These highlights do not include all the information needed to use AZILECT safely and effectively. See full prescribing information for AZILECT.�AZILECT� (rasagiline mesylate) Tablets for Oral Use Initial U.S. Approval: 2006
AZILECT Information
Company Name Teva Neuroscience, Inc.
Azilect (Rasagiline mesylate)
Azilect (Rasagiline mesylate) Indications And Usage
Azilect (Rasagiline mesylate) (rasagiline tablets) is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease as initial monotherapy and as adjunct therapy to levodopa.
The effectiveness of Azilect (Rasagiline mesylate) was demonstrated in patients with early Parkinson's disease who were receiving Azilect (Rasagiline mesylate) as monotherapy and who were not receiving any concomitant dopaminergic therapy. The effectiveness of Azilect (Rasagiline mesylate) as adjunct therapy was demonstrated in patients with Parkinson's disease who were treated with levodopa.
Azilect (Rasagiline mesylate) Dosage And Administration
Azilect (Rasagiline mesylate) is a selective inhibitor of monoamine oxidase (MAO)-B at recommended doses of 0.5 or 1 mg daily. Dietary tyramine restriction is not ordinarily required with recommended doses of Azilect (Rasagiline mesylate) . 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 mesylate) even at the recommended dose due to mild increased sensitivity to tyramine. The selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily dose .
Azilect (Rasagiline mesylate) Dosage Forms And Strengths
Azilect (Rasagiline mesylate) 0.5 mg Tablets: White to off-white, round, flat, beveled tablets, debossed with "GIL 0.5" on one side and plain on the other side containing, as the active ingredient, rasagiline mesylate equivalent to 0.5 mg of rasagiline base.
Azilect (Rasagiline mesylate) 1 mg Tablets: White to off-white, round, flat, beveled tablets, debossed with "GIL 1" on one side and plain on the other side containing, as the active ingredient, rasagiline mesylate equivalent to 1 mg of rasagiline base.
Azilect (Rasagiline mesylate) Contraindications
Azilect (Rasagiline mesylate) is contraindicated for use with meperidine. Serious adverse reactions have been precipitated with concomitant use of meperidine (e.g., Demerol and other tradenames) and MAO inhibitors (MAOIs) including selective MAO-B inhibitors. These adverse reactions are often described as "serotonin syndrome", a potentially serious condition, which can result in death. Typical clinical signs and symptoms include behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, hypotension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor). At least 14 days should elapse between discontinuation of Azilect (Rasagiline mesylate) and initiation of treatment with meperidine.
For similar reasons, Azilect (Rasagiline mesylate) should not be administered with the analgesic agents tramadol, methadone, and propoxyphene.
In the post-marketing period, serotonin syndrome has been reported in a patient erroneously treated with a higher than recommended dose of Azilect (Rasagiline mesylate) (4 mg daily) and tramadol.
Azilect (Rasagiline mesylate) Warnings And Precautions
Severe CNS toxicity associated with hyperpyrexia has been reported with the combined treatment of an antidepressant (e.g., selective serotonin reuptake inhibitors-SSRIs, serotonin-norepinephrine reuptake inhibitors-SNRIs, tricyclic antidepressants, tetracyclic antidepressants, triazolopyridine antidepressants) and a non-selective MAOI (e.g., phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline (Eldepryl) and rasagiline (Azilect (Rasagiline mesylate) ). These adverse reactions are often described as "serotonin syndrome" which can result in death. In the post-marketing period, non-fatal cases of serotonin syndrome have been reported in patients treated with antidepressants concomitantly with Azilect (Rasagiline mesylate) .
The symptoms of serotonin syndrome have included behavioral and cognitive/mental status changes (e.g., confusion, hypomania, hallucinations, agitation, delirium, headache, and coma), autonomic effects (e.g., syncope, shivering, sweating, high fever/hyperthermia, hypertension, tachycardia, nausea, diarrhea), and somatic effects (e.g., muscular rigidity, myoclonus, muscle twitching, hyperreflexia manifested by clonus, and tremor).
Azilect (Rasagiline mesylate) clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with Azilect (Rasagiline mesylate) , but the following antidepressants and doses were allowed in the Azilect (Rasagiline mesylate) 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 mesylate) with any antidepressant. At least 14 days should elapse between discontinuation of Azilect (Rasagiline mesylate) and initiation of treatment with a SSRI, SNRI, tricyclic, tetracyclic, or triazolopyridine antidepressant. Because of the long half lives of certain antidepressants (e.g., fluoxetine and its active metabolite), at least five weeks (perhaps longer, especially if fluoxetine has been prescribed chronically and/or at higher doses) should elapse between discontinuation of fluoxetine and initiation of Azilect (Rasagiline mesylate) .
Azilect (Rasagiline mesylate) is a selective inhibitor of monoamine oxidase (MAO)-B at the recommended doses of 0.5 or 1 mg daily. Azilect (Rasagiline mesylate) should not be used at daily doses exceeding 1 mg/day (or 0.5 mg/day for patients with mild hepatic impairment or in patients using concomitant ciprofloxacin or another CYP1A2 inhibitor) because of the risks of hypertensive crisis and other adverse reactions associated with nonselective inhibition of MAO .
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 mesylate) . 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 mesylate) 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 mesylate) because of the potential for large increases in blood pressure. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses.
There were no cases of hypertensive crisis in the clinical development program associated with 1 mg daily rasagiline treatment, in which most patients did not follow dietary tyramine restriction.
Rare cases of hypertensive crisis have been reported in the post-marketing period in patients after ingesting unknown amounts of tyramine-rich foods while taking recommended doses of Azilect (Rasagiline mesylate) .
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).
In placebo controlled studies of Azilect (Rasagiline mesylate) 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 mesylate) (1 mg/day) compared to 8.5 % with placebo.
At the 1 mg dose, the frequency of orthostatic hypotension at any time during the study was approximately 44 % for Azilect (Rasagiline mesylate) vs 33% for placebo for mild to moderate systolic blood pressure decrements (≥ 20 mm Hg), 40 % for Azilect (Rasagiline mesylate) vs 33 % for placebo for mild to moderate diastolic blood pressure decrements (≥ 10 mm Hg), 7 % for Azilect (Rasagiline mesylate) vs 3 % for placebo for severe systolic blood pressure decrements (≥ 40 mm Hg), and 9 % for Azilect (Rasagiline mesylate) 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 mesylate) treatment and tends to decrease over time.
Some patients treated with Azilect (Rasagiline mesylate) 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 30 or diastolic > 20 mm Hg) was higher for Azilect (Rasagiline mesylate) 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 mesylate) 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.
In studies in which Azilect (Rasagiline mesylate) (1 mg/day) was given in conjunction with levodopa, Azilect (Rasagiline mesylate) 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 mesylate) (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 mesylate) treatment vs placebo.
There was no observed increased risk for increasing blood pressure or high blood pressure (based upon various measurements and analyses) or for the development of hypertension as an adverse reaction in the monotherapy study for 1 mg daily Azilect (Rasagiline mesylate) treatment (vs placebo).
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 mesylate) , 4% of patients treated with 1 mg/day Azilect (Rasagiline mesylate) and 3% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in about 1% of patients treated with 0.5 mg/day or 1 mg/day rasagiline and none of the placebo-treated patients.
Patients should be informed of the possibility of developing hallucinations and instructed to report them to their health care provider promptly should they develop.
Patients with a major psychotic disorder should ordinarily not be treated with Azilect (Rasagiline mesylate) 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 mesylate) .
Azilect (Rasagiline mesylate) 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.
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. .
Withdrawal emergent hyperpyrexia was not reported in the Azilect (Rasagiline mesylate) clinical development program.
Azilect (Rasagiline mesylate) Adverse Reactions
During the clinical development of Azilect (Rasagiline mesylate) , 1361 Parkinson's disease patients received rasagiline as initial monotherapy or as adjunct therapy to levodopa. As these two populations differ, not only in the adjunct use of levodopa during rasagiline treatment, but also in the severity and duration of their disease, they may have differential risks for various adverse reactions. Therefore, most of the adverse reactions data in this section are presented separately for each population.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates of adverse reactions observed in practice.
Azilect (Rasagiline mesylate) Drug Interactions
The concomitant use of Azilect (Rasagiline mesylate) and sympathomimetic medications was not allowed in clinical studies. Severe hypertensive reactions have followed the administration of sympathomimetics and non-selective MAO inhibitors. One case of hypertensive crisis has been reported in a patient taking the recommended dose of a selective MAO-B inhibitor and a sympathomimetic medication (ephedrine). Elevated blood pressure was reported in another patient taking the recommended dose of Azilect (Rasagiline mesylate) and ophthalmic drops with a sympathomimetic medication (tetrahydrozoline).
Because Azilect (Rasagiline mesylate) is a selective MAOI, hypertensive reactions are not ordinarily expected with the concomitant use of sympathomimetic medications. Nevertheless, caution should be exercised when concomitantly using recommended doses of Azilect (Rasagiline mesylate) with any sympathomimetic medications including nasal, oral, and ophthalmic decongestants and cold remedies.
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MAO in the gastrointestinal tract and liver (primarily type A) is thought to provide vital protection from exogenous amines (e.g., tyramine) that have the capacity, if absorbed intact, to cause a "hypertensive crisis," the so-called "cheese reaction". If large amounts of certain exogenous amines (e.g., from fermented cheese, herring, over-the-counter cough/cold medications) gain access to the systemic circulation because MAO-A has been inhibited, they cause release of norepinephrine which may result in a rise in systemic blood pressure. MAOIs that selectively inhibit MAO-B are largely devoid of the potential to cause tyramine-induced hypertensive crisis.
Results of a special tyramine challenge study indicate that rasagiline is selective for MAO-B at recommended doses and can ordinarily be used without dietary tyramine restriction. However, certain foods (e.g., aged cheeses, such as Stilton cheese) may contain very high amounts (i.e., > 150 mg) of tyramine and could potentially cause a hypertensive cheese reaction in patients taking Azilect (Rasagiline mesylate) 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 mesylate) because of the potential for large increases in blood pressure. Selectivity for inhibiting MAO-B diminishes in a dose-related manner as the dose is progressively increased above the recommended daily doses.
There were no cases of hypertensive crisis in the clinical development program associated with 1 mg daily rasagiline treatment, in which most patients did not follow dietary tyramine restriction.
Despite the selective inhibition of MAO-B at recommended doses of Azilect (Rasagiline mesylate) , there have been post-marketing reports of patients who experienced significantly elevated blood pressure (including rare cases of hypertensive crisis) after ingestion of unknown amounts of tyramine-rich foods while taking recommended doses of Azilect (Rasagiline mesylate)
Azilect (Rasagiline mesylate) Use In Specific Populations
In rats rasagiline was shown to inhibit prolactin secretion and it may inhibit milk secretion in females.
It is not known whether rasagiline is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Azilect (Rasagiline mesylate) is administered to a nursing woman.
Azilect (Rasagiline mesylate) Overdose
No cases of Azilect (Rasagiline mesylate) overdose were reported in clinical trials.
Rasagiline was well tolerated in a single-dose study in healthy volunteers receiving 20 mg/day and in a ten-day study in healthy volunteers receiving 10 mg/day. Adverse events were mild or moderate. In a dose escalation study in patients on chronic levodopa therapy treated with 10 mg of rasagiline there were three reports of cardiovascular side effects (including hypertension and postural hypotension) which resolved following treatment discontinuation.
Symptoms of overdosage, although not observed with rasagiline during clinical development, may resemble those observed with non-selective MAO inhibitors (MAOIs).
Although no cases of overdose have been observed with rasagiline during the clinical development program, the following description of presenting symptoms and clinical course is based upon overdose descriptions of non-selective MAO inhibitors.
Characteristically, signs and symptoms of non-selective MAOI overdose may not appear immediately. Delays of up to 12 hours between ingestion of drug and the appearance of signs may occur. Importantly, the peak intensity of the syndrome may not be reached for upwards of a day following the overdose. Death has been reported following overdosage. Therefore, immediate hospitalization, with continuous patient observation and monitoring for a period of at least two days following the ingestion of such drugs in overdose, is strongly recommended.
The clinical picture of MAOI overdose varies considerably; its severity may be a function of the amount of drug consumed. The central nervous and cardiovascular systems are prominently involved.
Signs and symptoms of overdosage may include, alone or in combination, any of the following: drowsiness, dizziness, faintness, irritability, hyperactivity, agitation, severe headache, hallucinations, trismus, opisthotonos, convulsions, and coma; rapid and irregular pulse, hypertension, hypotension and vascular collapse; precordial pain, respiratory depression and failure, hyperpyrexia, diaphoresis, and cool, clammy skin.
There is no specific antidote for rasagiline overdose. The following suggestions are offered based upon the assumption that rasagiline overdose may be modeled after non-selective MAO inhibitor poisoning. Treatment of overdose with non-selective MAO inhibitors is symptomatic and supportive. Respiration should be supported by appropriate measures, including management of the airway, use of supplemental oxygen, and mechanical ventilatory assistance, as required. Body temperature should be monitored closely. Intensive management of hyperpyrexia may be required. Maintenance of fluid and electrolyte balance is essential. For this reason, in cases of overdose with Azilect (Rasagiline mesylate) , dietary tyramine restriction should be observed for several weeks to avoid the risk of a hypertensive/cheese reaction.
A poison control center should be called for the most current treatment guidelines.
A post-marketing report described a single patient who developed a non-fatal serotonin syndrome after ingesting 100 mg of Azilect (Rasagiline mesylate) in a suicide attempt. Another patient who was treated in error with 4 mg Azilect (Rasagiline mesylate) daily and tramadol also developed a serotonin syndrome. One patient who was treated in error with 3 mg Azilect (Rasagiline mesylate) daily experienced alternating episodes of vascular fluctuations consisting of hypertension and orthostatic hypotension.
Azilect (Rasagiline mesylate) Description
Azilect (Rasagiline mesylate) 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 (CHN)CHSO 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 (Rasagiline mesylate) tablet for oral administration contains rasagiline mesylate equivalent to 0.5 mg or 1 mg of rasagiline base.
Each Azilect (Rasagiline mesylate) tablet also contains the following inactive ingredients: mannitol, starch, pregelatinized starch, colloidal silicon dioxide, stearic acid and talc.
Azilect (Rasagiline mesylate) Clinical Pharmacology
Azilect (Rasagiline mesylate) functions as 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 (Rasagiline mesylate) 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 (Rasagiline mesylate) . 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 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.
Azilect (Rasagiline mesylate) Clinical Trials
The effectiveness of Azilect (Rasagiline mesylate) for the treatment of Parkinson's disease was established in three 18- to 26-week, randomized, placebo-controlled trials. In one of these trials Azilect (Rasagiline mesylate) was given as initial monotherapy and in the other two as adjunctive therapy to levodopa.
The monotherapy trial 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 any anti-Parkinson's disease medication before receiving rasagiline treatment.
In this trial, 404 patients were randomly assigned to receive placebo (138 patients), rasagiline 1 mg/day (134 patients) or rasagiline 2 mg/day (132 patients). Patients were not allowed to take levodopa, dopamine agonists, selegiline or amantadine, but if necessary, could take stable doses of anticholinergic medication. 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.
Rasagiline (1 or 2 mg once daily) had a significant beneficial effect relative to placebo on the primary measure of effectiveness in patients receiving six months of treatment and not on dopaminergic therapy. Patients who received rasagiline had significantly less worsening in the UPDRS score, compared to those who received placebo. The effectiveness of rasagiline 1 mg and 2 mg was comparable. Table 3 displays the results of the monotherapy trial.
For the comparison between rasagiline 1 mg/day and placebo, no differences in effectiveness based on age or gender were detected.
Two multicenter, randomized, multinational trials were 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.). The first (Study 1) was conducted in North America (U.S. and Canada) and compared two doses (0.5 mg and 1 mg daily) of rasagiline and placebo while the second (Study 2) was conducted outside of North America (several European countries, Argentina, Israel) and studied only a single dose (1 mg daily) of rasagiline and placebo. Patients had had Parkinson's disease for an average of 9 years (range 5 months to 33 years), had been taking levodopa for an average of 8 years (range 5 months to 32 years), and had been experiencing motor fluctuations for approximately 3 to 4 years (range 1 month to 23 years). Patients kept home 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 that which interferes with the patient's daily activity. All patients had been inadequately controlled and were experiencing motor fluctuations typical of advanced stage disease despite receiving levodopa/decarboxylase inhibitor. The average dose of levodopa/decarboxylase inhibitor was approximately 700 to 800 mg (range 150 to 3000 mg/day). Patients were also allowed to take stable doses of additional anti-PD medications at entry into the trials. In both trials, approximately 65% of patients were on dopamine agonists and in the North American study (Study 1) approximately 35% were on entacapone. The majority of patients taking entacapone were taking a dopamine agonist as well.
In both trials the primary measure of effectiveness was the change in the mean number of hours that were spent in the "OFF" state at baseline compared to the mean number of hours that were spent in the "OFF" state during the treatment period.
The first adjunct study (Study 1) was a double-blind, randomized, fixed-dose, parallel group trial conducted in 472 levodopa-treated Parkinson's disease patients who were experiencing motor fluctuations. Patients were randomly assigned to receive placebo (159 patients), rasagiline 0.5 mg/day (164 patients), or rasagiline 1 mg/day (149 patients), and were treated for 26 weeks. Patients averaged approximately 6 hours daily in the "OFF" state at baseline, as confirmed by home diaries.
The second adjunct study (Study 2) was a double-blind, randomized, parallel group trial conducted in 687 levodopa-treated Parkinson's disease patients who were experiencing motor fluctuations. Patients were randomly assigned to receive placebo (229 patients), rasagiline 1 mg/day (231 patients) or an active comparator, a COMT inhibitor taken along with scheduled doses of levodopa/decarboxylase inhibitor (227 patients). Patients were treated for 18 weeks. Patients averaged approximately 5.6 hours daily in the "OFF" state at baseline as confirmed by home diaries.
In both studies, rasagiline 1 mg once daily reduced "OFF" time compared to placebo when added to levodopa in patients experiencing motor fluctuations (Tables 4 and 5). The lower dose (0.5 mg) of rasagiline also significantly reduced "OFF" time (Table 4), but had a numerically smaller effect than the 1 mg dose of rasagiline. In Study 2, the active comparator also reduced "OFF" time when compared to placebo.
In both studies, dosage reduction of levodopa was allowed within the first 6 weeks if dopaminergic side effects, including dyskinesia and hallucinations, emerged. In Study 1, levodopa dosage reduction occurred in 8% of patients in the placebo group and in 16% and 17% of patients in the 0.5 mg/day and 1 mg/day rasagiline groups, respectively. In those patients who had levodopa dosage reduced, the dose was reduced on average by about 7%, 9%, and 13% in the placebo, 0.5 mg/day, and 1 mg/day groups, respectively. In Study 2, levodopa dosage reduction occurred in 6% of patients in the placebo group and in 9% in the rasagiline 1 mg/day group. In patients who had their levodopa dosage reduced, the dose was reduced on average by about 13% and 11% in the placebo and the rasagiline groups, respectively.
For the comparison between rasagiline 1 mg/day and placebo in both studies, no differences in effectiveness based on age or gender were detected.
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 6 and 7 show these results for Studies 1 and 2.
Azilect (Rasagiline mesylate) How Supplied
Azilect (Rasagiline mesylate) 0.5 mg Tablets:
White to off-white, round, flat, beveled tablets, debossed with "GIL 0.5" on one side and plain on the other side. Supplied as bottles of 30 tablets (NDC 68546-142-56).
Azilect (Rasagiline mesylate) 1 mg Tablets:
White to off-white, round, flat, beveled tablets, debossed with "GIL 1" on one side and plain on the other side. Supplied as bottles of 30 tablets (NDC 68546-229-56).
Storage:
Store at 25°C (77°F) with excursions permitted to 15°-30°C (59°-86°F).
Azilect (Rasagiline mesylate) Information For Patients
Patients should be advised not to exceed the maximum recommended daily dose of 1 mg/day (0.5 mg/day for subjects with mild hepatic impairment and subjects using concomitant ciprofloxacin and other CYP1A2 inhibitors).
The risk of using higher than recommended daily doses of Azilect (Rasagiline mesylate) should be explained, and a brief description of the hypertensive/cheese reaction provided.
The possibility exists that very tyramine-rich foods (e.g., aged cheese such as Stilton) could possibly cause an increase in blood pressure. Patients should be advised to avoid certain foods (e.g., aged cheese) containing a very large amount of tyramine while taking recommended doses of Azilect (Rasagiline mesylate) because of the potential for large increases in blood pressure. If patients eat foods very rich in tyramine and do not feel well soon after eating, they should contact their healthcare provider .
Azilect (Rasagiline mesylate)
Azilect (Rasagiline mesylate) Principal Display Panel - . Mg Tablet Bottle Label
NDC 68546-142-56
U.S. Patent Nos. 5387612, 5453446,5457133, 5532415, 5786390, 6126968
Azilect (Rasagiline mesylate) Principal Display Panel - Mg Tablet Bottle Label
NDC 68546-229-56
U.S. Patent Nos. 5387612, 5453446,5457133, 5532415, 5786390, 6126968
