor fluctuations (Tables 7 and 8). The lower dose (0.5 mg) of AZILECT also significantly reduced “OFF” time (Table 7), but had a numerically smaller effect than the 1 mg dose of AZILECT. In Study 4, the active comparator also reduced “OFF” time when compared to placebo.

Table 7: Change in mean total daily “OFF” time in Study 3

  Baseline (hours) Change from baseline to treatment period (hours) p-value vs. placebo
Placebo 6.0 -0.9
AZILECT 0.5 mg 6.0 -1.4 0.0199
AZILECT 1.0 mg 6.3 -1.9 < 0.0001

Table 8: Change in mean total daily “OFF” time in Study 4

  Baseline (hours) Change from baseline to treatment period (hours) p-value vs. placebo
Placebo 5.5 -0.40
AZILECT 1.0 mg 5.6 -1.2 0.0001

In Study 3 and Study 4, dose reduction of levodopa was allowed within the first 6 weeks, if dopaminergic side effects developed including dyskinesia or hallucinations. In Study 3, the levodopa dose was reduced 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 AZILECT groups, respectively. When levodopa was reduced, the dose was reduced by 7%, 9%, and 13% in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively. In Study 4, levodopa dose reduction occurred in 6% of patients in the placebo group and in 9% in the AZILECT 1 mg/day groups, respectively. When levodopa was reduced, it was reduced by 13% and 11% in the placebo and the AZILECT groups, respectively.

There were no differences in effectiveness based on age or gender between AZILECT 1 mg/day and placebo.

Several secondary outcome assessments in the two studies showed statistically significant improvements with rasagiline. These included effects on the activities of daily living (ADL) subscale of the UPDRS performed during an “OFF” period and the motor subscale of the UPDRS performed during an “ON” period. In both scales, a negative response represents improvement. Tables 9 and 10 show these results for Studies 3 and 4.

Table 9: Secondary Measures of Effectiveness in Study 3

  Baseline (score) Change from baseline to last value
UPDRS ADL (Activities of Daily Living) subscale score while “OFF”
Placebo 15.5 0.68
AZILECT 0.5 mg 15.8 -0.60
AZILECT 1 mg 15.5 -0.68
UPDRS Motor subscale score while “ON”
Placebo 20.8 1.21
AZILECT 0.5 mg 21.5 -1.43
AZILECT 1 mg 20.9 -1.30

Table 10: Secondary Measures of Effectiveness in Study 4

  Baseline (score) Change from baseline to last value
UPDRS ADL (Activities of Daily Living) subscale score while “OFF”
Placebo 18.7 -0.89
AZILECT 1 mg 19.0 -2.61
UPDRS Motor subscale score while “ON”
Placebo 23.5 -0.82
AZILECT 1 mg 23.8 -3.87

Azilect Drug Class

Azilect is part of the drug class:

  • Monoamine oxidase B inhibitors

Inform MD

Before receiving Azilect, tell your doctor if you are allergic to any of the ingredients found in Azilect.

Tell your doctor about all of your medical conditions including if you have liver disease. 

Tell your doctor if you are pregnant or breastfeeding.

Tell your doctor if you are taking, or are planning to take, prescription or non-prescription medicines, vitamins, or herbal supplements.

Adverse Effects

>10%

EPS (dyskinesia/dystonia) (18%)

Headache (14%)

Nausea (10-12%)

1-10%

Postural hypotension (6-9%)

Constipation (4-9%)

Weight loss (2-9%)

Arthralgia (7%)

Dyspepsia (7%)

Xerostomia (2-6%)

Depression (5%)

Fall (5%)

Flu-like syndrome (5%)

Hallucination (4-5%)

Conjunctivitis (3%)

Fever (3%)

Gastroenteritis (3%)

Rhinitis (3%)

Arthritis (2%)

Bruising (2%)

Malaise (2%)

Neck pain (2%)

Parasthesia (2%)

Vertigo (2%)

<1%

CVA

MI

Bundle branch block

Gastrointestinal hemorrhage

What is rasagiline?

Rasagiline is a monoamine oxidase-B (MAO-B) inhibitor. It works by increasing the levels of certain chemicals in the brain.

Rasagiline is used to treat the symptoms of Parkinson's disease (stiffness, tremors, spasms, poor muscle control). Rasagiline is sometimes used with another drug called levodopa.

Rasagiline may also be used for purposes not listed in this medication guide.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Overdose symptoms may include drowsiness, dizziness, severe headache, hallucinations, feeling agitated or irritable, fast and uneven heart rate, muscle spasms, sweating, cold or clammy skin, shallow breathing, fainting, or seizure (convulsions).

Azilect Dosage and Administration

General

Concomitant Levodopa/Carbidopa Therapy

  • Consider reduction of levodopa dosage if adverse dopaminergic effects (e.g., dyskinesia, hallucinations) occur.1 In clinical studies, approximately 9–17% of patients receiving 0.5 or 1 mg rasagiline daily required reduction of levodopa dosage (average reduction: about 9–13%).1

Administration

Oral Administration

Administer orally once daily without regard to meals.1 2

Dosage

Available as rasagiline mesylate; dosage expressed in terms of rasagiline.1

Adults

Parkinsonian Syndrome Monotherapy Oral

1 mg once daily.1

Adjunctive Therapy with Levodopa Oral

Initially, 0.5 mg once daily.1

If adequate response is not achieved, may increase dosage to 1 mg once daily.1

Special Populations

Hepatic Impairment

0.5 mg once daily in patients with mild (Child-Pugh score of 5–6) hepatic impairment.1 2

Use not recommended in patients with moderate or severe (Child-Pugh score ≥7) hepatic impairment.1 2 (See Special Populations under Pharmacokinetics.)

Renal Impairment

No dosage adjustment required in patients with mild or moderate renal impairment.1

Geriatric Patients

No dosage adjustment required.1

Cautions for Azilect

Contraindications

  • Concomitant use with cyclobenzaprine, dextromethorphan, meperidine, methadone, propoxyphene (no longer commercially available in the US), tramadol, St. John’s wort (Hypericum perforatum), or other MAO inhibitors.1 (See Interactions.)

Warnings/Precautions

Concomitant Use with Antidepressants or Certain Opiate Agonists

Severe, potentially fatal reactions resembling serotonin syndrome reported following concomitant use of selective (e.g., rasagiline, selegiline) or nonselective (e.g., phenelzine, tranylcypromine) MAO inhibitors with antidepressants (e.g., SNRIs, SSRIs, tricyclic or tetracyclic antidepressants, triazolopyridine-derivative antidepressants) or certain opiate agonists (i.e., meperidine, tramadol).1 (See Interactions.) Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile BP, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).1 10

Concomitant use with certain opiate agonists (i.e., meperidine, methadone, propoxyphene [no longer commercially available in the US], tramadol) is contraindicated.1 Concomitant use with antidepressants generally should be avoided.1 (See Specific Drugs and Foods under Interactions.)

Concomitant Use with Ciprofloxacin or Other CYP1A2 Inhibitors

Concomitant use with ciprofloxacin or other CYP1A2 inhibitors shown, or expected, to increase plasma rasagiline concentrations by up to twofold.1 Adjustment of rasagiline dosage recommended.1 8 (See Drugs Affecting Hepatic Microsomal Enzymes under Interactions.)

Hypertensive Crisis

Hypertensive crisis (i.e., cheese reaction) reported rarely following concomitant use of recommended dosages of a selective MAO inhibitor (including rasagiline) with tyramine-rich foods or sympathomimetic amines (e.g., ephedrine).1 (See Interactions and see also Advice to Patients.)

Risk of hypertensive reactions increases at dosages exceeding recommended daily dosage (selectivity of rasagiline for MAO-B diminishes as dosage increases).1 Do not exceed recommended dosage of 1 mg daily (or 0.5 mg daily in patients with mild hepatic impairment or in patients receiving concomitant ciprofloxacin or other CYP1A2 inhibitors).1

Melanoma

Epidemiologic studies indicate patients with Parkinson’s disease have a twofold to approximately sixfold greater risk of developing melanoma than the general population.1 Unclear whether increased risk is related to Parkinson's disease or other factors (e.g., drugs used to treat the disease).1

Monitor for melanoma on a frequent and regular basis.1 Perform dermatologic examinations periodically;1 frequency of examinations determined by patient’s dermatologist.8

Exacerbation of Levodopa-associated Adverse Effects

When used as adjunctive therapy with levodopa, rasagiline may precipitate or exacerbate levodopa-associated adverse effects (e.g., dyskinesias), presumably by increasing dopaminergic activity; effects generally can be mitigated by reducing levodopa dosage.1

Orthostatic Hypotension and Lowering of BP

Orthostatic hypotension, with or without manifestations such as dizziness, nausea, syncope, and sometimes sweating, reported when used as adjunctive therapy with levodopa.1 Occurs most frequently during the first 2 months of therapy (and less frequently over time) and may occur at any time following dosage increase.1 Substantial decreases in BP in the supine position and posttreatment hypotension also reported following use as adjunctive therapy.1

Risk of hypotension or orthostatic hypotension not increased when used as monotherapy.1

Elevation of BP

Substantial increases in BP and posttreatment hypertension (SBP >180 mm Hg or DBP >100 mm Hg) reported when used as adjunctive therapy with levodopa.1

Risk of hypertension not increased when used as monotherapy.1

Hallucinations and Psychotic-like Behavior

Hallucinations reported when used as monotherapy or as adjunctive therapy with levodopa.1 (See Advice to Patients.)

New onset or exacerbation of psychotic-like behavior (manifested as paranoia, confusional state or confusion, psychotic disorder, agitation, delusion, and hallucinations) reported.1 Use not recommended in patients with a major psychotic disorder.1 (See Specific Drugs and Foods under Interactions.)

Neuroleptic Malignant Syndrome

A symptom complex resembling neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability) reported following rapid dosage reduction, withdrawal of, or changes in drugs that increase central dopaminergic tone.1 Hyperpyrexia not reported following discontinuance of rasagiline.1

Intense Urges

Intense urges (e.g., urge to gamble, increased sexual urges, other intense urges) and inability to control these urges reported in some patients receiving antiparkinsonian agents that increase central dopaminergic tone (including rasagiline).1 Although causal relationship not established, urges stopped in some cases when dosage was reduced or drug was discontinued.1

Consider reducing dosage or discontinuing rasagiline if a patient develops such urges.1

Specific Populations

Pregnancy

Category C.1

Lactation

Inhibits prolactin secretion in rats; may inhibit milk secretion in women.1 8 Not known whether rasagiline is distributed into milk; caution if used in nursing women.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1 8

Geriatric Use

No overall differences in safety relative to younger adults.1

Hepatic Impairment

Dosage adjustment recommended in patients with mild (Child-Pugh score of 5–6) hepatic impairment.1

Use not recommended in patients with moderate or severe (Child-Pugh score ≥7) hepatic impairment.1 2 (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Monotherapy: Flu syndrome,1 arthralgia,1 5 depression,1 dyspepsia.1

Adjunctive therapy with levodopa: Dyskinesia,1 3 4 accidental injury,1 weight loss,1 4 orthostatic hypotension,1 3 vomiting,1 3 4 anorexia,1 4 arthralgia,1 abdominal pain,1 nausea,1 3 constipation,1 3 dry mouth,1 3 rash,1 abnormal dreams,1 3 fall.1

Uses For Azilect

Rasagiline is used alone or together with levodopa for the treatment of Parkinson's disease. Parkinson's disease is a condition of the brain that becomes worse over time and may cause movement problems, rigidity, tremors, and slowed physical movement.

This medicine is only available with your doctor's prescription.

Proper Use of Azilect

Take this medicine only as directed by your doctor, to help your condition as much as possible. Do not take more or less of it, and do not take it more or less often than your doctor ordered.

Take this medicine with or without food.

If you take this medicine and consume tyramine-rich foods, beverages, or dietary supplements or amines (from over-the-counter medicines), you could experience a hypertensive crisis or "cheese reaction". A hypertensive crisis (increase in blood pressure) is very serious and requires immediate medical attention. It is very important that you restrict dietary tyramine by avoiding the following tyramine-rich foods and beverages:

  • Aged cheese
  • Air dried, aged and fermented meats, sausages and salamis (eg, cacciatore, hard salami and mortadella)
  • Animal livers that are spoiled or improperly stored
  • Beers and tap beers, all varieties that have not been pasteurized so as to allow for ongoing fermentation
  • Broad bean pods (eg, fava bean pods)
  • Meat, poultry, or fish that is spoiled or stored improperly (eg, foods with changes in coloration, odor, or mold)
  • OTC supplements containing tyramine
  • Pickled herring
  • Red wine
  • Sauerkraut
  • Soybean products including soy sauce and tofu
  • Yeast extract, concentrated.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

  • For treatment of Parkinson's disease:
    • For oral dosage form (tablets):
      • For patients taking rasagiline alone:
        • Adults—1 milligram (mg) once a day.
        • Children—Use and dose must be determined by your doctor.
      • For patients taking rasagiline with levodopa:
        • Adults—At first, 0.5 milligram (mg) once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 1 mg per day.
        • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Azilect Side Effects

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

Less common
  • Abdominal or stomach pain
  • arm, back, or jaw pain
  • black, tarry stools
  • chest pain or discomfort
  • chest tightness or heaviness
  • chills
  • cloudy urine
  • cough
  • diarrhea
  • difficulty swallowing
  • dizziness
  • fainting
  • fast or irregular heartbeat
  • fever
  • hives, itching, or skin rash
  • loss of appetite
  • nausea
  • painful or difficult urination
  • persistent, non-healing sore
  • pink growth on the skin
  • puffiness or swelling of the eyelids or around the eyes
  • reddish patch or irritated area
  • redness, blistering, peeling, or loosening of the skin
  • seeing, hearing, or feeling things that are not there
  • shiny bump
  • sore throat
  • sores, ulcers, or white spots on lips or in mouth
  • sweating
  • swollen glands
  • tests that show problems with the liver
  • tightness in the chest
  • unusual bleeding or bruising
  • unusual tiredness or weakness
  • weakness
  • white, yellow or waxy scar-like area

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common
  • Acid or sour stomach
  • belching
  • difficulty with moving
  • headache
  • heartburn
  • indigestion
  • muscle pain or stiffness
  • pain in the joints
  • stomach discomfort or upset
Less common
  • Bruising
  • burning, crawling, itching, numbness, prickling, "pins and needles" or tingling feelings
  • burning, dry, or itching eyes
  • decreased interest in sexual intercourse
  • difficulty breathing
  • difficulty with moving
  • discouragement
  • excessive tearing
  • eye discharge
  • fall
  • feeling of constant movement of self or surroundings
  • feeling sad or empty
  • general feeling of discomfort or illness
  • hair loss
  • inability to have or keep an erection
  • irritability
  • joint pain
  • lack of appetite
  • large, flat, blue or purplish patches in the skin
  • lightheadedness
  • loss in sexual ability, desire, drive, or performance
  • loss of interest or pleasure
  • muscle aches
  • neck pain
  • noisy breathing
  • redness, pain, swelling of the eye, eyelid, or inner lining of the eyelid
  • runny nose
  • sensation of spinning
  • shivering
  • sneezing
  • stuffy nose
  • swelling or redness in the joints
  • thinning of the hair
  • tiredness
  • trouble concentrating
  • trouble sleeping
  • vomiting
  • weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

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)]

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.

Azilect Description

Azilect® tablets contain rasagiline (as the mesylate), a propargylamine-based drug indicated for the treatment of idiopathic Parkinson’s disease. It is designated chemically as: 1H-Inden-1-amine, 2, 3-dihydro-N-2-propynyl-, (1R)-, methanesulfonate. The empirical formula of rasagiline mesylate is (C12H13N)CH4SO3 and its molecular weight is 267.34.

Its structural formula is:

Rasagiline mesylate is a white to off-white powder, freely soluble in water or ethanol and sparingly soluble in isopropanol. Each Azilect tablet for oral administration contains rasagiline mesylate equivalent to 0.5 mg or 1 mg of rasagiline base.

Each Azilect tablet also contains the following inactive ingredients: mannitol, starch, pregelatinized starch, colloidal silicon dioxide, stearic acid and talc.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

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

In mice, there was an increase in lung tumors (combined adenomas/carcinomas) at 15 and 45 mg/kg in males and females. At the lowest dose tested, plasma AUCs were approximately 5 times those expected in humans at the MRHD.

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 human lymphocytes in the presence of metabolic activation and was mutagenic and clastogenic in the in vitro mouse lymphoma tk assay in the absence and presence of metabolic activation. Rasagiline was negative in the in vitro bacterial reverse mutation (Ames) assay and in the in vivo micronucleus assay in mice. Rasagiline was also negative in the in vivo micronucleus assay in mice when administered in combination with levodopa/carbidopa.

Impairment of Fertility

Rasagiline had no effect on mating performance or fertility in rats treated prior to and throughout the mating period and continuing in females through gestation day 17 at oral doses of up to 3 mg/kg/day (approximately 30 times the plasma AUC in humans at the MRHD). The effect of rasagiline administered in combination with levodopa/carbidopa on mating and fertility has not been examined.

Clinical Studies

The effectiveness of Azilect for the treatment of Parkinson’s disease was established in four 18- to 26-week, randomized, placebo-controlled trials, as initial monotherapy or adjunct therapy.

Monotherapy Use of Azilect

Study 1 was a double-blind, randomized, fixed-dose parallel group, 26-week study in early Parkinson’s disease patients not receiving any concomitant dopaminergic therapy at the start of the study. The majority of the patients were not treated with medications for Parkinson’s disease before receiving Azilect.

In Study 1, 404 patients were randomly assigned to receive placebo (138 patients), Azilect 1 mg/day (134 patients) or Azilect 2 mg/day (132 patients). Patients were not allowed to take levodopa, dopamine agonists, selegiline or amantadine, but could take stable doses of anticholinergic medication, if necessary. The average Parkinson’s disease duration was approximately 1 year (range 0 to 11 years).

The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS), [mentation (Part I) + activities of daily living (ADL) (Part II) + motor function (Part III)]. The UPDRS is a multi-item rating scale that measures the ability of a patient to perform mental and motor tasks as well as activities of daily living. A reduction in the score represents improvement and a beneficial change from baseline appears as a negative number.

Azilect (1 or 2 mg once daily) was superior to placebo on the primary measure of effectiveness in patients receiving six months of treatment and not on dopaminergic therapy. The effectiveness of Azilect 1 mg and 2 mg was comparable. Table 4 shows the results of Study 1. There were no differences in effectiveness based on age or gender between Azilect 1 mg/day and placebo.

Table 4: Change in Total UPDRS Score in Study 1

Baseline score

Change from baseline to termination score

p-value vs. placebo

Placebo

24.5

3.9

---

Azilect 1 mg

24.7

0.1

0.0001

Azilect 2 mg

25.9

0.7

0.0001

Adjunct Use of Azilect

Study 2 was a double-blind, randomized, placebo-controlled, parallel group, 18-week study, investigating Azilect 1 mg as adjunct therapy to dopamine agonists without levodopa. Patients were on a stable dose of dopamine agonist (ropinirole, mean 8 mg/day or pramipexole, mean 1.5 mg/day) therapy for ≥ 30 days, but at doses not sufficient to control Parkinson’s disease symptoms.

In Study 2, 321 patients randomly received placebo (162 patients) or Azilect 1 mg/day (159 patients) and had a post-baseline assessment. The average Parkinson’s disease duration was approximately 2 years (range 0.1 to 14.5 years).

The primary measure of effectiveness was the change from baseline in the total score of the Unified Parkinson’s Disease Rating Scale (UPDRS) [mentation (Part I) + activities of daily living (ADL) (Part II) + motor function (Part III)].

In Study 2, Azilect 1 mg was superior to placebo on the primary measure of effectiveness (see Table 5).

Table 5: Change in Total UPDRS Score in Study 2

Baseline score

Change from baseline to termination score*

p-value vs. placebo

Placebo

29.8

–1.2

---

Azilect1 mg

32.1

–3.6

0.012

*A negative change from baseline indicates improvement in the UPDRS

Secondary outcome assessment of the individual subscales of the UPDRS indicates that the UPDRS Part III motor subscale was primarily responsible for the overall Azilect effect on the UPDRS score (see Table 6).

Table 6: Secondary Measures of Effectiveness in Study 2

Baseline (score)

Change from baseline to termination score

UPDRS Part II ADL (Activities of Daily Living) subscale score

Placebo

7.9

0.4

Azilect 1 mg

8.6

-0.3

UPDRS Part III Motor subscale score

Placebo

20.4

-1.2

Azilect 1 mg

22.2

-3.7

Study 3 and Study 4 were randomized, multinational trials conducted in more advanced Parkinson’s disease patients treated chronically with levodopa and experiencing motor fluctuations (including but not limited to, end of dose “wearing off,” sudden or random “off,” etc.). Study 3 was conducted in North America (U.S. and Canada) and compared Azilect 0.5 mg and 1 mg daily to placebo. Study 4 was conducted outside of North America in Europe, Argentina and Israel, and compared Azilect 1 mg daily to placebo.

Patients had Parkinson’s disease for an average of 9 years (range 5 months to 33 years), had taken levodopa for an average of 8 years (range 5 months to 32 years), and had motor fluctuations for approximately 3 to 4 years (range 1 month to 23 years). Patients kept home Parkinson’s disease diaries just prior to baseline and at specified intervals during the trial. Diaries recorded one of the following four conditions for each half-hour interval over a 24-hour period: “ON” (period of relatively good function and mobility) as either “ON” with no dyskinesia or without troublesome dyskinesia, or “ON” with troublesome dyskinesia, “OFF” (period of relatively poor function and mobility) or asleep. “Troublesome” dyskinesia is defined as dyskinesia that interferes with the patient’s daily activity. All patients had inadequate control of their motor symptoms with motor fluctuations typical of advanced stage disease despite receiving levodopa/decarboxylase inhibitor. The average dose of levodopa taken with a decarboxylase inhibitor was approximately 700 to 800 mg (range 150 to 3000 mg/day). Patients continued their stable doses of additional anti-PD medications at entry into the trials. Approximately 65% of patients in both studies were also taking a dopamine agonist. In the North American study (Study 3), approximately 35% of patients took entacapone with levodopa/decarboxylase inhibitor. The majority of patients taking entacapone were also taking a dopamine agonist.

In Study 3 and Study 4, the primary measure of effectiveness was the change in the mean number of hours spent in the “OFF” state at baseline compared to the mean number of hours spent in the “OFF” state during the treatment period.

In Study 3, patients were randomly assigned to receive placebo (159 patients), Azilect 0.5 mg/day (164 patients), or Azilect 1 mg/day (149 patients) for 26 weeks. Patients averaged 6 hours daily in the “OFF” state at baseline as confirmed by home diaries.

In Study 4, patients were randomly assigned to receive placebo (229 patients), Azilect 1 mg/day (231 patients) or a COMT inhibitor (active comparator), taken along with scheduled doses of levodopa/decarboxylase inhibitor (227 patients) for 18 weeks. Patients averaged 5.6 hours daily in the “OFF” state at baseline as confirmed by home diaries.

In Study 3 and Study 4, Azilect 1 mg once daily reduced “OFF” time compared to placebo when added to levodopa in patients experiencing motor fluctuations (Tables 7 and 8). The lower dose (0.5 mg) of Azilect also significantly reduced “OFF” time (Table 7), but had a numerically smaller effect than the 1 mg dose of Azilect. In Study 4, the active comparator also reduced “OFF” time when compared to placebo.

Table 7: Change in mean total daily “OFF” time in Study 3

Baseline (hours)

Change from baseline to treatment period (hours)

p-value vs. placebo

Placebo

6.0

-0.9

---

Azilect 0.5 mg

6.0

-1.4

0.0199

Azilect 1.0 mg

6.3

-1.9

< 0.0001

Table 8: Change in mean total daily “OFF” time in Study 4

Baseline (hours)

Change from baseline to treatment period (hours)

p-value vs. placebo

Placebo

5.5

- 0.40

---

Azilect 1.0 mg

5.6

-1.2

0.0001

In Study 3 and Study 4, dose reduction of levodopa was allowed within the first 6 weeks, if dopaminergic side effects developed including dyskinesia or hallucinations. In Study 3, the levodopa dose was reduced 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 Azilect groups, respectively. When levodopa was reduced, the dose was reduced by 7%, 9%, and 13% in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively. In Study 4, levodopa dose reduction occurred in 6% of patients in the placebo group and in 9% in the Azilect 1 mg/day groups, respectively. When levodopa was reduced, it was reduced by 13% and 11% in the placebo and the Azilect groups, respectively.

There were no differences in effectiveness based on age or gender between Azilect 1 mg/day and placebo.

Several secondary outcome assessments in the two studies showed statistically significant improvements with rasagiline. These included effects on the activities of daily living (ADL) subscale of the UPDRS performed during an “OFF” period and the motor subscale of the UPDRS performed during an “ON” period. In both scales, a negative response represents improvement. Tables 9 and 10 show these results for Studies 3 and 4.

Table 9: Secondary Measures of Effectiveness in Study 3

Baseline (score)

Change from baseline to last value

UPDRS ADL (Activities of Daily Living) subscale score while “OFF”

Placebo

15.5

0.68

Azilect 0.5 mg

15.8

-0.60

Azilect 1 mg

15.5

-0.68

UPDRS Motor subscale score while “ON”

Placebo

20.8

1.21

Azilect 0.5 mg

21.5

-1.43

Azilect 1 mg

20.9

-1.30

Table 10: Secondary Measures of Effectiveness in Study 4

Baseline (score)

Change from baseline to last value

UPDRS ADL (Activities of Daily Living) subscale score while “OFF”

Placebo

18.7

-0.89

Azilect 1 mg

19.0

-2.61

UPDRS Motor subscale score while “ON”

Placebo

23.5

-0.82

Azilect 1 mg

23.8

-3.87

Package/Label Display Panel

Azilect® (rasagiline tablets) 0.5 mg, 30s Label Text

NDC 68546-142-56

Azilect®

(rasagiline tablets)

0.5 mg

30 Tablets Rx only

TEVA®

NEUROSCIENCE

Drug Interactions

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

  • Amphetamine
  • Apraclonidine
  • Atomoxetine
  • Benzphetamine
  • Brimonidine
  • Bupropion
  • Carbamazepine
  • Carbinoxamine
  • Citalopram
  • Clomipramine
  • Cyclobenzaprine
  • Cyproheptadine
  • Desipramine
  • Desvenlafaxine
  • Dexmethylphenidate
  • Dextroamphetamine
  • Dextromethorphan
  • Diethylpropion
  • Doxylamine
  • Duloxetine
  • Ephedrine
  • Escitalopram
  • Fluoxetine
  • Fluvoxamine
  • Guanadrel
  • Guanethidine
  • Hydroxytryptophan
  • Imipramine
  • Isocarboxazid
  • Levomethadyl
  • Levomilnacipran
  • Linezolid
  • Lisdexamfetamine
  • Maprotiline
  • Mazindol
  • Meperidine
  • Methadone
  • Methamphetamine
  • Methyldopa
  • Methylphenidate
  • Milnacipran
  • Mirtazapine
  • Nefopam
  • Nortriptyline
  • Opipramol
  • Paroxetine
  • Phendimetrazine
  • Phenelzine
  • Phenmetrazine
  • Phentermine
  • Phenylalanine
  • Phenylephrine
  • Phenylpropanolamine
  • Procarbazine
  • Propoxyphene
  • Pseudoephedrine
  • Rasagiline
  • Reserpine
  • Safinamide
  • Selegiline
  • Sertraline
  • St John's Wort
  • Sumatriptan
  • Tapentadol
  • Tetrabenazine
  • Tramadol
  • Tranylcypromine
  • Trazodone
  • Trimipramine
  • Tryptophan
  • Venlafaxine
  • Vilazodone
  • Vortioxetine

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Altretamine
  • Amitriptyline
  • Amoxapine
  • Atropine
  • Balofloxacin
  • Besifloxacin
  • Buprenorphine
  • Ciprofloxacin
  • Difenoxin
  • Diphenoxylate
  • Dolasetron
  • Dothiepin
  • Doxepin
  • Droperidol
  • Enoxacin
  • Epinephrine
  • Ethchlorvynol
  • Fentanyl
  • Flumequine
  • Frovatriptan
  • Gatifloxacin
  • Gemifloxacin
  • Granisetron
  • Guarana
  • Hydrocodone
  • Hydromorphone
  • Iobenguane I 123
  • Kava
  • Levofloxacin
  • Licorice
  • Lofepramine
  • Lomefloxacin
  • Lorcaserin
  • Ma Huang
  • Mate
  • Methylene Blue
  • Metoclopramide
  • Mibefradil
  • Morphine
  • Morphine Sulfate Liposome
  • Moxifloxacin
  • Nadifloxacin
  • Naratriptan
  • Nefazodone
  • Norfloxacin
  • Ofloxacin
  • Oxycodone
  • Oxymetazoline
  • Palonosetron
  • Pazufloxacin
  • Pefloxacin
  • Peginterferon Alfa-2b
  • Pixantrone
  • Protriptyline
  • Prulifloxacin
  • Reboxetine
  • Rufloxacin
  • Sibutramine
  • Sparfloxacin
  • Tyrosine
  • Ziprasidone

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Acarbose
  • Chlorpropamide
  • Ginseng
  • Glimepiride
  • Glipizide
  • Glyburide
  • Insulin
  • Insulin Aspart, Recombinant
  • Insulin Bovine
  • Insulin Degludec
  • Insulin Detemir
  • Insulin Glargine, Recombinant
  • Insulin Glulisine
  • Insulin Lispro, Recombinant
  • Metformin
  • Nateglinide
  • Repaglinide
  • Tolazamide
  • Tolbutamide

Where can i get more information?

Your pharmacist has more information about rasagiline.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

Copyright 1996-2013 Cerner Multum, Inc. Version: 3.02. Revision date: 12/15/2010.

Your use of the content provided in this service indicates that you have read,understood and agree to the End-User License Agreement,which can be accessed by clicking on this link.

Side effects

The following adverse reactions are described in more detail in the WARNINGS AND PRECAUTIONS section of the label:

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

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
  AZILECT 1 mg (N=149) Placebo (N=151)
  % of Patients % of Patients
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
  AZILECT 1 mg (N=149) AZILECT 0.5 mg (N=164) Placebo
(N=159)
  % of patients % of patients % of patients
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.

Read the entire FDA prescribing information for Azilect (Rasagiline)

Read More »

Before taking Azilect

You should not take Azilect if you are allergic to rasagiline.

Many medicines can interact with rasagiline and should not be used at the same time. Your doctor may need to change your treatment plan if you use any of the following drugs:

  • cyclobenzaprine (a muscle relaxer);

  • dextromethorphan (contained in many over-the-counter cough medicines);

  • meperidine (Demerol);

  • methadone;

  • St. John's wort; or

  • tramadol (Ultram, Ultracet).

Do not use Azilect if you have used any other MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, methylene blue injection, phenelzine, selegiline, tranylcypromine, and others.

To make sure rasagiline is safe for you, tell your doctor if you have:

  • high or low blood pressure;

  • liver disease;

  • if you take an antidepressant; or

  • if you take ciprofloxacin (an antibiotic).

People with Parkinson's disease may have a higher risk of skin cancer (melanoma). Talk to your doctor about this risk and what skin symptoms to watch for.

It is not known whether Azilect will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether rasagiline passes into breast milk or if it could harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Rasagiline Pregnancy Warnings

This drug should be used during pregnancy only if clearly needed and the benefit outweighs the risk to the fetus. AU TGA pregnancy category: B3 US FDA pregnancy category: C

Animal studies have revealed evidence of embryolethality when rasagiline was used in high doses in combination with levodopa/carbidopa. There are no controlled data in human pregnancy. AU TGA pregnancy category B3: Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

(web3)