Consumer medicine information

Azilect

Rasagiline

BRAND INFORMATION

Brand name

Azilect Tablets

Active ingredient

Rasagiline

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Azilect.

What is in this leaflet

This leaflet answers some common questions about Azilect. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Azilect against the benefits they expect it will have for you.

If you have any concerns about taking this medicine ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again

What Azilect is used for

Azilect is used to treat the symptoms of Parkinson's disease. It can be taken with or without dopamine agonist or levodopa therapy.

Parkinson's disease is a condition of the brain that mainly affects body movement. The three main symptoms of Parkinson's disease are:

  • Shaking (tremor)
  • Muscle stiffness
  • Slow and unsteady movement

In Parkinson's disease, there is a loss of cells producing dopamine in certain areas in the brain.

Azilect works by increasing and maintaining the level of dopamine in your brain which will decrease symptoms of Parkinson's disease.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription. It is not addictive.

Azilect should not be given to children under 18 years of age as there is no specific information about such use. Always ask your doctor before giving medicines to children.

Before you take Azilect

When you must not take it.

Do not take Azilect if you have ever had an allergic reaction to rasagiline or any of the ingredients listed at the end of this leaflet.

If you have an allergic reaction you may get a skin rash, have difficulty in breathing, get symptoms of hay fever or feel faint.

If you are already taking Azilect, do not take another medicine called:

  • monoamine oxidase inhibitors (MAOI), whether used to treat depression, Parkinson's disease or any other condition
  • Other medicinal and natural products without prescription which have MAOI activity (e.g. St. John's Wort)
  • pethidine, a strong pain killer
  • ciprofloxacin, an antibiotic used to treat infection

Wait, at least 14 days between stopping Azilect and starting your MAOI medicine or pethidine.

Do not take Azilect if you have a problem with your liver.

Do not take Azilect after the expiry date (EXP) printed on the pack.

It may have not work as well

Do not take Azilect if the packaging is torn or shows signs of having been tampered with.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have a problem with your liver.

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding.

Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you smoke.

Nicotine can affect the amount of rasagiline that is in your body.

Tell your doctor if you notice any unusual skin lumps or moles which are new or have changed.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

The following medicines require specific medical advice before being taken together with Azilect:

  • medicines used to treat depression, anxiety, panic disorder, obsessive compulsive disorder or pre-menstrual dysphoric disorders. Examples of such medicines include selective serotonin reuptake inhibitors (SSRIs), tricyclic and tetracyclic antidepressants
  • other medicines used to treat depression called fluoxetine and fluvoxamine
    Wait at least 5 weeks between stopping fluoxetine treatment and starting treatment with Azilect, and 14 days between stopping Azilect treatment and starting treatment with fluoxetine or fluvoxamine.
  • dextromethorphan, a medicine for cough
  • substances with sympathomimetic activity such as those present in 'cold and flu' oral tablets and nasal drops containing ephedrine or pseudoephedrine
  • clozapine, a medicine used to treat schizophrenia
  • other medicines used to treat symptoms of Parkinson's disease

Your doctor or pharmacist can tell you what to do if you are taking this or any other medicines.

If you have not told your doctor about any of these things, tell them before you take Azilect.

How to take Azilect

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much Azilect to take each day. Take the amount your doctor tells you to.

The usual dose for Azilect is one tablet of 1 mg taken orally once a day.

How to take it

Swallow the tablets whole with a full glass of water.

Azilect can be taken with or without food.

When to take it

Take your medicine at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take it

Do not stop taking this medicine without first checking with your doctor.

If you forget to take it

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (Overdose)

Immediately telephone your doctor or Poisons Information Centre (Telephone 13 11 26) for advice, or go to the Accident and Emergency department at your nearest hospital if you think that you or anyone else may have taken too much Azilect. Do this even if there are no signs of discomfort or poisoning. Keep telephone numbers for these places handy.

While you are taking Azilect

Things you must do

Tell your doctor immediately if you become pregnant while taking Azilect.

Tell all doctors, dentists and pharmacists who are treating you that you are taking Azilect, especially if you are being started on any new medicines.

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take Azilect to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if their symptoms seem similar to yours.

Do not drive, operate machinery or work at heights during treatment if you have fallen asleep without warning, prior to the use of Azilect.

Things to be aware of

As with any new medicine, make sure you know how Azilect affects you before you drive or operate machinery.

Azilect may cause you to feel sleepy in the daytime during daily activities.

Be careful when drinking alcohol while you are taking this medicine.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

Standing up slowly, especially when you get up from a bed or chair, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Scientific evidence suggests that Parkinson's disease is associated with a higher risk of skin cancer, (including melanoma). During the development (placebo-controlled clinical trials), melanoma was observed in both Azilect- and placebo-treated patients (around 0.5% vs 0.2% respectively). People with Parkinson's disease, including those taking Azilect, should undergo periodic examination of the skin.

Eating excessive amounts of foods rich in tyramine (e.g. aged cheese, red wine) while you are taking Azilect could very rarely cause an increase in your blood pressure and should be avoided. If you do eat these foods while you are taking Azilect and do not feel well, you should contact your treating doctor. Your treating doctor or pharmacist can advise you on what foods are rich in tyramine and what your risk of having a reaction may be.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Azilect.

This medicine helps most people with Parkinson's disease, but it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following side effects and they worry you:

  • headache
  • flu syndrome
  • malaise
  • neck pain
  • indigestion
  • joint pain
  • depression
  • eye inflammation
  • abdominal pain
  • accidental injury (primarily falls)
  • dizziness when you stand up due to low blood pressure
  • constipation
  • vomiting
  • weight loss
  • difficulty in moving normally
  • obsessive thoughts or impulsive behaviour.

Tell your doctor or pharmacist if you notice anything else that is making you feel unwell.

Some people may get other side effects while using Azilect.

After taking Azilect

Storage

Keep Azilect in the blister pack until it is time to take them.

Keep Azilect in a cool dry place where the temperature stays below 25°C.

Do not store Azilect or any other medicine in the bathroom or near a sink or stove. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep Azilect where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above ground is a good place to store medicines.

Disposal

Dispose of the tablets where children cannot reach them.

Ask your pharmacist what to do with any Azilect you may have left over if your doctor tells you to stop using it, or you find that the tablets have passed the expiry date.

Azilect description

What Azilect tablets look like

White to off-white, round, flat, bevelled tablets, debossed with "GIL" and "1" underneath on one side.

Ingredients

Azilect tablets contain 1 mg of rasagiline (as rasagiline mesilate).

The tablets also contain:

  • mannitol
  • silica - colloidal anhydrous
  • starch maize
  • starch-pregelatinised maize
  • stearic acid*
  • talc-purified

* Vegetable origin.

Manufacturer

Azilect is supplied in Australia by:

Teva Pharma Australia Pty Ltd
37 Epping Rd
Macquarie Park, NSW 2113
Australia
Telephone: 1800 288 382

This leaflet was revised in March 2018

Australian Registration Numbers are:

1mg (blister): AUST R 170172

1mg (bottle): AUST R 172457

Azilect is the registered trade mark of Teva.

BRAND INFORMATION

Brand name

Azilect Tablets

Active ingredient

Rasagiline

Schedule

S4

 

1 Name of Medicine

Rasagiline 1 mg tablets.

6.7 Physicochemical Properties

Chemical name: N-propargyl-1(R)-aminoindan mesilate.
Empirical formula: (C12H13N). CH4SO3.
Molecular weight: 267.34.

Chemical structure.

Structure formula:

CAS number.

Chemical Abstracts No.: 161735-79-1.

2 Qualitative and Quantitative Composition

Each tablet contains 1 mg rasagiline (as mesilate).
Rasagiline mesilate is a white to off-white powder, freely soluble in water or ethanol and sparingly soluble in isopropanol.

Dissociation constant.

pKa (R2NH2+/R2NH) = 7.4.

Partition coefficient (Log P).

Octanol/Water. See Table 1.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

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

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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. In clinical studies rasagiline at the recommended therapeutic dose was also shown to be a potent and irreversible inhibitor of MAO-B in platelets.
Because of rasagiline's selectivity for MAO-B as compared to MAO-A at the recommended clinical dose it will induce significant inhibition of MAO-B only. Aminoindan, a major metabolite, is not a MAO-B inhibitor, but may contribute to rasagiline's effect in experimental models.
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.
It has been shown that, in vivo within the human body, there is no bioconversion of rasagiline mesilate (R-enantiomer) to its S-enantiomer (as determined in plasma samples for healthy volunteers dosed with rasagiline).

Clinical trials.

The efficacy of rasagiline was established in four randomized, placebo controlled trials. In one of these trials rasagiline was given as initial monotherapy treatment, in one trial as adjuvant therapy to dopamine agonists and in the other two trials as adjunct therapy to levodopa.

Monotherapy.

In the monotherapy trial (TEMPO), 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. The average duration of Parkinson's disease in patients in this trial was 1 year (range 0-11 years). Patients were not allowed to take levodopa, dopamine agonists, selegiline, amantadine, but if necessary, could take stable doses of anticholinergic medication. The primary analysis was in the intention to treat (ITT) population.
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: 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.
In the primary measure of efficacy the difference between the mean change from baseline to week 26/ termination (LOCF) was statistically significant for rasagiline 1 mg compared to placebo (-4.2, 95% CI [-5.7, -2.7]; p < 0.0001) and for rasagiline 2 mg compared to placebo (-3.6, 95% CI [-5.0, -2.1]; p < 0.0001). The efficacy of rasagiline 1 mg and 2 mg was comparable.
Table 5 displays the results of the trial.

Adjunctive use of Azilect with dopamine agonists.

The trial that investigated rasagiline 1 mg as adjunctive therapy to dopamine agonists was a double-blind, randomized, placebo-controlled, parallel group, 18-week study (ANDANTE). Patients were on a stable dose of dopamine agonist (pramipexole ≥ 1mg/day or ropinirole ≥ 6mg/day) therapy for ≥ 30 days and were either unable to receive an optimal therapeutic dose of dopamine agonist due to intolerable side effects or required an additional therapeutic agent because their previously optimal dose of dopamine agonist was no longer sufficient to control Parkinson's Disease symptoms.
In this trial, 321 patients were randomly assigned to receive placebo (162 patients) or rasagiline 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 to week 18 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)]. Rasagiline 1 mg had a significant beneficial effect relative to placebo on the primary measure of effectiveness in patients receiving stable dopamine agonist therapy (see Table 6).

Adjunct use of Azilect with levodopa.

Patients had Parkinson's disease for an average of 9 years (range 5 months to 33 years) in both studies, 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 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 approximately 35% were on entacapone. The primary analysis was in the intention to treat (ITT) population.
In both trials the primary measure of efficacy was the change from baseline to the end of the 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). The secondary measures of efficacy included global assessments of improvement by the examiner, ADL subscale scores when OFF and UPDRS motor while ON.
In the first trial (LARGO), patients were randomly assigned to receive placebo (229 patients), or rasagiline 1 mg/day (231 patients) or the COMT inhibitor, entacapone, 200 mg taken along with scheduled doses of levodopa/ decarboxylase inhibitor (227 patients), and were treated for 18 weeks. Patients averaged approximately 5.6 hours daily in the "OFF" state at baseline as confirmed by home diaries and were taking 3 to 10 daily doses of levodopa/ decarboxylase inhibitor. In the analysis of the measures of efficacy there was no direct comparison between rasagiline and entacapone; rasagiline 1 mg/day and entacapone with each levodopa dose were each separately compared to placebo. The comparison between entacapone and placebo serves for validation and exploratory purposes.
In the second trial (PRESTO), 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.
In LARGO, the mean difference in the number of hours spent in the OFF state compared to placebo was -0.78 h, 95% CI [-1.18, -0.39 h], p = 0.0001. The mean total daily decrease in the OFF time was similar in the entacapone group (-0.80 h, 95% CI [-1.20, -0.41], p < 0.0001) to that observed in the rasagiline 1 mg group. In PRESTO, the mean difference compared to placebo was -0.94 h, 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 observed decrease in total daily OFF time were accounted for by an increase in total daily ON time (adjusted mean difference 0.86 h, 95% CI [0.47, 1.26] for rasagiline 1 mg vs. placebo in the first trial, 1.02 h 95% CI [0.59, 1.46] in the second trial). This was predominantly found to be for good ON (ON1) time, with a similar magnitude of improvement between studies (0.81 h, 95% CI [0.36, 1.27] for LARGO, 0.78 h, 95% CI [0.26, 1.31] for PRESTO). In LARGO, there was almost no change in the amount of "troublesome" ON ("ON2") compared with baseline (adjusted mean difference vs. placebo 0.09 h, 95% CI [-0.28, 0.46], p = 0.6209). In PRESTO, "ON2" time increased slightly but significantly for rasagiline 1 mg (adjusted mean difference vs. placebo 0.37 h [95% CI 0.00, 0.74] p = 0.0479), though was almost unchanged for rasagiline 0.5 mg. In these studies the change in levodopa dose was allowed only in the first six weeks of treatment.
Tables 7 and 8 display the results of the two studies.

5.2 Pharmacokinetic Properties

Absorption.

Rasagiline is rapidly absorbed, reaching peak plasma concentration (Cmax) in approximately 0.5 hours. The absolute bioavailability of rasagiline after a single oral dose is about 36%. First pass metabolism is responsible for the incomplete bioavailability.
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, rasagiline can be administered with or without food.

Distribution.

The mean volume of distribution following a single i.v. dose is 243 L indicating that there is significant tissue uptake of rasagiline. In vitro 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 nanogram/mL.

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 (CYP) system, with CYP1A2 being the major isoenzyme 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 of radioactive material 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 drug in urine.

Linearity/ non-linearity.

Rasagiline pharmacokinetics are linear for Cmax but show a more than proportional increase in AUC for the 1-2 mg dose range. Its terminal half-life is 0.6-2 hours for the 1 mg dose and longer for higher doses, but there is no correlation with its pharmacological effect due to irreversible inhibition of MAO-B.

Elderly patients.

Population pharmacokinetics analysis in early PD patients on rasagiline monotherapy (n = 352) indicates that a decrease in oral clearance is associated with increasing age (e.g. a 30% decrease in clearance as age increases from 32 to 79 years). Specific studies with elderly subjects have shown that there is no effect of age on rasagiline's pharmacokinetics either as monotherapy or as adjunct to levodopa. Rasagiline was well tolerated in elderly PD patients in both monotherapy and adjunct therapy and no dosage adjustments are required for the elderly.

Children and adolescents (< 18 years).

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

Gender.

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

Patients with 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 Section 4.3).

Patients with renal impairment.

Following repeat dose administration (7 days) of rasagiline (1 mg/day) in subjects with mild renal impairment (ClCr 50-80 mL/min), slightly higher AUC was observed, while Cmax was unchanged. In subjects with moderate renal impairment (ClCr 30-49 mL/min), a lower Cmax (44%) and AUC (17%) compared to healthy subjects was observed. An additional study in moderately renal impaired patients demonstrated similar results. Since impaired renal function has little influence on rasagiline pharmacokinetics, it can be administered at the recommended dose to subjects with moderate renal impairment.

5.3 Preclinical Safety Data

Genotoxicity.

In the presence of metabolic activation, rasagiline was clastogenic in vitro in chromosomal aberration assays in human lymphocytes and in the mouse lymphoma tk assay. Rasagiline was negative in bacterial reverse mutation assays in vitro (in the presence and absence of metabolic activation) and in vivo assays (unscheduled DNA synthesis assay, mouse micronucleus assay). Rasagiline was also negative in the in vivo micronucleus assay in mice when administered in combination with levodopa/ carbidopa.

Carcinogenicity.

Two year oral carcinogenicity studies were conducted in mice at doses of 1, 15 and 45 mg/kg/day, and in rats at 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 were no increases in tumours; plasma exposures (AUC) at the highest doses were about 80 times (males) and 450 times (females) the anticipated human exposure at the maximum recommended clinical dose (1 mg/day). In mice, there was an increase in lung tumours (combined adenomas/ carcinomas) at 15 and 45 mg/kg/day in both sexes. Plasma exposures (AUC) at these doses were about 180 times and greater than 470 times the anticipated human exposures at the maximum recommended clinical dose (1 mg/day), while exposure at the no effect dose (1 mg/kg/day) was about 5 times anticipated clinical exposure.
The carcinogenic potential of rasagiline administered in combination with levodopa/ carbidopa has not been examined.

4 Clinical Particulars

4.1 Therapeutic Indications

Azilect is indicated for the symptomatic treatment of idiopathic Parkinson's disease (PD) as monotherapy and as adjunct therapy to dopamine agonists or to levodopa.

4.3 Contraindications

Rasagiline is contraindicated for use in patients who have demonstrated hypersensitivity to rasagiline or tablet excipients.
Concomitant treatment with monoamine oxidase inhibitors (MAOIs) should be avoided (see Section 4.5). At least 14 days should elapse between discontinuation of rasagiline and initiation of treatment with MAO inhibitors.
Concomitant treatment with pethidine should be avoided (see Section 4.5). At least 14 days should elapse between discontinuation of rasagiline and initiation of treatment with pethidine.
Concomitant treatment with tramadol, tapentadol, methadone, dextropropoxyphene, dextromethorphan and St. John's wort should be avoided.
Concomitant administration of rasagiline with ciprofloxacin and other potent CYP1A2 inhibitors should be avoided (see Section 4.5).
Hepatic impairment (see Section 4.2; Section 5.2).

4.4 Special Warnings and Precautions for Use

Serotonin syndrome.

Severe CNS toxicity associated with hyperpyrexia has been reported with the combined treatment of an antidepressant e.g. selective serotonin reuptake inhibitors (SSRIs), serotonin noradrenaline reuptake inhibitors (SNRIs), tricyclic antidepressants, tetracyclic antidepressants, and a non-selective MAOI (e.g. phenelzine, tranylcypromine) or selective MAO-B inhibitors, such as selegiline and rasagiline (Azilect). These adverse reactions are often described as 'serotonin syndrome' which can result in death. In the postmarketing period, non-fatal cases of serotonin syndrome have been reported in patients treated with antidepressants concomitantly with Azilect.
The symptoms of serotonin syndrome have included behavioural 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, diarrhoea), and somatic effects (e.g. muscular rigidity, myoclonus, muscle twitching, hyper-reflexia manifested by clonus and tremor).

Risk for hypertensive crisis and nonselective monoamine oxidase inhibition above the recommended dose.

Azilect is a selective inhibitor of monoamine oxidase (MAO)-B at the recommended doses of 1 mg daily. Azilect should not be used at daily doses exceeding 1 mg/day 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. However, certain foods (e.g. aged cheeses) may contain very high amounts of tyramine and could potentially cause a hypertensive "cheese" reaction in patients taking Azilect 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 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. In addition, the results of five tyramine challenge studies in volunteers and PD patients exposed to high to very high doses of dietary tyramine, indicate that rasagiline can ordinarily be used safely without dietary tyramine restrictions.
Very 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.

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

Rasagiline may cause daytime drowsiness, somnolence, and occasionally (especially if used with other dopaminergic medications), falling asleep during activities of daily living. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with rasagiline. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines (see Section 4.7).

Dyskinesia due to levodopa treatment.

When used as an adjunct to levodopa, Azilect may potentiate dopaminergic side effects and may therefore exacerbate pre-existing dyskinesia (dyskinesia occurred in 10.3% of 380 patients treated with 1 mg Azilect and 6.4% of 388 patients treated with placebo). Decreasing the dose of levodopa may ameliorate this side effect.

Postural hypotension.

Dopaminergic therapy in Parkinson's disease patients has been associated with postural hypotension. When used as monotherapy, postural hypotension was reported as an adverse event in 2.7% of 149 patients treated with 1 mg Azilect and 4.6% of 151 patients treated with placebo. In the monotherapy trial, postural hypotension did not lead to drug discontinuation and premature withdrawal from clinical trials in the Azilect treated patients or the placebo treated patients. When used as an adjunct to levodopa, postural hypotension was reported as an adverse event in 4.7% of 380 patients treated with 1 mg Azilect and 1.3% of 388 patients treated with placebo. Postural hypotension led to drug discontinuation and premature withdrawal from clinical trials in 2 (0.5%) of the Azilect treated patients, and none of the placebo treated patients.
When used as an adjunct therapy to dopamine agonists, orthostatic hypotension was reported in 3.1% of patients treated with 1 mg rasagiline and in 0.6% of patients treated with placebo.
Clinical trial data suggest that postural hypotension occurs most frequently in the first two months of Azilect treatment and tends to decrease over time.
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 effects of hypotension due to existing gait issues.

Hallucinations.

Dopaminergic therapy in Parkinson's disease patients has been associated with hallucinations. When used as monotherapy, hallucinations were reported as an adverse event in 1.3% of 149 patients treated with 1 mg Azilect and in 0.7% of 151 patients treated with placebo. In the monotherapy trial, hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 2 (1.3%) of the 1 mg Azilect treated patients and in none of the placebo treated patients. When used as an adjunct to levodopa, hallucinations were reported as an adverse event in 2.9% of 380 patients treated 1 mg/day Azilect and 2.1% of 388 patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from clinical trials in 2 (0.5%) patients treated with Azilect 1 mg/day and in 1 (0.3%) of the placebo treated patients.
When used as an adjunct to dopamine agonists, hallucinations were reported as an adverse reaction in 1.2% of patients treated with 1 mg/day Azilect and 1.8% of patients treated with placebo. Hallucinations led to drug discontinuation and premature withdrawal from the clinical trial in 0.6% of patients treated with 1 mg/day Azilect and in none of the placebo-treated patients.

Impulse control disorders.

Impulse control disorders (ICDs) can occur in patients treated with dopamine agonists and/or dopaminergic treatments. Similar reports of ICDs have also been received post-marketing with rasagiline. Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware of the behavioural symptoms of impulse control disorders that were observed in patients treated with rasagiline, including cases of compulsions, obsessive thoughts, pathological gambling, increased libido, hypersexuality, impulsive behaviour and compulsive spending or buying.

Melanoma.

During the entire development program, the rate of melanoma in Azilect treated patients was 7.2 cases/1000 person years (17 melanomas in 2363 person years). After the sixth case of melanoma was detected in the Azilect development program, subjects in ongoing studies were screened for melanoma through a skin examination every three months, which is likely to have increased the number of melanomas detected. During the placebo controlled trial portion of the Azilect development program, melanomas occurred in rasagiline treated subjects at a rate of 11.6 cases/1000 person years (4 melanomas in 344 person years) and in placebo treated subjects at a rate of 4.8 cases/1000 person years (1 melanoma in 210 person years).
For the subjects treated with Azilect rasagiline, median duration of treatment until melanoma diagnosis was 15.6 months (mean 22.9 months), with a range of 2 to 54 months. Five of the melanomas were in patients who received rasagiline only and 12 were in patients who received rasagiline and levodopa (in most cases also additional dopaminergic therapy). There was no increased incidence of melanomas observed in rasagiline clinical trial with increased extent of exposure over time.
Epidemiologic studies of Parkinson disease patients demonstrate higher rates of melanoma in such patients than in the general population (perhaps 2 to 4-fold higher). In addition, two epidemiological cohort studies that assessed the prevalence of melanoma in PD patients (studies conducted in: North American n = 2106, in which a total of 24 melanomas were detected, prevalence 1.1%, and Israel: n = 1395, in which 10 melanomas were detected, prevalence 0.7%) have shown that the prevalence of melanoma in PD patients is substantially higher (as compared to other data sources of the general population).
During the clinical development program, 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.
The relationships between Parkinson's disease, its treatments, and melanoma are not completely understood. Until the melanoma risk associated with Parkinson's disease and/or dopaminergic therapy (including Azilect) is better understood, it is recommended that Parkinson's disease patients, including those being treated with Azilect, should undergo periodic examination of the skin.
Patients are advised to seek immediate medical review if a new or changing skin lesion is identified between periodic skin examinations.

Tyramine/ rasagiline interaction.

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 noradrenaline 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) may contain very high amounts of tyramine and could potentially cause a hypertensive cheese reaction in patients taking Azilect 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 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, there have been postmarketing reports of patients who experienced significantly elevated blood pressure (including very rare cases of hypertensive crisis) after ingestion of unknown amounts of tyramine rich foods while taking recommended doses of Azilect.

Concomitant illnesses.

During the Azilect development program patients with concomitant illnesses (such as cardiovascular, gastrointestinal) and with new or deteriorating concomitant illnesses were allowed to participate or continue the study.

Use in hepatic impairment.

Rasagiline plasma concentration may increase (up to 2 and 7-fold) in patients with mild (Child-Pugh score 5-6) and moderate (Child-Pugh score 7-9) insufficiency respectively. Therefore, rasagiline should not be used in patients with any degree of hepatic insufficiency (see Section 4.3).

Use in renal impairment.

No data available. See Section 5.2.

Use in the elderly.

No data available. See Section 5.2.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

MAO inhibitors.

Rasagiline should not be administered concomitantly with other MAO inhibitors whether used as antidepressants, for the treatment of Parkinson's disease, or for any other indication as there may be a risk of non-selective MAO inhibition that may lead to hypertensive crisis (see Section 4.3). At least 14 days should elapse between discontinuation of rasagiline and initiation of treatment with MAO inhibitors.

Medicinal and natural products without prescription which have MAOI activity.

Rasagiline should not be administered concomitantly with non-prescription medicines which have MAOI activity (e.g. St. John's wort) (see Section 4.3).

Pethidine.

The concomitant administration of rasagiline and pethidine is contraindicated (see Section 4.3). Serious adverse events have been reported with the concomitant use of pethidine and MAO inhibitors including selective MAO-B inhibitors. At least 14 days should elapse between discontinuation of rasagiline and initiation of treatment with pethidine.

Fluoxetine and fluvoxamine.

The concomitant use of the SSRIs fluoxetine and fluvoxamine should be avoided. The concomitant use of rasagiline and fluoxetine should be avoided due to the long pharmacodynamic half-life of rasagiline and the long pharmacokinetic half-lives of fluoxetine and its active metabolite. The concomitant use of rasagiline and fluvoxamine should be avoided as it is also metabolized by CYP1A2. At least five weeks (approximately 5 half-lives) 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.

Serotonergic drugs.

During the Azilect development program there were no cases of the serotonin syndrome. Treatment with serotonergic drugs in patients primarily with psychiatric illness, taken alone or in combination with other drugs such as MAOIs, has been uncommonly associated with symptoms of myoclonus, tremor, confusion, restlessness, ataxia and hyper-reflexia. While usually short lived, this syndrome can lead to intensive care admissions and is potentially fatal. The occurrence of serotonin syndrome may occur after the use of SSRIs, SNRIs, tricyclic, tetracylic antidepressants, 3-4-methylenedioxy-metamphetamine (MDMA or ecstasy), other 5-HT potentiating agents and the antipsychotic agent clozapine. The treatment of choice is the cessation of the drugs responsible.

Selective serotonin reuptake inhibitors (SSRIs), SNRIs, tricyclic/ tetracyclic antidepressants and MAO inhibitors.

No formal clinical pharmacology studies were conducted with the combination of rasagiline with antidepressants. The use of selected antidepressants was allowed in the Phase III clinical trials and a number of patients treated with rasagiline were concomitantly treated with antidepressants without any reports of CNS toxicity (serotonin syndrome). 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. The total exposure for concomitant antidepressant use was: tricyclics n = 115, maximum exposure of 6.2 years; SSRIs/ SNRIs n = 141, maximum exposure of 5.2 years and trazodone n = 45, maximum exposure of 5.8 years. 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. Therefore, in view of the MAO inhibitory activity of rasagiline, antidepressants should be administered with caution.
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/ SSRIs/ SNRIs concomitantly with rasagiline.

Dextromethorphan or sympathomimetics medications.

The concomitant use of rasagiline and dextromethorphan or sympathomimetics including nasal and oral decongestants and cold remedies is not recommended.

Levodopa.

Data from population pharmacokinetics in early PD patients (n = 31/352) requiring concomitant levodopa therapy showed there was a small decrease in rasagiline clearance (31%). Data from the population pharmacokinetics study in patients receiving chronic levodopa treatment as adjunct therapy to rasagiline (n = 276) showed there was no effect of levodopa treatment on rasagiline clearance. In view of the results of these two studies, the true effect of levodopa on rasagiline clearance is not yet known.

Effects of other drugs on the metabolism of rasagiline.

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 the concomitant use with rasagiline 1 mg/day is contraindicated (see Section 4.3).
Concomitant administration of rasagiline and entacapone increased rasagiline oral clearance by 28%.

Effect of rasagiline on other drugs.

In vitro studies have shown that rasagiline therapeutic concentrations are not expected to cause any clinically significant interference with substrates of cytochrome P450 isoenzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP4A).

Effects of alcohol.

No studies on the combined effects of rasagiline and alcohol have been performed. However, because of dopaminergic side effects of rasagiline such as postural hypotension, caution should be urged if patients taking rasagiline do intend to drink alcohol (postural hypotension was reported as an adverse event in rasagiline patients treated with 1 mg vs. patients treated with placebo in monotherapy in: 2.7% vs. 4.6% and in adjunct therapy in: 4.7% vs. 1.3%).

Effect of smoking.

Population pharmacokinetics analysis in early PD patients indicated an increase (30-40%) in rasagiline clearance in smokers (% of smokers in the study: 4.8%). Data from the population pharmacokinetics in patients treated with rasagiline as adjunct therapy to levodopa (% of smokers in the study: 5%) showed no effect of smoking on rasagiline clearance. In view of the results of these two studies, the true effect of smoking on rasagiline clearance is not yet known. There is a possibility that rasagiline plasma levels in smoking patients could be decreased, due to induction of the metabolising enzyme CYP1A2.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No impairment of mating or fertility was seen in male rats treated prior to and throughout the mating period or in female rats treated from prior to mating through late gestation at oral doses up to 3 mg/kg/day (more than 30 times human exposure (AUC) at the maximum recommended dose of 1 mg/day). The effect of rasagiline administered in combination with levodopa/ carbidopa on mating and fertility has not been examined.
(Category B3)
No effect on embryofetal development was observed in a combined mating/ fertility/ embryofetal development study in female rats at oral doses up to 3 mg/kg/day (at least 30-fold anticipated clinical exposure (plasma AUC) at the maximum recommended dose, 1 mg/day).
In a study in which pregnant rats were dosed with rasagiline (0.1, 0.3, 1 mg/kg/day) orally from the beginning of organogenesis to weaning, both offspring survival and body weights were reduced at 0.3 and 1 mg/kg/day (at least 10 times anticipated human exposure based on AUC, at 1 mg/day); the no effect dose was 0.1 mg/kg/day (no exposure data). In rabbits administered rasagiline orally during the period of organogenesis, an increased incidence of post-implantation loss (resorption or abortion) and lower fetal body weight were noted at high exposures (about 1000-fold or greater the anticipated human exposure based on AUC at 1 mg/day), along with maternotoxicity. The no adverse effect exposure (AUC) was greater than 60-fold the anticipated human exposure. No increase in fetal malformations was seen in any of the animal reproductive toxicity studies with rasagiline.
Rasagiline may be given as an adjunct therapy to levodopa/ carbidopa treatment. In a study in which pregnant rats were dosed orally with rasagiline (0.1, 0.3, 1 mg/kg/day) and levodopa/ carbidopa (80/20 mg/kg/day), alone and in combination throughout the organogenesis period, there was an increased incidence of wavy ribs in fetuses from rats treated with 1/80/20 mg/kg/day (approximately 8 times the human exposure to rasagiline at 1 mg/day on an AUC basis). The clinical significance of the wavy ribs in rodent fetuses is likely to be low. In a study in which pregnant rabbits were dosed orally during the organogenesis period with rasagiline alone (3 mg/kg/day) or at doses of 0.1, 0.6 and 1.2 mg/kg/day in combination with levodopa/ carbidopa 80/20 mg/kg/day, an increase in embryofetal death was noted at rasagiline doses of 0.6 and 1.2 mg/kg/day (7 and 13 times anticipated human systemic exposure (AUC) at 1 mg/day, respectively). There was an increase in cardiovascular abnormalities with levodopa/ carbidopa alone and to a greater extent when rasagiline (at all doses; 1-13 times the plasma rasagiline AUC at the MRHD) was administered in combination with levodopa/ carbidopa. This increase is most likely mediated by elevated levodopa levels.
There are no adequate and well controlled studies of rasagiline in pregnant women. Because animal reproduction studies are not always predictive of human response, Azilect should be used during pregnancy only if clearly needed.
Experimental data indicated that rasagiline inhibits prolactin secretion and, thus, may inhibit lactation. It is not known whether rasagiline is excreted in human milk, therefore caution should be exercised when rasagiline is administered to a nursing mother.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

Monotherapy.

Table 2 lists treatment emergent adverse events that occurred in ≥ 1% of patients receiving 1 mg/day rasagiline as monotherapy participating in the double blind, placebo controlled trial and were with a higher incidence in the rasagiline treated patients (rasagiline group n = 149, placebo group n = 151).
Other events that occurred at an incidence of < 1% of patients receiving rasagiline as monotherapy, and were more frequent than in placebo are listed below within body system categories.

Body as a whole.

Abscess, cellulitis, chills, gangrene, infection fungal.

Cardiovascular system.

Cerebrovascular accident, heart arrest, myocardial infarct, pallor, thrombosis, vascular disorder.

Digestive system.

Colitis, eructation, gastritis, gastrointestinal disorder, nausea and vomiting, periodontitis.

Haematological and lymphatic systems.

Anaemia, eosinophilia, leucocytosis.

Metabolic and nutritional disorders.

Hyperlipaemia.

Musculoskeletal system.

Tendinous contracture.

Nervous system.

Abnormal dreams, dystonia, myoclonus, paranoid reaction.

Skin and appendages.

Dry skin, urticaria.

Special senses.

Eye haemorrhage, glaucoma.

Urogenital system.

Breast neoplasm, breast pain, dysmenorrhoea, prostatic specific antigen increase.

Adjunct therapy.

Patients receiving Azilect as adjunct to dopamine agonist therapy.

Adverse reactions leading to discontinuation in controlled clinical trials.

In a double-blind, randomized, placebo-controlled trial conducted in patients receiving Azilect 1 mg as adjunct therapy to dopamine agonists, approximately 8% of the 162 patients treated with rasagiline discontinued rasagiline treatment due to adverse reactions compared to 4% of the 164 patients who received placebo. The only adverse reactions that led to the discontinuation of more than one patient were nausea and dizziness.

Adverse reaction incidence in controlled clinical trials.

The most commonly observed adverse reactions (incidence in Azilect-treated patients ≥ 3% greater than the incidence in placebo-treated patients) included peripheral oedema, fall, arthralgia, cough, and insomnia. Table 3 lists treatment-emergent adverse reactions that occurred in ≥ 2% of patients receiving Azilect as adjunct therapy to dopamine agonists participating in the trial and numerically more frequent than in the placebo group.
Other events of potential clinical importance reported by 1% or more of patients receiving Azilect as adjunct therapy to dopamine agonists, and at least as frequent as in the placebo group, have been listed below.

Body as a whole.

Pain.

Cardiovascular system.

Hypotension, presyncope, chest pain.

Gastrointestinal system.

Gastroesophageal reflux disease, flatulence, oropharyngeal pain, viral gastroenteritis.

Nervous system.

Somnolence, nervousness, cognitive disorder, dyskinesia, abnormal rapid eye movement sleep.

Respiratory system.

Bronchitis, sinusitis, rhinnorrhea, streptococcal pharyngitis.

Skin and appendages.

Rash, skin papilloma.

Special senses.

Blurred vision.
There were no significant differences in the safety profile based on age or gender.

Patients receiving Azilect as adjunct to levodopa therapy.

Table 4 lists treatment emergent adverse events that occurred in ≥ 1 % of patients treated with rasagiline 1 mg/day as adjunct to levodopa therapy participating in the double-blind, placebo-controlled trials and were with a higher incidence in the rasagiline treated patients. (rasagiline group n=380, placebo group n=388).
Other events that occurred at an incidence of < 1% of patients receiving rasagiline as adjunct to levodopa therapy, and were more frequent than in placebo are listed below within body system categories.

Body as a whole.

Cyst, halitosis, Kaposi's sarcoma, sepsis.

Cardiovascular system.

Bradycardia, vasodilatation, angina pectoris, arrhythmia, bundle branch block, cerebrovascular accident, pulmonary embolus, AV block complete, AV block second degree, blood pressure fluctuations, cardiovascular disorder, myocardial infarct, palpitation, thrombosis, ventricular arrhythmia, ventricular extrasystoles.

Digestive system.

Gastroenteritis, gingivitis, dysphagia, oesophagitis, flatulence, gastritis, intestinal obstruction, faecal impaction, gastrointestinal haemorrhage, liver function tests abnormal, megacolon, mouth ulceration.

Endocrine system.

Goiter.

Haematological and lymphatic system.

Leucopenia, megaloblastic anaemia, thrombocytopenia.

Metabolic and nutritional disorders.

Weight gain, gout, blood urea nitrogen increased, hyperlipaemia, hyperphosphatemia, hypokalaemia, lactic dehydrogenase increased.

Musculoskeletal system.

Leg cramps, bursitis, myositis.

Nervous system.

Amnesia, hyperkinesias, speech disorder, spinal stenosis, dysautonomia, libido decreased, meningitis, nystagmus, paranoid reaction, personality disorder.

Respiratory system.

Asthma, epistaxis, pneumothorax, rhinitis allergic.

Skin and appendages.

Pruritus, herpes simplex, skin melanoma, skin ulcer, alopecia, nail disorder, psoriasis.

Special senses.

Eye disorder, blindness, diplopia, vitreous disorder.

Urogenital system.

Dysuria, albuminuria, urinary urgency, anuria, bladder carcinoma, dysmenorrhoea, kidney pain, nocturia, testis disorder, urogenital anomaly, vaginal haemorrhage.
Other important adverse events that were reported in clinical studies with rasagiline (of different rasagiline doses or without placebo control) and occurred in very few patients each were: rhabdomyolysis following fall and prolonged immobilization and inappropriate antidiuretic hormone (ADH) secretion. The complicated nature of these cases makes it impossible to determine what role, if any, rasagiline played in the pathogenesis of these conditions.

Post-marketing data.

In the post-marketing period, cases of elevated blood pressure, including very 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.

Impulse control disorders.

Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists and/or other dopaminergic treatments. A similar pattern of impulse control disorders has been reported post-marketing with rasagiline, which also included compulsions, obsessive thoughts and impulsive behaviour (see Section 4.4).

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

Excessive daily sleepiness (hypersomnia, lethargy, sedation, sleep attacks, somnolence, and sudden onset of sleep) can occur in patients treated with dopamine agonists and/or other dopaminergic treatments. A similar pattern of excessive daily sleepiness has been reported post-marketing with rasagiline.
Cases of patients, treated with rasagiline and other dopaminergic medications, falling asleep while engaged in activities of daily living have been reported. Although many of these patients reported somnolence while on rasagiline with other dopaminergic medications, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events have been reported several months after initiation of treatment.

4.2 Dose and Method of Administration

Rasagiline should be administered orally, at a dose of 1 mg once daily in both monotherapy and adjunct therapy. It may be taken with or without food. Clinical trials have demonstrated no efficacy advantage for higher doses of rasagiline.
Change of levodopa dose in adjunct therapy: When rasagiline is used in combination with levodopa, a reduction of the levodopa dosage may be considered based upon individual response.

Elderly patients (> 65 years).

No change in dosage is required for elderly patients.
Rasagiline was shown to be well-tolerated in elderly PD patients in both monotherapy and adjunct therapy.

Children and adolescents (< 18 years).

Not recommended as the safety and efficacy have not been established in this population.

Patients with hepatic impairment.

Rasagiline should not be used in patients with hepatic insufficiency (see Section 4.3).

Patients with renal impairment.

No change in dosage is required for moderate renal impairment.

4.7 Effects on Ability to Drive and Use Machines

Rasagiline may affect the ability to drive and use machines. Patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that rasagiline does not affect them adversely.
Patients being treated with rasagiline and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until they have gained sufficient experience with rasagiline and other dopaminergic medications to gauge whether or not it affects 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 patients should not drive or participate in potentially dangerous activities.
Patients should not drive, operate machinery, or work at heights during treatment if they have previously experienced somnolence and/or have fallen asleep without warning prior to use of rasagiline.
Patients should be cautioned about possible additive effects of sedating medications, alcohol, or other central nervous system depressants (e.g. benzodiazepines, antipsychotics, antidepressants) in combination with rasagiline, or when taking concomitant medications that increase plasma levels of rasagiline (e.g. ciprofloxacin).

4.9 Overdose

Symptoms reported following overdose of 3-100 mg rasagiline included dysphoria, hypomania, hypertensive crisis and serotonin syndrome. 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 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 side effects (including hypertension and postural hypotension), which resolved following treatment discontinuation. Theoretically, overdose can cause significant inhibition of both MAO-A and MAO-B. 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.
There is no specific antidote. In case of overdose, patients should be monitored and the appropriate symptomatic and supportive therapy instituted.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Mannitol, silica-colloidal anhydrous, starch maize, starch-pregelatinised maize, stearic acid and talc-purified.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

3 years.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Blisters: 10, 30 tablets.
Bottle*: 30 tablets.
*Registered in Australia but not marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes