AZILECT 1mg tablets medication leaflet

AZILECT 1 mg tablets

Each tablet contains 1 mg rasagiline (as mesilate).

For the 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 sideand plain on the other side.

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

The recommended dose of rasagiline is 1 mg (one tablet of AZILECT) once daily, to be taken with orwithout levodopa.

No change in dose is required for elderly patients (see section 5.2).

Rasagiline is contraindicated in patients with severe hepatic impairment (see section 4.3). Rasagilineuse in patients with moderate hepatic impairment should be avoided. Caution should be used wheninitiating treatment with rasagiline in patients with mild hepatic impairment. In case patients progressfrom mild to moderate hepatic impairment rasagiline should be stopped (see section 4.4 and 5.2).

No special precautions are required in patients with renal impairment.

The safety and efficacy of AZILECT in children and adolescents have not been established. There isno relevant use of AZILECT in the paediatric population in the indication Parkinson’s disease.

For oral use.

AZILECT may be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant treatment with other monoamine oxidase (MAO) inhibitors (including medicinal andnatural products without prescription e.g. St. John's Wort) or pethidine (see section 4.5). At least14 days must elapse between discontinuation of rasagiline and initiation of treatment with MAOinhibitors or pethidine.

Concomitant use of rasagiline with other medicinal products

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 treatmentwith rasagiline. At least 14 days should elapse between discontinuation of rasagiline and initiation oftreatment with fluoxetine or fluvoxamine.

The concomitant use of rasagiline and dextromethorphan or sympathomimetics such as those presentin nasal and oral decongestants or cold medicinal product containing ephedrine or pseudoephedrine isnot recommended (see section 4.5).

Concomitant use of rasagiline and levodopa

Since rasagiline potentiates the effects of levodopa, the adverse reactions of levodopa may beincreased and pre-existing dyskinesia exacerbated. Decreasing the dose of levodopa may amelioratethis adverse reaction.

There have been reports of hypotensive effects when rasagiline is taken concomitantly with levodopa.

Patients with Parkinson’s disease are particularly vulnerable to the adverse reactions of hypotensiondue to existing gait issues.

Dopaminergic effects

Excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes

Rasagiline may cause daytime drowsiness, somnolence, and, occasionally, especially if used withother dopaminergic medicinal products - falling asleep during activities of daily living. Patients mustbe informed of this and advised to exercise caution while driving or operating machines duringtreatment with rasagiline. Patients who have experienced somnolence and/or an episode of suddensleep onset must refrain from driving or operating machines (see section 4.7).

Impulse control disorders (ICDs)

ICDs can occur in patients treated with dopamine agonists and/or dopaminergic treatments. Similarreports of ICDs have also been received post-marketing with rasagiline. Patients should be regularlymonitored for the development of impulse control disorders. Patients and carers should be made awareof the behavioural symptoms of impulse control disorders that were observed in patients treated withrasagiline, including cases of compulsions, obsessive thoughts, pathological gambling, increasedlibido, hypersexuality, impulsive behaviour and compulsive spending or buying.

A retrospective cohort study suggested a possibly increased risk of melanoma with the use ofrasagiline, especially in patients with longer duration of rasagiline exposure and/or with the highercumulative dose of rasagiline. Any suspicious skin lesion should be evaluated by a specialist. Patientsshould therefore be advised to seek medical review if a new or changing skin lesion is identified.

Caution should be used when initiating treatment with rasagiline in patients with mild hepaticimpairment. Rasagiline use in patients with moderate hepatic impairment should be avoided. In casepatients progress from mild to moderate hepatic impairment, rasagiline should be stopped (seesection 5.2).

MAO Inhibitors

Rasagiline is contraindicated along with other MAO inhibitors (including medicinal and naturalproducts without prescription e.g. St. John's Wort) as there may be a risk of non-selective MAOinhibition that may lead to hypertensive crises (see section 4.3).

Pethidine

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

Sympathomimetics

With MAO inhibitors there have been reports of medicinal product interactions with the concomitantuse of sympathomimetic medicinal products. Therefore, in view of the MAO inhibitory activity ofrasagiline, concomitant administration of rasagiline and sympathomimetics such as those present innasal and oral decongestants or cold medicinal products, containing ephedrine or pseudoephedrine, isnot recommended (see section 4.4).

Dextromethorphan

There have been reports of medicinal product interactions with the concomitant use ofdextromethorphan and non-selective MAO inhibitors. Therefore, in view of the MAO inhibitoryactivity of rasagiline, the concomitant administration of rasagiline and dextromethorphan is notrecommended (see section 4.4).

SNRI/SSRI/tri- and tetracyclic antidepressants

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)/selectiveserotonin-norepinephrine 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 inhibitoryactivity of rasagiline, antidepressants should be administered with caution.

Agents that affect CYP1A2 activity

In vitro metabolism studies have indicated that cytochrome P450 1A2 (CYP1A2) is the major enzymeresponsible for the metabolism of rasagiline.

Co-administration of rasagiline and ciprofloxacin (an inhibitor of CYP1A2) increased the AUC ofrasagiline by 83%. Co-administration of rasagiline and theophylline (a substrate of CYP1A2) did notaffect the pharmacokinetics of either product. Thus, potent CYP1A2 inhibitors may alter rasagilineplasma levels and should be administered with caution.

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

Other cytochrome P450 isoenzymes

In vitro studies showed that rasagiline at a concentration of 1 µg/ml (equivalent to a level that is160 times the average Cmax ~ 5.9-8.5 ng/ml in Parkinson’s disease patients after 1 mg rasagilinemultiple dosing), did not inhibit cytochrome P450 isoenzymes, CYP1A2, CYP2A6, CYP2C9,

CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A. These results indicate that rasagiline’stherapeutic concentrations are unlikely to cause any clinically significant interference with substratesof these enzymes (see section 5.3).

Levodopa and other Parkinson’s disease medicinal products

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

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

Tyramine/rasagiline interaction

Results of five tyramine challenge studies (in volunteers and Parkinson’s disease patients), togetherwith results of home monitoring of blood pressure after meals (of 464 patients treated with 0.5 or1 mg/day of rasagiline or placebo as adjunct therapy to levodopa for six months without tyraminerestrictions), and the fact that there were no reports of tyramine/rasagiline interaction in clinicalstudies conducted without tyramine restriction, indicate that rasagiline can be used safely withoutdietary tyramine restrictions.

There are no data from the use of rasagiline in pregnant women. Animal studies do not indicate director indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionarymeasure, it is preferable to avoid the use of rasagiline during pregnancy.

Non-clinical data indicate 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 whenrasagiline is administered to a breast-feeding mother.

No human data on the effect of rasagiline on fertility are available. Non-clinical data indicate thatrasagiline has no effect on fertility.

In patients experiencing somnolence/sudden sleep episodes, rasagiline may have major influence onthe ability to drive and use machines.

Patients should be cautioned about operating hazardous machines, including motor vehicles, until theyare reasonably certain that rasagiline does not affect them adversely.

Patients being treated with rasagiline and presenting with somnolence and/or sudden sleep episodesmust be informed to refrain from driving or engaging in activities where impaired alertness may putthemselves or others at risk of serious injury or death (e.g. operating machines) until they have gainedsufficient experience with rasagiline and other dopaminergic medications to gauge whether or not itaffects their mental and/or motor performance adversely.

If increased somnolence or new episodes of falling asleep during activities of daily living (e.g.watching television, passenger in a car, etc.) are experienced at any time during treatment, the patientsshould not drive or participate in potentially dangerous activities.

Patients should not drive, operate machinery, or work at heights during treatment if they havepreviously experienced somnolence and/or have fallen asleep without warning prior to use ofrasagiline.

Patients should be cautioned about possible additive effects of sedating medicinal products, alcohol, orother central nervous system depressants (e.g. benzodiazepines, antipsychotics, antidepressants) incombination with rasagiline, or when taking concomitant medications that increase plasma levels ofrasagiline (e.g. ciprofloxacin) (see section 4.4).

In clinical studies in Parkinson's disease patients the most commonly reported adverse reactions were:headache, depression, vertigo, and flu (influenza and rhinitis) in monotherapy; dyskinesia, orthostatichypotension, fall, abdominal pain, nausea and vomiting, and dry mouth in adjunct to levodopa therapy;musculoskeletal pain, as back and neck pain, and arthralgia in both regimens. These adverse reactionswere not associated with an elevated rate of drug discontinuation.

Adverse reactions are listed below in Tables 1 and 2 by system organ class and frequency using thefollowing conventions: very common (≥1/10), common (≥1/100 to <1/10), uncommon(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot beestimated from the available data).

The tabulated list below includes adverse reactions which were reported with a higher incidence inplacebo-controlled studies, in patients receiving 1 mg/day rasagiline.

System Organ Very common Common Uncommon Not known

Class

Infections and Influenzainfestations

Neoplasms Skin carcinomabenign,malignant andunspecified(including cystsand polyps)

Blood and Leucopenialymphatic systemdisorders

Immune system Allergydisorders

Metabolism and Decreased appetitenutritiondisorders

System Organ Very common Common Uncommon Not known

Class

Psychiatric Depression, Impulse controldisorders Hallucinations* disorders*

Nervous system Headache Cerebrovascular Serotonindisorders accident syndrome*,

Excessive daytimesleepiness (EDS)and sudden sleeponset (SOS)episodes*

Eye disorders Conjunctivitis

Ear and Vertigolabyrinthdisorders

Cardiac Angina pectoris Myocardialdisorders infarction

Vascular Hypertension*disorders

Respiratory, Rhinitisthoracic andmediastinaldisorders

Gastrointestinal Flatulencedisorders

Skin and Dermatitis Vesiculobulloussubcutaneous rashtissue disorders

Musculoskeletal Musculoskeletaland connective pain,tissue disorders Neck pain,

Arthritis

Renal and Urinary urgencyurinary disorders

General Fever,disorders and Malaiseadministrationsite conditions

*See section description of selected adverse reactions

Adjunct Therapy

The tabulated list below includes adverse reactions which were reported with a higher incidence inplacebo-controlled studies in patients receiving 1 mg/day rasagiline.

System Organ Very common Common Uncommon Not known

Class

Neoplasms Skin melanoma*benign,malignant andunspecified

Metabolism and Decreased appetitenutritiondisorders

Psychiatric Hallucinations*, Confusion Impulse controldisorders Abnormal dreams disorders*

Nervous system Dyskinesia Dystonia, Cerebrovascular Serotonin

System Organ Very common Common Uncommon Not known

Classdisorders Carpal tunnel accident syndrome*,syndrome, Excessive daytime

Balance disorder sleepiness (EDS)and sudden sleeponset (SOS)episodes*

Cardiac Angina pectorisdisorders

Vascular Orthostatic Hypertension*disorders hypotension*

Gastrointestinal Abdominal pain,disorders Constipation,

Nausea andvomiting,

Dry mouth

Skin and Rashsubcutaneoustissue disorders

Musculoskeletal Arthralgia,and connective Neck paintissue disorders*

Investigations Decreased weight

Injury, poisoning Falland proceduralcomplications

*See section description of selected adverse reactions

In blinded placebo-controlled studies, severe orthostatic hypotension was reported in one subject(0.3%) in the rasagiline arm (adjunct studies), none in the placebo arm. Clinical trial data furthersuggest that orthostatic hypotension occurs most frequently in the first two months of rasagilinetreatment and tends to decrease over time.

Rasagiline selectively inhibits MAO-B and is not associated with increased tyramine sensitivity at theindicated dose (1 mg/day). In blinded placebo-controlled studies (monotherapy and adjunct) severehypertension was not reported in any subjects in the rasagiline arm. In the post-marketing period,cases of elevated blood pressure, including rare serious cases of hypertensive crisis associated withingestion of unknown amounts of tyramine-rich foods, have been reported in patients takingrasagiline. In post-marketing period, there was one case of elevated blood pressure in a patient usingthe ophthalmic vasoconstrictor tetrahydrozoline hydrochloride while taking rasagiline.

Impulse control disorders

One case of hypersexuality was reported in monotherapy placebo-controlled study. The followingwere reported during post-marketing exposure with unknown frequency: compulsions, compulsiveshopping, dermatillomania, dopamine dysregulation syndrome, impulse-control disorder, impulsivebehaviour, kleptomania, theft, obsessive thoughts, obsessive-compulsive disorder, stereotypy,gambling, pathological gambling, libido increased, hypersexuality, psychosexual disorder, sexuallyinappropriate behaviour. Half of the reported ICD cases were assessed as serious. Only single cases ofreported cases had not recovered at the time they were reported.

Excessive daytime sleepiness (EDS) and sudden sleep onset (SOS) episodes

Excessive daily sleepiness (hypersomnia, lethargy, sedation, sleep attacks, somnolence, sudden onsetof sleep) can occur in patients treated with dopamine agonists and/or other dopaminergic treatments. Asimilar pattern of excessive daily sleepiness has been reported post-marketing with rasagiline.

Cases of patients, treated with rasagiline and other dopaminergic medicinal products, falling asleepwhile engaged in activities of daily living have been reported. Although many of these patientsreported somnolence while on rasagiline with other dopaminergic medicinal products, some perceivedthat they had no warning signs, such as excessive drowsiness, and believed that they were alertimmediately prior to the event. Some of these events have been reported more than 1-year afterinitiation of treatment.

Hallucinations

Parkinson’s disease is associated with symptoms of hallucinations and confusion. In post-marketingexperience, these symptoms have also been observed in Parkinson’s disease patients treated withrasagiline.

Serotonin syndrome

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, andparoxetine ≤ 30 mg/daily (see section 4.5).

In the post-marketing period, cases of potentially life-threating serotonin syndrome associated withagitation, confusion, rigidity, pyrexia and myoclonus have been reported by patients treated withantidepressants, meperidine, tramadol, methadone, or propoxyphene concomitantly with rasagiline.

Malignant melanoma

Incidence of skin melanoma in placebo-controlled clinical studies was 2/380 (0.5%) in rasagiline 1 mgas adjacent to levodopa therapy group vs. 1/388 (0.3%) incidence in placebo group. Additional casesof malignant melanoma were reported during post-marketing period. These cases were consideredserious in all reports.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Symptoms reported following overdose of rasagiline in doses ranging from 3 mg to 100 mg includedhypomania, hypertensive crisis and serotonin syndrome.

Overdose can be associated with significant inhibition of both MAO-A and MAO-B. In a single-dosestudy healthy volunteers received 20 mg/day and in a ten-day study healthy volunteers received10 mg/day. Adverse reactions were mild or moderate and not related to rasagiline treatment. In a doseescalation study in patients on chronic levodopa therapy treated with 10 mg/day of rasagiline, therewere reports of cardiovascular adverse reactions (including hypertension and postural hypotension)which resolved following treatment discontinuation. These symptoms may resemble those observedwith non-selective MAO inhibitors.

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

Pharmacotherapeutic group: Anti-Parkinson-Drugs, monoamine oxidase -B inhibitors, ATC code:

N04BD02

Rasagiline was shown to be a potent, irreversible MAO-B selective inhibitor, which may cause anincrease in extracellular levels of dopamine in the striatum. The elevated dopamine level andsubsequent increased dopaminergic activity are likely to mediate rasagiline's beneficial effects seen inmodels of dopaminergic motor dysfunction.

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

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

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 activecomparator.

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 meanchange from baseline to week 26/termination (LOCF, Last Observation Carried Forward) wasstatistically 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 wasevident, although its magnitude was modest in this patient population with mild disease. There was asignificant and beneficial effect in quality of life (as assessed by PD-QUALIF scale).

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 takenalong with scheduled doses of levodopa (LD)/decarboxylase inhibitor (227 patients), and were treatedfor 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 for26 weeks.

In both studies, the primary measure of efficacy was the change from baseline to treatment period inthe 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 placebowas -0.78h, 95% CI [-1.18, -0.39], p=0.0001. The mean total daily decrease in the OFF time wassimilar in the entacapone group (-0.80h, 95% CI [-1.20, -0.41], p<0.0001) to that observed in therasagiline 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 therasagiline 0.5 mg group, yet the magnitude of improvement was lower. The robustness of the resultsfor the primary efficacy endpoint, was confirmed in a battery of additional statistical models and wasdemonstrated 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. Rasagilineproduced statistically significant benefit compared to placebo.

Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 0.5 hours.

The absolute bioavailability of a single rasagiline dose is about 36%.

Food does not affect the Tmax of rasagiline, although Cmax and exposure (AUC) are decreased byapproximately 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.

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

Rasagiline undergoes almost complete biotransformation in the liver prior to excretion. Themetabolism of rasagiline proceeds through two main pathways: N-dealkylation and/or hydroxylationto yield: 1-aminoindan, 3-hydroxy-N-propargyl-1 aminoindan and 3-hydroxy-1-aminoindan. In vitroexperiments indicate that both routes of rasagiline metabolism are dependent on cytochrome P450system, with CYP1A2 being the major iso-enzyme involved in rasagiline metabolism. Conjugation ofrasagiline and its metabolites was also found to be a major elimination pathway to yield glucuronides.

Ex vivo and in vitro experiments demonstrate that rasagiline is neither inhibitor nor inducer of major

CYP450 enzymes (see section 4.5).

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 of38 days. Less than 1% of rasagiline is excreted as unchanged product in urine.

Rasagiline pharmacokinetics is linear with dose over the range of 0.5-2 mg in Parkinson’s diseasepatients. Its terminal half-life is 0.6-2 hours.

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

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

Age has little influence on rasagiline pharmacokinetics in the elderly (> 65 years) (see section 4.2)

Non-clinical data reveal no special hazard for humans based on the standard studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenicity, reproduction and development.

Rasagiline did not present genotoxic potential in vivo and in several in vitro systems using bacteria orhepatocytes. In the presence of metabolite activation rasagiline induced an increase of chromosomalaberrations at concentrations with excessive cytotoxicity which are unattainable at the clinicalconditions of use.

Rasagiline was not carcinogenic in rats at systemic exposure, 84 - 339 times the expected plasmaexposures in humans at 1 mg/day. In mice, increased incidences of combined bronchiolar/alveolaradenoma and/or carcinoma were observed at systemic exposures, 144 - 213 times the expected plasmaexposure 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 30ºC.

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

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 for disposal.

Teva B.V.

Swensweg 52031 GA Haarlem

The Netherlands

EU/1/04/304/001-07

AUTHORISATION

Date of first authorisation: 21 February 2005

Date of latest renewal: 21 September 2009

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