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Azilect

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Summary for the public


What is Azilect?

Azilect is a medicine that contains the active substance rasagiline. It is available as white, round tablets (1 mg).


What is Azilect used for?

Azilect is used to treat of Parkinson’s disease. Parkinson’s disease is a progressive brain disorder that causes shaking, slow movement and muscle stiffness. Azilect can be used either alone, or as an add-on to levodopa (another medicine used in Parkinson’s disease) in patients who are having ‘fluctuations’ towards the end of the period between levodopa doses. Fluctuations are linked with a reduction in the effects of levodopa, when the patient experiences sudden switches between being ‘on’ and able to move, and being ‘off’ and immobile.

Azilect can only be obtained with a prescription.


How is Azilect used?

The standard dose of Azilect is one tablet once a day, taken with or without food.


How does Azilect work?

The active substance in Azilect, rasagiline, is a ‘monoamine oxidase-B inhibitor’. It blocks the enzyme monoamine oxidase type B, which breaks down the neurotransmitter dopamine in the brain. Neurotransmitters are chemicals that allow nerve cells to communicate with one another. In patients with Parkinson’s disease, the cells that produce dopamine begin to die and the amount of dopamine in the brain decreases. The patients then lose their ability to control their movements reliably. By increasing levels of dopamine in the parts of the brain that control movement and co-ordination, Azilect improves the signs and symptoms of Parkinson’s disease, such as stiffness and slowness of movement.


How has Azilect been studied?

Azilect has been studied in three main studies involving a total of 1,563 patients with Parkinson’s disease. In the first study, two different doses of Azilect taken alone were compared with placebo (a dummy treatment) in 404 patients with early-stage disease. The main measure of effectiveness was the change in symptoms over 26 weeks, as assessed on a standard scale (Unified Parkinson’s Disease Rating Scale, UPDRS). The other two studies involved a total of 1,159 patients with later stage disease, where Azilect was added to the patients’ existing treatment including levodopa. It was compared with placebo or entacapone (another medicine for Parkinson’s disease). The studies lasted 26 and 18 weeks, respectively. The main measure of effectiveness was the time spent in the ‘off’ state during the day, as recorded in patient diaries.


What benefit has Azilect shown during the studies?

Azilect was more effective than placebo in all of the studies. In the study where Azilect was used alone, patients taking 1 mg of the medicine once a day had an average fall in UPDRS score of 0.13 points over the 26-week study from a starting value of 24.69. This was compared with a rise of 4.07 points in the patients taking placebo from a starting value of 24.54. A fall in the UPDRS score indicates an improvement in symptoms, while a rise indicates a worsening of symptoms.

When used as an add-on to levodopa, 1 mg Azilect reduced the time in the ‘off’ state more than placebo did. In both studies, patients adding Azilect spent an average of around one hour less in the ‘off’ state than those adding placebo. A similar decrease in time spent in the ‘off’ state was seen in patients taking entacapone.


What is the risk associated with Azilect?

The most common side effect with Azilect (seen in more than 1 patient in 10) is headache. For the full list of all side effects reported with Azilect, see the Package Leaflet.

Azilect should not be used in people who may be hypersensitive (allergic) to rasagiline or any of the other ingredients. Azilect must not be used with other monoamine oxidase inhibitors including medicines and herbal preparations without prescription such as St John’s wort. It must also not be used with pethidine (a painkiller). There should be at least 14 days between stopping treatment with Azilect and starting treatment with another monoamine oxidase inhibitor or with pethidine. Azilect must not be used in patients who have severe problems with their liver. It is not recommended for patients with moderate liver problems. Patients with mild liver problems should use Azilect with caution and should stop treatment if their liver problems get worse.


Why has Azilect been approved?

The Committee for Medicinal Products for Human Use (CHMP) decided that Azilect’s benefits are greater than its risks 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 Committee recommended that Azilect be given marketing authorisation.


Other information about Azilect

The European Commission granted a marketing authorisation valid throughout the European Union for Azilect to Teva Pharma GmbH on 21 February 2005. The marketing authorisation was renewed on 21 February 2010.

Authorisation details
Name: Azilect
EMEA Product number: EMEA/H/C/000574
Active substance: rasagiline
INN or common name: rasagiline
Therapeutic area: Parkinson Disease
ATC Code: N04BD02
Marketing Authorisation Holder: Teva Pharma GmbH
Revision: 9
Date of issue of Market Authorisation valid throughout the European Union: 21/02/2005
Contact address:
Teva Pharma GmbH
Kandelstr 10
D-79199 Kirchzarten
Germany



Product Characteristics

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS


1. NAME OF THE MEDICINAL PRODUCT
AZILECT 1 mg tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 1 mg rasagiline (as mesilate).
For a full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet
White to off-white, round, flat, bevelled tablets, debossed with “GIL” and “1” underneath on one side and
plain on the other side.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
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.
4.2 Posology and method of administration
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.
: AZILECT is not recommended for use in children and adolescents due to lack of
data on safety and efficacy.
: Rasagiline use in patients with severe hepatic impairment is
contraindicated (see section ) . 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. In case patients progress from mild to moderate hepatic impairment rasagiline should be
stopped (see section 4.4) .
Patients with renal impairment
: No change in dose is required for renal impairment.
4.3 Contraindications
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.
2
Paediatric population
Patients with hepatic impairment
4.3
 
4.4 Special warnings and precautions for use
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 product containing ephedrine or pseudoephedrine is not
recommended (see section 4.5) .
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.
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. In case
patients progress from mild to moderate hepatic impairment, rasagiline should be stopped (see section
5.2) .
4.5 Interaction with other medicinal products and other forms of interaction
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-
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 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.
3
 
 
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 1 µg/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.
4.6 Fertility, pregnancy and lactation
For rasagiline no clinical data on exposed pregnancies is available. Animals 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.
4.7 Effects on ability to drive and use machines
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 that AZILECT does not affect them adversely.
4.8 Undesirable effects
In the rasagiline clinical program overall, 1,361 patients were treated with rasagiline for 3,076.4 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.
4
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).
Common: influenza (4.7% vs. 0.7%)
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Common: skin carcinoma (1.3% vs. 0.7%)
Blood and lymphatic system disorders
Common: leucopenia (1.3% vs. 0%)
Immune system disorders
Common: allergy (1.3% vs. 0.7%)
Metabolism and nutrition disorders
Uncommon: decreased appetite (0.7% vs. 0%)
Psychiatric disorders
Common: depression (5.4% vs. 2%) , hallucinations (1.3% vs. 0.7%)
Nervous system disorders
Uncommon: cerebrovascular accident (0.7% vs. 0%)
Common: conjunctivitis (2.7% vs . 0.7%)
Ear and labyrinth disorders
Common: vertigo (2.7% vs. 1.3%)
Cardiac disorders
Common: angina pectoris (1.3% vs. 0%);
Uncommon: myocardial infarction (0.7% vs. 0%)
Respiratory, thoracic and mediastinal disorders
Gastrointestinal disorders
Common : flatulence (1.3% vs.0%)
Skin and subcutaneous tissue disorders
Common: dermatitis ( 2.0% vs. 0% )
Uncommon: vesiculobullous rash (0.7% vs. 0%)
Common: musculoskeletal pain (6.7% vs. 2.6%), neck pain (2.7% vs. 0%) , arthritis (1.3% vs.
0.7%)
Renal and urinary disorders
Common: urinary urgency (1.3% vs. 0.7%).
General disorders and administration site conditions
Common: fever (2.7% vs. 1.3%), malaise (2% vs. 0%)
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Infections and infestations
Very common : headache (14.1% vs. 11.9%)
Eye disorders
Common: rhinitis ( 3.4% vs. 0.7 %)
Musculoskeletal and connective tissue disorders
 
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, <1/10), uncommon ( 1/1000, <1/100), rare ( 1/10000, <1/1000), very rare
(<1/10000).
Neoplasms benign, malignant and unspecified
Metabolism and nutrition disorders
Common: decreased appetite (2.4% vs. 0.8%)
Psychiatric disorders
Common: hallucinations (2.9% vs. 2.1%), abnormal dreams (2.1% vs. 0.8%)
Uncommon: confusion (0.8% vs. 0.5%)
Very common : dyskinesia (10.5% vs. 6.2%)
Common: dystonia (2.4% vs. 0.8%), carpal tunnel syndrome (1.3% vs. 0%), balance disorder
(1.6% vs. 0.3%)
Uncommon: cerebrovascular accident (0.5% vs. 0.3%)
Cardiac disorders
Uncommon: angina pectoris (0.5% vs. 0%)
Vascular disorders
Common: orthostatic hypotension (3.9% vs. 0.8%)
Gastrointestinal disorders
Common: abdominal pain ( 4.2% vs. 1.3% ), constipation (4.2% vs. 2.1%) , nausea and vomiting
(8.4% vs. 6.2%) , dry mouth (3.4% vs. 1.8%)
Skin and subcutaneous tissue disorders
Common: rash (1.1% vs. 0.3%)
Musculoskeletal and connective tissue disorders
Common: arthralgia (2.4% vs. 2.1%), neck pain (1.3% vs. 0.5%)
Common: decreased weight (4.5% vs. 1.5%)
Injury, poisoning and procedural complications
Common: fall (4.7% vs. 3.4%)
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 the 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 program in which 115
patients were exposed concomitantly to rasagiline and tricyclics and 141 patients were exposed to
rasagiline and SSRIs/ SNRIs.
6
Uncommon: skin melanoma (0.5% vs. 0.3%)
Nervous system disorders
Investigations
 
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.
4.9 Overdose
Overdosage: Symptoms reported following overdose of Azilect in doses ranging from 3 mg to 100 mg
included dysphoria, 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.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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,
7
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.
5.2 Pharmacokinetic properties
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 14 C-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 14 C-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) .
8
 
Patients with renal impairment : 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.
5.3 Preclinical safety data
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.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Mannitol
Maize starch
Pregelatinised maize starch
Colloidal anhydrous silica
Stearic acid
Talc
6.2 Incompatibilities
Not applicable
6.3 Shelf life
Blisters: 3 years
Bottles: 3 years
6.4 Special precautions for storage
Do not store above 25ºC.
6.5 Nature and contents of container
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.
6.6 Special precautions for disposal
No special requirements.
9
 
 
7. MARKETING AUTHORISATION HOLDER
Teva Pharma GmbH
Kandelstr 10
D-79199 Kirchzarten
Germany
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/04/304/001-007
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation:
21 February 2005
Date of latest renewal:
21 September 2009
10. DATE OF REVISION OF THE TEXT
Detailed information on this product is available on the website of the European Medicines Agency
10
ANNEX II
A. MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
11
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer responsible for batch release
Teva Pharmaceuticals Europe B.V.
Computerweg 10
3542 DR Utrecht
The Netherlands
B. CONDITIONS OF THE MARKETING AUTHORISATION
CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE IMPOSED ON
THE MARKETING AUTHORISATION HOLDER
Medicinal product subject to medical prescription.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
PSURs
The next PSUR will be submitted with a 3-year frequency (covering period 3 January 2010 to 2 January
2013).
12
ANNEX III
LABELLING AND PACKAGE LEAFLET
13
A. LABELLING
14
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
(CARTON FOR BLISTER PACK)
1.
NAME OF THE MEDICINAL PRODUCT
AZILECT 1 mg tablets
rasagiline
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 1 mg of rasagiline (as mesilate).
3.
LIST OF EXCIPIENTS
4.
PHARMACEUTICAL FORM AND CONTENTS
7 tablets
10 tablets
28 tablets
30 tablets
100 tablets
112 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY}
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
15
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Teva Pharma GmbH
D-79199 Kirchzarten, Germany
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/04/304/001
EU/1/04/304/002
EU/1/04/304/003
EU/1/04/304/004
EU/1/04/304/005
EU/1/04/304/006
13. BATCH NUMBER
Lot {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
AZILECT
16
 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS
1.
NAME OF THE MEDICINAL PRODUCT
AZILECT 1 mg tablets
rasagiline
2.
NAME OF THE MARKETING AUTHORISATION HOLDER
Teva Pharma GmbH
3.
EXPIRY DATE
EXP {MM/YYYY}
4.
BATCH NUMBER
Lot {number}
5.
OTHER
17
 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
(CARTON FOR BOTTLE AND BOTTLE LABEL)
1.
NAME OF THE MEDICINAL PRODUCT
AZILECT 1 mg tablets
rasagiline
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 1 mg of rasagiline (as mesilate).
3.
LIST OF EXCIPIENTS
4.
PHARMACEUTICAL FORM AND CONTENTS
30 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP {MM/YYYY }
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25°C.
18
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER
Teva Pharma GmbH
D-79199 Kirchzarten, Germany
12. MARKETING AUTHORISATION NUMBER(S)
EU/1/04/304/007
13. BATCH NUMBER
Lot {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
AZILECT
19
 
B. PACKAGE LEAFLET
20
PACKAGE LEAFLET: INFORMATION FOR THE USER
AZILECT 1 mg tablets
Rasagiline
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if
their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
1. What AZILECT is and what it is used for
:
2. Before you take AZILECT
3. How to take AZILECT
4. Possible side effects
5. How to store AZILECT
6. Further information
1. WHAT AZILECT IS AND WHAT IT IS USED FOR
AZILECT is used for the treatment of Parkinson’s disease. It can be used together with or without
Levodopa (another medicine that is used to treat Parkinson’s disease).
With Parkinson’s disease, there is a loss of cells that produce dopamine in the brain. Dopamine is a
chemical in the brain involved in movement control. AZILECT helps to increase and sustain levels of
dopamine in the brain.
2.
BEFORE YOU TAKE AZILECT
Do not
-
take AZILECT
-
if you are allergic (hypersensitive) to rasagiline or any of the other ingredients of AZILECT.
Do not
-
monoamine oxidase (MAO) inhibitors (e.g. for treatment of depression or Parkinson’s disease, or
used for any other indication), including medicinal and natural products without prescription e.g.
St. John's Wort.
take the following medicines while taking AZILECT:
- pethidine (a strong pain killer).
You must wait at least 14 days after stopping AZILECT treatment and starting treatment with MAO
inhibitors or pethidine.
Take special care with AZILECT
-
if you have mild to moderate liver problems
-
You should speak with your doctor about any suspicious skin changes.
Children
AZILECT is not recommended for use under the age of 18.
21
-
If you have any further questions, ask your doctor or pharmacist.
if you have severe liver problems.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without prescription or if you are smoking or intend to stop smoking.
Ask your doctor
- Certain antidepressants (selective serotonin reuptake inhibitors, selective serotonin-norepinephrine
reuptake inhibitors, tricyclic or tetracyclic antidepressants)
for advice before taking any of the following medicines together with AZILECT:
- the antibiotic ciprofloxacin used against infections
- the cough suppressant dextromethorphan
- sympathomimetics such as those present in eye drops, nasal and oral decongestants and cold
medicine containing ephedrine or pseudoephedrine
The use of AZILECT together with the antidepressants containing fluoxetine or fluvoxamine should be
avoided.
If you are starting treatment with AZILECT, you should wait at least 5 weeks after stopping fluoxetine
treatment.
If you are starting treatment with fluoxetine or fluvoxamine, you should wait at least 14 days after
stopping AZILECT treatment.
Taking AZILECT with food and drink
AZILECT may be taken with or without food.
Pregnancy and breast-feeding
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
No studies on the effects on the ability to drive and use machines have been performed. Ask
your doctor for advice prior to driving or using machines.
3.
HOW TO TAKE AZILECT
Always take AZILECT exactly as your doctor has told you. You should check with your doctor or
pharmacist if you are not sure.
The usual dose of AZILECT is 1 tablet of 1 mg taken by mouth once daily. AZILECT may be taken with
or without food.
If you take more AZILECT than you should
If you think that you may have taken too many AZILECT tablets, contact your doctor or pharmacist
immediately. Take the AZILECT carton/bottle with you to show the doctor or pharmacist.
If you forget to take AZILECT
Do not take a double dose to make up for a forgotten dose. Take the next dose normally, when it is time
to take it.
If you stop taking AZILECT
Do not stop taking AZILECT without first talking to your doctor.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, AZILECT can cause side effects, although not everybody gets them.
The following side effects have been reported in placebo controlled clinical trials:
22
The frequency of possible side effects listed below is defined using the following convention:
Very common (affects more than 1 user in 10)
Common (affects 1 to 10 users in 100)
Uncommon (affects 1 to 10 users in 1,000)
Rare (affects 1 to 10 users in 10,000)
Very rare (affects less than 1 user in 10,000)
Not known (frequency cannot be estimated from the available data)
Very common
- abnormal movements (dyskinesia)
- headache
Common:
- abdominal pain
- fall
- allergy
- fever
- flu (influenza)
- general feeling of being unwell (malaise)
- neck pain
- chest pain (angina pectoris)
- low blood pressure when rising to a standing position with symptoms like dizziness/light-headedness
(orthostatic hypotension)
- Decreased appetite
- constipation
- dry mouth
- nausea and vomiting
- flatulence
- abnormal results of blood tests (leucopenia)
- joint pain (arthralgia)
- musculoskeletal pain
- joint inflammation (arthritis)
- numbness and muscle weakness of the hand (carpal tunnel syndrome )
- decreased weight
- abnormal dreams
- difficulty in muscular coordination (balance disorder)
- depression
- dizziness (vertigo)
- prolonged muscle contractions (dystonia)
- runny nose (rhinitis)
- irritation of the skin (dermatitis)
- rash
- bloodshot eyes (conjunctivitis)
- urinary urgency
Uncommon:
- stroke (cerebrovascular accident)
- heart attack (myocardial infarction)
- blistering rash (vesiculobullous rash)
In addition, skin cancer was reported in around 1% of patients in the placebo controlled clinical trials.
Nevertheless, scientific evidence suggests that Parkinson’s disease, and not any medicine in particular, is
associated with a higher risk of skin cancer (not exclusively melanoma). You should speak with your
doctor about any suspicious skin changes.
23
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 AZILECT.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
5.
HOW TO STORE AZILECT
Keep out of the reach and sight of children.
Do not use AZILECT after the expiry date which is stated on the carton, bottle or blister. The
expiry date refers to the last day of that month.
Do not store above 25 o C.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6. FURTHER INFORMATION
What AZILECT contains
-
The other ingredients are mannitol, colloidal anhydrous silica, maize starch, pregelatinised maize
starch, stearic acid, talc.
What AZILECT looks like and contents of the pack
AZILECT tablets are presented as white to off-white, round, flat, bevelled tablets, debossed with “GIL”
and “1” underneath on one side and plain on the other side.
The tablets are available in blister packs of 7, 10, 28, 30, 100 and 112 tablets or in a bottle containing 30
tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Manufacturer
Teva Pharma GmbH
Teva Pharmaceuticals Europe B.V.
D-79199 Kirchzarten
Computerweg 10
Germany
The Netherlands
24
-
The active substance is rasagiline. Each tablet contains 1 mg rasagiline (as mesilate).
Kandelstrasse 10
3542 DR Utrecht
For any information about this medicinal product, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Lundbeck S.A./N.V.
Avenue Molière 225
B-1050 Bruxelles/Brussel/Brüssel
Tél/Tel: +32 2 340 2828
Luxembourg/Luxemburg
Lundbeck S.A.
Avenue Molière 225
B-1050 Bruxelles/Brüssel
Belgique/Belgien
Tél/Tel: +32 2 340 2828
България
Лундбек Експорт
Търговско представителство
ЕКСПО 2000
Бул. “Н. Вапцаров” №55
София 1407
Тел.: +359 2 962 46 96
Magyarország
Teva Magyarország Zrt.
Rákóczi út 70-72.
H-1074 Budapest
Tel.: +36 1 288 6400
Česká republika
Lundbeck Česká republika s.r.o.
Bozděchova 7
Malta
Charles di Giorgio Ltd
Triq il-Kanonku Karmenu
MT-1114 B’Kara BKR
Tel: +356 25600500
CZ-150 00 Praha 5
Tel: +420 225 275 600
Danmark
Lundbeck Pharma A/S
Dalbergstrøget 5
DK-2630 Taastrup
Tlf: +45 4371 4270
Nederland
Teva Pharma B.V.
Swensweg 5
NL-2003 RN Haarlem
Tel: +31 23 514 7147
Deutschland
Lundbeck GmbH
Karnapp 25
D-21079 Hamburg
Tel: +49 40 23649 0
Norge
H. Lundbeck AS
Postboks 361
N-1326 Lysaker
Tlf: +47 91300800
Eesti
Lundbeck Eesti AS
Weizenbergi 29
EE-10150 Tallinn
Tel: +372 605 9350
Österreich
Lundbeck Austria GmbH
Dresdner Straße 82
A-1200 Wien
Tel: +43 1 33107 0
Ελλάδα
Lundbeck Hellas S.A.
Λεωφόρος Κηφισίας 64
GR-151 25 Μαρούσι, Αθήνα
Τηλ: +30 210 610 5036
Polska
Lundbeck Poland Sp. z o. o.
ul. Krzywickiego 34
PL-02-078 Warszawa
Tel: +48 22 626 93 00
España
Lundbeck España S.A.
Av. Diagonal, 605, 9-1a
E-08028 Barcelona
Tel: +34 93 494 9620
Portugal
Lundbeck Portugal, Lda.
Quinta da Fonte
Edifício D. João I – Piso 0 Ala A
P-2770-203 Paço d’Arcos
Tel: +351 21 00 45 900
25
France
Lundbeck SAS
37-45, quai du Président Roosevelt
F-92445 Issy-les-Moulineaux Cedex
Tél: + 33 1 79 41 29 00
România
Lundbeck Export A/S Reprezentanţa din România
Str. Ghiocei no.7A, Sector 2
Bucureşti 020571 RO
Tel: +40 21 319 88 26
Ireland
Lundbeck (Ireland) Limited
7 Riverwalk
Citywest Business Campus
IRL - Dublin 24
Tel: +353 1 4689800
Slovenija
Lundbeck Pharma d.o.o.
Titova cesta 8
SI-2000 Maribor
Tel: +386 2 229 45 00
Ísland
Lundbeck Export A/S, útibú á Íslandi
Ármúla 1
IS-108 Reykjavik
Sími: +354 414 7070
Slovenská republika
Lundbeck Slovensko s.r.o.
Zvolenská 19
SK-821 09 Bratislava 2
Tel: +421 2 5341 4218
Italia
Lundbeck Italia S.p.A.
Via G. Fara 35
I-20124 Milano
Tel: +39 02 677 4171
Suomi/Finland
Oy H. Lundbeck Ab
Itäinen Pitkäkatu 4
FIN-20520 Turku (Åbo)
Puh/Tel: +358 2 276 5000
Κύπρος
Lundbeck Hellas A .E
Θεµ. ∆έρβη – Φλωρίνης
STADYL BUILDING
CY-1066 Λευκωσία
Τηλ: +357 22490305
Sverige
H. Lundbeck AB
Rundgången 30 B
Box 23
S-250 53 Helsingborg
Tel: +46 42 254300
Latvija
SIA Lundbeck Latvia
Kleistu iela 24
LV-1067 Riga
Tel: +371 7 067 884
United Kingdom
Lundbeck Limited
Lundbeck House
Caldecotte Lake Business Park
Caldecotte
Milton Keynes MK7 8LG - UK
Tel: +44 1908 64 9966
Lietuva
UAB Lundbeck Lietuva
L. Stuokos-Gucevičiaus 9-3
LT-01122 Vilnius
Tel: +370 5 231 4188
This leaflet was last approved in .
26


Source: European Medicines Agency



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