AZILECT^® 1 mg tablets

Each tablet contains 1 mg rasagiline (as mesilate).

For a full list of excipients, see section 6.1.

Tablet

White to off-white, round, flat, bevelled tablets, debossed with “GIL” and “1” underneath on one side and plain on the other side.

AZILECT is indicated for the treatment of idiopathic Parkinson's disease (PD) as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in patients with end of dose fluctuations.

Posology

Rasagiline is administered orally, at a dose of 1 mg once daily with or without levodopa.

It may be taken with or without food.

Elderly: No change in dose is required for elderly patients.

Paediatric population: AZILECT is not recommended for use in children and adolescents due to lack of data on safety and efficacy.

Patients with hepatic impairment: Rasagiline use in patients with severe hepatic impairment is contraindicated (see section 4.3). Rasagiline use in patients with moderate hepatic impairment should be avoided. Caution should be used when initiating treatment with rasagiline in patients with mild hepatic impairment. If patients progress from mild to moderate hepatic impairment rasagiline should be stopped (see section 4.4).

Patients with renal impairment: No change in dosage is required for renal impairment.

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

Concomitant treatment with other monoamine oxidase (MAO) inhibitors (including medicinal and natural products without prescription e.g. St. John's Wort) or pethidine (see section 4.5). At least 14 days must elapse between discontinuation of rasagiline and initiation of treatment with MAO inhibitors or pethidine.

Rasagiline is contraindicated in patients with severe hepatic impairment.

The concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided (see section 4.5). At least five weeks should elapse between discontinuation of fluoxetine and initiation of treatment with rasagiline. At least 14 days should elapse between discontinuation of rasagiline and initiation of treatment with fluoxetine or fluvoxamine.

The concomitant use of rasagiline and dextromethorphan or sympathomimetics such as those present in nasal and oral decongestants or cold medicinal products containing ephedrine or pseudoephedrine is not recommended (see section 4.5).

During the clinical development programme, the occurrence of cases of melanoma prompted the consideration of a possible association with rasagiline. The data collected suggests that Parkinson's disease, and not any medicinal products in particular, is associated with a higher risk of skin cancer (not exclusively melanoma). Any suspicious skin lesion should be evaluated by a specialist.

Caution should be used when initiating treatment with rasagiline in patients with mild hepatic impairment. Rasagiline use in patients with moderate hepatic impairment should be avoided. If patients progress from mild to moderate hepatic impairment, rasagiline should be stopped (see section 5.2).

There are a number of known interactions between non-selective MAO inhibitors and other medicinal products.

Rasagiline must not be administered along with other MAO inhibitors (including medicinal and natural products without prescription e.g. St John's Wort) as there may be a risk of non-selective MAO inhibition that may lead to hypertensive crises (see section 4.3).

Serious adverse reactions have been reported with the concomitant use of pethidine and MAO inhibitors including another selective MAO-B inhibitor. The concomitant administration of rasagiline and pethidine is contraindicated (see section 4.3).

With MAO inhibitors there have been reports of medicinal product interactions with the concomitant use of sympathomimetic medicinal products. Therefore, in view of the MAO inhibitory activity of rasagiline, concomitant administration of rasagiline and sympathomimetics such as those present in nasal and oral decongestants or cold medicinal products, containing ephedrine or pseudoephedrine, is not recommended (see section 4.4).

There have been reports of medicinal product interactions with the concomitant use of dextromethorphan and non-selective MAO inhibitors. Therefore, in view of the MAO inhibitory activity of rasagiline, the concomitant administration of rasagiline and dextromethorphan is not recommended (see section 4.4).

The concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided (see section 4.4).

For concomitant use of rasagiline with selective serotonin reuptake inhibitors (SSRIs)/selective serotonin-noradrenaline reuptake inhibitors (SNRIs) in clinical trials (see section 4.8).

Serious adverse reactions have been reported with the concomitant use of SSRIs, SNRIs, tricyclic, tetracyclic antidepressants and MAO inhibitors. Therefore, in view of the MAO inhibitory activity of rasagiline, antidepressants should be administered with caution.

In Parkinson's disease patients receiving chronic levodopa treatment as adjunct therapy, there was no clinically significant effect of levodopa treatment on rasagiline clearance.

In vitro metabolism studies have indicated that cytochrome P450 1A2 (CYP1A2) is the major enzyme responsible for the metabolism of rasagiline. Co-administration of rasagiline and ciprofloxacin (an inhibitor of CYP1A2) increased the AUC of rasagiline by 83%. Co-administration of rasagiline and theophylline (a substrate of CYP1A2) did not affect the pharmacokinetics of either product. Thus, potent CYP1A2 inhibitors may alter rasagiline plasma levels and should be administered with caution.

There is a risk that the plasma levels of rasagiline in smoking patients could be decreased, due to induction of the metabolising enzyme CYP1A2.

In vitro studies showed that rasagiline at a concentration of 1μg/ml (equivalent to a level that is 160 times the average C_max ~ 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's therapeutic concentrations are unlikely to cause any clinically significant interference with substrates of these enzymes.

Concomitant administration of rasagiline and entacapone increased rasagiline oral clearance by 28%.

Tyramine/rasagiline interaction: Results of five tyramine challenge studies (in volunteers and PD patients), together with results of home monitoring of blood pressure after meals (of 464 patients treated with 0.5 or 1 mg/day of rasagiline or placebo as adjunct therapy to levodopa for six months without tyramine restrictions), and the fact that there were no reports of tyramine/rasagiline interaction in clinical studies conducted without tyramine restriction, indicate that rasagiline can be used safely without dietary tyramine restrictions.

For rasagiline no clinical data on exposed pregnancies is available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3). Caution should be exercised when prescribing to pregnant women.

Experimental data indicated that rasagiline inhibits prolactin secretion and, thus, may inhibit lactation. It is not known whether rasagiline is excreted in human milk. Caution should be exercised when rasagiline is administered to a breast-feeding mother.

No studies on the effects on the ability to drive and use machines have been performed.

Patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain AZILECT does not affect them adversely.

In the rasagiline clinical programme overall 1361 patients were treated with rasagiline for 3076.4 patient years. In the double-blind, placebo-controlled studies, 529 patients were treated with rasagiline 1 mg/day for 212 patient years and 539 patients received placebo for 213 patient years.

Monotherapy

The list below includes adverse reactions which were reported with a higher incidence in placebo-controlled studies, in patients receiving 1 mg/day rasagiline (rasagiline group n=149, placebo group n=151).

Adverse reactions with at least 2% difference over placebo are marked in italics. In parentheses is the adverse reaction incidence (% of patients) in rasagiline vs. placebo, respectively.

Adverse reactions are ranked under headings of frequency using the following conventions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000).

Adjunct Therapy

The list below includes adverse reactions which were reported with a higher incidence in placebo-controlled studies in patients receiving 1 mg/day rasagiline (rasagiline group n=380, placebo group n=388). In parentheses is the adverse reaction incidence (% of patients) in rasagiline vs. placebo, respectively.

Adverse reactions with at least 2% difference over placebo are in italics.

Adverse reactions are ranked under headings of frequency using the following conventions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), very rare (<1/10000).

Parkinson's disease is associated with symptoms of hallucinations and confusion. In post-marketing experience, these symptoms have also been observed in Parkinson's disease patients treated with rasagiline.

Serious adverse reactions are known to occur with concomitant use of SSRIs, SNRIs, tricyclic, tetracyclic antidepressants and MAO inhibitors. In the post-marketing period, cases of serotonin syndrome associated with agitation, confusion, rigidity, pyrexia and myoclonus have been reported by patients treated with antidepressants/SNRI concomitantly with rasagiline.

Rasagiline clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with rasagiline, but the following antidepressants and doses were allowed in the rasagiline trials: amitriptyline ≤ 50 mg/daily, trazodone ≤ 100 mg/daily, citalopram ≤ 20 mg/daily, sertraline≤ 100 mg/daily and paroxetine ≤ 30 mg/daily. There were no cases of serotonin syndrome in the rasagiline clinical programme in which 115 patients were exposed concomitantly to rasagiline and tricyclics and 141 patients were exposed to rasagiline and SSRIs/SNRIs.

In the post-marketing period, cases of elevated blood pressure, including rare cases of hypertensive crisis associated with ingestion of unknown amounts of tyramine-rich foods, have been reported in patients taking rasagiline.

With MAO inhibitors, there have been reports of drug interactions with the concomitant use of sympathomimetic medicinal products. In post-marketing period, there was one case of elevated blood pressure in a patient using the ophthalmic vasoconstrictor tetrahydrozoline hydrochloride while taking rasagiline.

Overdosage: Symptoms reported following overdose of AZILECT in doses ranging from 3 mg to 100 mg included dysophoria, hypomania, hypertensive crisis and serotonin syndrome.

Overdose can be associated with significant inhibition of both MAO-A and MAO-B. In a single-dose study healthy volunteers received 20 mg/day and in a ten-day study healthy volunteers received 10 mg/day. Adverse events were mild or moderate and not related to rasagiline treatment. In a dose escalation study in patients on chronic levodopa therapy treated with 10 mg/day of rasagiline, there were reports of cardiovascular undesirable reactions (including hypertension and postural hypotension) which resolved following treatment discontinuation. These symptoms may resemble those observed with non-selective MAO inhibitors.

There is no specific antidote. In case of overdose, patients should be monitored and the appropriate symptomatic and supportive therapy instituted.

Pharmacotherapeutic group: Anti-Parkinson-Drugs, Monoamine oxidase-B inhibitors.

ATC code: N04BD02

Mechanism of action:

Rasagiline was shown to be a potent, irreversible MAO-B selective inhibitor, which may cause 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.

1-Aminoindan is an active major metabolite and it is not a MAO-B inhibitor.

Clinical studies:

The efficacy of rasagiline was established in three studies: as monotherapy treatment in study I and as adjunct therapy to levodopa in the studies II and III.

Monotherapy:

In study I, 404 patients were randomly assigned to receive placebo (138 patients), rasagiline 1 mg/day (134 patients) or rasagiline 2 mg/day (132 patients) and were treated for 26 weeks, there was no active comparator.

In this study, the primary measure of efficacy was the change from baseline in the total score of the Unified Parkinson's Disease Rating Scale (UPDRS, parts I-III). The difference between the mean change from baseline to week 26/termination (LOCF, Last Observation Carried Forward) was statistically significant (UPDRS, parts I-III: for rasagiline 1 mg compared to placebo -4.2, 95% CI [-5.7, -2.7]; p<0.0001; for rasagiline 2 mg compared to placebo -3.6, 95% CI [-5.0, -2.1]; p<0.0001, UPDRS Motor, part II: for rasagiline 1 mg compared to placebo -2.7, 95% CI [-3.87, -1.55], p<0.0001; for rasagiline 2 mg compared to placebo -1.68, 95% CI [-2.85, -0.51], p=0.0050). The effect was evident, although its magnitude was modest in this patient population with mild disease. There was a significant and beneficial effect in quality of life (as assessed by PD-QUALIF scale).

Adjunct therapy:

In study II, patients were randomly assigned to receive placebo (229 patients), or rasagiline 1 mg/day (231 patients) or the catechol-O-methyl transferase (COMT) inhibitor, entacapone, 200 mg taken along with scheduled doses of levodopa (LD)/decarboxylase inhibitor (227 patients), and were treated for 18 weeks. In study III, 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.

In both studies, the primary measure of efficacy was the change from baseline to treatment period in the mean number of hours that were spent in the "OFF" state during the day (determined from "24-hour" home diaries completed for 3 days prior to each of the assessment visits).

In study II, the mean difference in the number of hours spent in the "OFF" state compared to placebo was -0.78h, 95% CI [-1.18, -0.39], p=0.0001. The mean total daily decrease in the OFF time was similar in the entacapone group (-0.80h, 95% CI [-1.20, -0.41], p<0.0001) to that observed in the rasagiline 1 mg group. In study III, the mean difference compared to placebo was -0.94h, 95% CI [-1.36, -0.51], p<0.0001. There was also a statistically significant improvement over placebo with the rasagiline 0.5 mg group, yet the magnitude of improvement was lower. The robustness of the results for the primary efficacy endpoint, was confirmed in a battery of additional statistical models and was demonstrated in three cohorts (ITT, per protocol and completers).

The secondary measures of efficacy included global assessments of improvement by the examiner, Activities of Daily Living (ADL) subscale scores when OFF and UPDRS motor while ON. Rasagiline produced statistically significant benefit compared to placebo.

Absorption:

Rasagiline is rapidly absorbed, reaching peak plasma concentration (C_max) in approximately 0.5 hours. The absolute bioavailability of a single rasagiline dose is about 36%. Food does not affect the T_max of rasagiline, although C_max and exposure (AUC) are decreased by approximately 60% and 20%, respectively, when the medicinal product is taken with a high fat meal. Because AUC is not substantially affected, rasagiline can be administered with or without food.

Distribution:

The mean volume of distribution following a single intravenous dose of rasagiline is 243 l. Plasma protein binding following a single oral dose of ¹⁴C-labelled rasagiline is approximately 60 to 70%.

Metabolism:

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, 3-hydroxy-N-propargyl-1 aminoindan and 3-hydroxy-1-aminoindan. In vitro experiments indicate that both routes of rasagiline metabolism are dependent on cytochrome P450 system, with CYP1A2 being the major iso-enzyme involved in rasagiline metabolism. Conjugation of rasagiline and its metabolites was also found to be a major elimination pathway to yield glucuronides.

Excretion:

After oral administration of ¹⁴C-labelled rasagiline, elimination occurred primarily via urine (62.6%) and secondarily via faeces (21.8%), with a total recovery of 84.4% of the dose over a period of 38 days. Less than 1% of rasagiline is excreted as unchanged product in urine.

Linearity/non-linearity:

Rasagiline pharmacokinetics are linear with dose over the range of 0.5-2 mg. Its terminal half-life is 0.6-2 hours.

Characteristics in patients

Patients with hepatic impairment: In subjects with mild hepatic impairment, AUC and C_max were increased by 80% and 38%, respectively. In subjects with moderate hepatic impairment, AUC and C_max were increased by 568% and 83%, respectively (see section 4.4).

Patients with renal impairment: Rasagiline's pharmacokinetic characteristics in subjects with mild (CLcr 50-80 ml/min) and moderate (CLcr 30-49 ml/min) renal impairment were similar to healthy subjects.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity and reproduction toxicity.

Rasagiline did not present genotoxic potential in vivo and in several in vitro systems using bacteria or hepatocytes. In the presence of metabolite activation rasagiline induced an increase of chromosomal aberrations at concentrations with excessive cytotoxicity which are unattainable at the clinical conditions of use.

Rasagiline was not carcinogenic in rats at systemic exposure, 84 - 339 times the expected plasma exposures in humans at 1 mg/day. In mice, increased incidences of combined bronchiolar/alveolar adenoma and/or carcinoma were observed at systemic exposures, 144 - 213 times the expected plasma exposure in humans at 1 mg/day.

Mannitol

Maize starch

Pregelatinised maize starch

Colloidal anhydrous silica

Stearic acid

Talc

Not applicable

Blisters: 3 years

Bottles: 3 years

Do not store above 25°C.

Blisters: Aluminium/aluminium blister packs of 7, 10, 28, 30, 100 or 112 tablets.

Bottles: White, high-density polyethylene bottle with or without a child-resistant cap containing 30 tablets.

Not all pack sizes may be marketed.

No special requirements.

Teva Pharma GmbH

Graf-Arco-Str. 3

89079 Ulm

Germany

EU/1/04/304/001-007

Date of first authorisation: 21 February 2005

Date of latest renewal: 21 September 2009

December 2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu