Rasagilin Accord Healthcare 1 mg Tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

09-10-2019

Produktens egenskaper Produktens egenskaper (SPC)

09-10-2019

Aktiva substanser:
rasagilintartrat
Tillgänglig från:
Accord Healthcare B.V. ,
ATC-kod:
N04BD02
INN (International namn):
rasagilintartrat
Dos:
1 mg
Läkemedelsform:
Tablett
Sammansättning:
rasagilintartrat 1,44 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Blister, 10 tabletter; Blister, 28 tabletter; Blister, 30 tabletter; Blister, 56 tabletter; Blister, 60 tabletter; Blister, 100 tabletter; Burk, 30 tabletter; Burk, 100 tabletter; Burk, 112 tabletter
Bemyndigande status:
Godkänd
Godkännandenummer:
52665
Tillstånd datum:
2015-12-16

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Package leaflet: Information for the user

Rasagilin Accord Healthcare 1 mg tablets

rasagiline

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side

effects not listed in this leaflet. See section 4.

What is in this leaflet

What /…/ is and what it is used for

What you need to know before you take /…/

How to take /…/

Possible side effects

How to store /…/

Contents of the pack and other information

1.

What /…/ is and what it is used for

/.../ contains the active substance rasagiline and it is used for the treatment of Parkinson’s disease in

adults.. 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. /.../ helps to increase and sustain levels of

dopamine in the brain.

2.

What you need to know before you take /…/

Do not take /…/

If you are allergic to rasagiline or any of the other ingredients of this medicine (listed in section

If you have severe liver problems.

Do not take the following medicines while taking /.../:

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.

Pethidine (a strong pain killer).

You must wait at least 14 days after stopping /.../ treatment and starting treatment with MAO

inhibitors or pethidine.

Warnings and precautions

Talk to your doctor or pharmacist before taking /…/

If you have mild to moderate liver problems.

You should speak with your doctor about any suspicious skin changes.

Tell your doctor if you or your family/carer notices that you are developing unusual behaviours where

you cannot resist the impulse, urges or cravings to carry out certain harmful or detrimental activities to

yourself or others. These are called impulse control disorders. In patients taking /.../ and/or other

medications used to treat Parkinson’s disease, behaviours such as compulsions, obsessive thoughts,

addictive gambling, excessive spending, impulsive behaviour and an abnormally high sex drive or an

increase in sexual thoughts or feelings have been observed. Your doctor may need to adjust or stop

your dose (see section 4).

/…/ may cause drowsiness and may cause you to suddenly fall asleep during day time activities,

especially if you are taking other dopaminergic medicinal products (used for the treatment of

Parkinson’s disease). For further information please refer to section driving and using machines.

Children and adolescents

/.../ is not recommended for use under the age of 18.

Other medicines and /…/

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines. Including medicines obtained without prescription or if you are smoking or intend to stop

smoking.

Ask your doctor for advice before taking any of the following medicines together with /.../:

Certain antidepressants (selective serotonin reuptake inhibitors, selective serotonin-

norepinephrine reuptake inhibitors, tricyclic or tetracyclic antidepressants)

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 /.../ together with the antidepressants containing fluoxetine or fluvoxamine should be

avoided.

If you are starting treatment with /..., 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 /.../ treatment.

Pregnancy, breast-feeding and fertility

/…/ may affect the ability to breast-feed your baby.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask

your doctor or pharmacist for advice before taking this medicine.

You should avoid taking /…/ if you are pregnant, as the effects of /…/ on pregnancy and the unborn

child are not known.

Driving and using machines

Ask your doctor for advice before you drive and operate machines, since

Parkinson’s disease itself as

well as the treatment with /…/may influence your ability to drive and operate machines. /…/may make

you feel dizzy or drowsy; it can also cause episodes of sudden sleep onset. This might be enhanced if

you take other medicines to treat the symptoms of your Parkinson’s disease, or if you take medicines

which can make you feel drowsy, or if you drink alcohol while taking /…/. If you are experiencing

somnolence or new episodes of falling asleep without warning during daily activities, do not drive or

operate machinery (see section 2). Ask your doctor for advice prior to driving or using machines.

3.

How to take /…/

Always take this medicine exactly as your doctorhas told you. Check with your doctor or pharmacist

or if you are not sure.

The recommended dose of /…/ is 1 tablet of 1 mg taken by mouth once daily. /.../ may be taken with

or without food.

If you take more /…/ than you should

If you think that you may have taken too many /.../ tablets, contact your doctor or pharmacist

immediately. Take the /.../ carton/bottle with you to show the doctor or pharmacist.

Symptoms reported following overdose of /…/ included slightly euphoric mood (light form of mania),

extremely high blood pressure and serotonin syndrome (see section 4).

If you forget to take /…/

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 /…/

Do not stop taking /.../ without first talking to your doctor.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.-

Seek medical help straight away, if you notice any of the following symptoms You may need urgent

medical advice or treatment

:

If you develop unusual behaviours such as compulsions, obsessive thoughts, addictive

gambling, excessive shopping or spending, impulsive behaviour and an abnormally high sex

drive or an increase in sexual thoughts (impulse control disorders) (see section 2).

If you see or hear things which are not there (hallucinations).

Any combination of hallucinations, fever, restlessness, tremor and sweating (serotonin

syndrome)

If you notice any suspicious skin changes because there is a higher risk of skin cancer (not

exclusively melanoma) in patients with Parkinson’s disease (see section 2).

Other side effects

Very common (may affect more than 1 in 10 people)

Involuntary movements (dyskinesia)

Headache

Common (may affect up to 1 in 10 people)

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 (may affect up to 1 in 100 people)

Stroke (cerebrovascular accident)

Heart attack (myocardial infarction)

Blistering rash (vesiculobullous rash)

Not known: frequency cannot be estimated from the available data

Elevated blood pressure

Excessive drowsiness

Sudden onset of sleep

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via the national reporting system

listed in Appendix V. By reporting side effects you can help provide more information on the safety of

this medicine.

5.

How to store /…/

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton, bottle or blister after EXP.

The expiry date refers to the last day of that month.

Store in the original package in order to protect from light.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to

throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What /…/ contains

The active substance is rasagiline. Each tablet contains 1 mg rasagiline (as tartrate).

The other ingredients are: Calcium sulfate dehydrate, Starch, pregelatinised (maize), Maize

starch, Stearic acid 50, Talc, Citric acid anhydrous, Silica colloidal anhydrous.

What /…/ looks like and contents of the pack

White, round bevel edge, 7 mm, debossed with “A486” on one side and plain on the other side.

The tablets are available in blister packs of 10, 28, 30 56, 60 or 100 tablets or in a bottle containing 30,

100 or 112 tablets.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

<[To be completed nationally]>

{Name and address}

<{tel}>

<{fax}>

<{e-mail}>

This medicinal product is authorised in the Member States of the EEA under the following

names:

<{Name of the Member State}> <{Name of the medicinal product}>

<{Name of the Member State}> <{Name of the medicinal product}>

This leaflet was last revised in

2019-10-09

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SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Rasagilin Accord Healthcare 1 mg tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1 mg rasagiline (as tartrate).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Tablet

White, round bevel edge, 7 mm, debossed with “A486” on one side and plain on the other side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

/.../ is indicated for the treatment in adults 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

The recommened dose of Rasagiline is1 mg (1 tablet of /…/) once daily administered orally, to be

taken with or without levodopa.

Elderly

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

Hepatic impairment

Rasagiline is contraindicated in patients with severe hepatic impairment (see section 4.3). Rasagiline

use in patients with moderate hepatic impairment should be avoided. Caution should be used when

initiating treatment with rasagiline in patients with mild hepatic impairment. In case patients progress

from mild to moderate hepatic impairment rasagiline use should be stopped (see section 4.4 and 5.2).

Renal impairment

No special precautions are required in patients with renal impairment.

Paediatric population

The safety and efficacy of /.../ in children and adolescents have not been established. There is no

relevant use of /…/ in the paediatric population in the indication Parkinson’s disease

Method of administration

For oral use.

/…/may be taken with or without food.

4.3

Contraindications

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

Concomitant treatment with other monoamine oxidase (MAO) inhibitors (including medicinal 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.

Severe hepatic impairment.

4.4

Special warnings and precautions for use

Concomitant use of rasagiline with other medicinal products

The concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided (see section 4.5).

At least five weeks should elapse between discontinuation of fluoxetine and initiation of 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).

Concomitant use of rasagiline and levodopa

Since rasagiline potentiates the effects of levodopa, the adverse reactions of levodopa may be

increased and pre-existing dyskinesia exacerbated. Decreasing the dose of levodopa may ameliorate

this adverse reaction.

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

Patients with Parkinson’s disease are particularly vulnerable to the adverse reactions of hypotension

due to existing gait issues.

Dopaminergic effects

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

Rasagiline may cause daytime drowsiness, somnolence, and occasionally, especially if used with other

dopaminergic medicinal products - 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)

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 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.

Hepatic impairment

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 use 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.

MAO Inhibitors

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).

Pethidine

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).

Sympathomimetics

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).

Dextromethorphan

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).

SNRI/SSRI/tri- and tetracyclic antidepressants

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

For concomitant use of rasagiline with selective serotonin reuptake inhibitors (SSRIs)/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.

Agents that affect CYP1A2 activity

In vitro

metabolism studies have indicated that cytochrome P450 1A2 (CYP1A2) is the major enzyme

responsible for the metabolism of rasagiline.

CYP1A2 inhibitors

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.

CYP1A2 inducers

There is a risk that the plasma levels of rasagiline in smoking patients could be decreased, due to

induction of the metabolising enzyme CYP1A2.

Other cytochrome P450 isoenzymes

In vitro

studies showed that rasagiline at a concentration of 1 µg/ml (equivalent to a level that is

160 times the average C

~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.

Levodopa and other Parkinson’s disease medicinal products

In Parkinson's disease patients receiving rasagiline as adjunct therapy to chronic levodopa treatment,

there was no clinically significant effect of levodopa treatment on rasagiline clearance.

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

Tyramine/rasagiline interaction

Results of five tyramine challenge studies (in volunteers and Parkinson´s disease patients), 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

Pregnancy

There are no data from the use of rasagiline in pregnant women. Animal studies do not indicate direct

or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary

measure, it is preferable to avoid the use of rasagiline during pregnancy.

Breast-feeding

Non-clinical data indicate that rasagiline inhibits prolactin secretion and thus, may inhibit lactation. It

is not known whether rasagiline is excreted in human milk. Caution should be exercised when

rasagiline is administered to a breast-feeding mother.

Fertility

There are no data available

on the effect of rasagiline

on fertility in humans.

Non-clinical data

does not show any effect of rasagiline on fertility.

4.7

Effects on ability to drive and use machines

In patients experiencing somnolence/sudden sleep episodes, rasagiline may have major influenceon

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

rasagiline.

Patients should be cautioned about possible additive effects of sedating medications, alcohol, or other

central

nervous

system

depressants

(e.g.,

benzodiazepines,

antipsychotics,

antidepressants)

combination with rasagiline, or when taking concomitant medications that increase plasma levels of

rasagiline (e.g., ciprofloxacin) (see section 4.4)

4.8

Undesirable effects

Summary of the safety profile

In clinical studies in Parkinson's disease patients the most commonly reported adverse reactions were:

a) headache, depression, vertigo, and flu (influenza and rhinitis) in monotherapy; b) dyskinesia,

orthostatic hypotension, fall, abdominal pain, nausea/vomiting, and dry mouth in adjunct to levodopa

therapy; c) musculoskeletal pain, as back and neck pain and arthralgia in both regimens. These adverse

reactions were not associated with an elevated rate of drug discontinuation.

Tabulated list of adverse reactions

Adverse reactions are listed below in Tables 1 and 2 by system organ class and frequency using the

following conventions: very common (≥1/10), common (≥1/100 to <1/10), uncommon

(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be

estimated from the available data).

Monotherapy

The tabulated list below includes adverse reactions which were reported with a higher incidence in

placebo- controlled studies, in patients receiving 1 mg/day rasagiline.

System Organ

class

Very

common

Common

Uncommon

Not known

Infections and

infestations

Influenza

Neoplasms

benign, malignant

and unspecified

(including cysts

and polyps)

Skin carcinoma

Blood and

lymphatic system

disorders

Leucopenia

Immune system

disorders

Allergy

Metabolism and

Decreased

System Organ

class

Very

common

Common

Uncommon

Not known

nutrition

disorders

appetite

Psychiatric

disorders

Depression

Hallucinations*

Impulse control

disorders*

Nervous system

disorders

Headache

Cerebrovascular

accident

Serotonin

syndrome*,

Excessive daytime

sleepiness (EDS)

and sudden sleep

onset (SOS)

episodes*

Eye disorders

Conjunctivitis

Ear and labyrinth

disorders

Vertigo

Cardiac disorders

Angina pectoris

Myocardial

infarction

Vascular

disorders

Hypertension*

Respiratory,

thoracic and

mediastinal

disorders

Rhinitis

Gastrointestinal

disorders

Flatulence

Skin and

subcutaneous

tissue disorders

Dermatitis

Vesiculobullous

rash

Musculoskeletal

and connective

tissue disorders

Musculoskeletal

pain,

Neck pain

Arthritis

Renal and urinary

disorders

Urinary urgency

General disorders

administration

site conditions

Fever,

Malaise

*See section description of selected adverse reactions

Adjunct Therapy

The tabulated list below includes adverse reactions which were reported with a higher incidence in

placebo- controlled studies in patients receiving 1 mg/day rasagiline.

System Organ

class

Very

common

Common

Uncommon

Not known

Neoplasms

benign,

malignant and

unspecified

Skin melanoma*

Metabolism and

nutrition

disorders

Decreased

appetite

Psychiatric

Hallucinations*,

Confusion

Impulse control

System Organ

class

Very

common

Common

Uncommon

Not known

disorders

Abnormal

dreams

disorders*

Nervous system

disorders

Dyskinesia

Dystonia,

Carpal tunnel

syndrome,

Balance disorder

Cerebrovascular

accident

Serotonin

syndrome*,

Excessive

daytime

sleepiness (EDS)

and sudden sleep

onset (SOS)

episodes*

Cardiac disorders

Angina pectoris

Vascular

disorders

Orthostatic

hypotension*

Hypertension*

Gastrointestinal

disorders

Abdominal pain,

Constipation,

Nausea and

vomiting,

Dry mouth

Skin and

subcutaneous

tissue disorders

Rash

Musculoskeletal

and connective

tissue disorders

Arthralgia,

Neck pain

Investigations

Decreased

weight

Injury, poisoning

and procedural

complications

Fall

*See section description of selected adverse reactions

Description of selected adverse reactions

Orthostatic hypotension

In blinded placebo-controlled studies, severe orthostatic hypotension was reported in one subject

(0.3%) in the rasagiline arm (adjunct studies), none in the placebo arm. Clinical trial data further

suggest that orthostatic hypotension occurs most frequently in the first two months of rasagiline

treatment and tends to decrease over time.

Hypertension

Rasagiline selectively inhibits MAO-B and is not associated with increased tyramine sensitivity at the

indicated dose (1 mg/day). In blinded placebo-controlled studies (monotherapy and adjunct) severe

hypertension was not reported in any subjects in the rasagiline arm. In the post-marketing period,

cases of elevated blood pressure, including rare serious cases of hypertensive crisis associated with

ingestion of unknown amounts of tyramine-rich foods, have been reported in patients taking

rasagiline. 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

One case of hypersexuality was reported in monotherapy placebo-controlled study on rasagiline. The

following were reported during post-marketing exposure of rasagiline with unknown frequency:

compulsions, compulsive shopping, dermatillomania, dopamine dysregulation syndrome, impulse-

control disorder, impulsive behaviour, kleptomania, theft, obsessive thoughts, obsessive-compulsive

disorder, stereotypy, gambling, pathological gambling, libido increased, hypersexuality, psychosexual

disorder, sexually inappropriate behaviour. Half of the reported ICD cases were assessed as serious.

Only single case of reported cases had not recovered at the time they were reported.

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

Excessive daily sleepiness (hypersomnia, lethargy, sedation, sleep attacks, somnolence, 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 more than 1-year after

initiation of treatment.

Hallucinations

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.

Serotonin syndrome

Rasagiline clinical trials did not allow concomitant use of fluoxetine or fluvoxamine with rasagiline,

but the following antidepressants and doses were allowed in the rasagiline trials: amitriptyline

≤ 50 mg/daily, trazodone ≤ 100 mg/daily, citalopram ≤ 20 mg/daily, sertraline ≤ 100 mg/daily, and

paroxetine ≤ 30 mg/daily (see section 4.5).

Cases of potentially life-threating serotonin syndrome associated with agitation, confusion, rigidity,

pyrexia and myoclonus have been reported by patients treated with antidepressants, meperidine,

tramadol, methadone, or propoxyphene concomitantly with rasagiline (post marketing period).

Malignant melanoma

Incidence of skin melanoma in placebo-controlled clinical studies was 2/380 (0.5%) in rasagiline 1 mg

as adjacent to levodopa therapy group vs. 1/388 (0.3%) incidence in placebo group. Additional cases

of malignant melanoma were reported during post-marketing period. These cases were considered

serious in all reports.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system

listed in Appendix V.

4.9

Overdose

Symptoms

Symptoms reported following overdose of rasagiline in doses ranging from 3 mg to 100 mg included,

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 reactions 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 adverse reactions (including hypertension and postural hypotension)

which resolved following treatment discontinuation. These symptoms may resemble those observed

with non-selective MAO inhibitors.

Management

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 efficacy and safety

The efficacy of rasagiline was established in three studies: as monotherapy treatment in study I and as

adjunct therapy to levodopa in the studies II and III.

Monotherapy

In study I, 404 patients were randomly assigned to receive placebo (138 patients), rasagiline 1 mg/day

(134 patients) or rasagiline 2 mg/day (132 patients) and were treated for 26 weeks, there was no active

comparator.

In this study, the primary measure of efficacy was the change from baseline in the total score of the

Unified Parkinson’s Disease Rating Scale (UPDRS, parts I-III). The difference between the mean

change from baseline to week 26/termination (LOCF, Last Observation Carried Forward) was

statistically significant (UPDRS, parts I-III: for rasagiline 1 mg compared to placebo -4.2, 95%

CI [-5.7, -2.7]; p<0.0001; for rasagiline 2 mg compared to placebo -3.6, 95% CI [-5.0,-2.1]; p<0.0001,

UPDRS Motor, part II: for rasagiline 1 mg compared to placebo -2.7, 95% CI [-3.87,-1.55], p<0.0001;

for rasagiline 2 mg compared to placebo -1.68, 95% CI [-2.85,-0.51], p = 0.0050). The effect was

evident, although its magnitude was modest in this patient population with mild disease. There was a

significant and beneficial effect in quality of life (as assessed by PD-QUALIF scale).

Adjunct therapy

In study II, patients were randomly assigned to receive placebo (229 patients), or rasagiline 1 mg/day

(231 patients) or the catechol-O-methyl transferase (COMT) inhibitor, entacapone, 200 mg taken

along with scheduled doses of levodopa (LD)/decarboxylase inhibitor (227 patients), and were treated

for 18 weeks.

In study III, patients were randomly assigned to receive placebo (159 patients), rasagiline 0.5 mg/day

(164 patients), or rasagiline 1 mg/day (149 patients), and were treated for 26 weeks.

In both studies, the primary measure of efficacy was the change from baseline to treatment period in

the mean number of hours that were spent in the “OFF” state during the day (determined from

“24-hour” home diaries completed for 3 days prior to each of the assessment visits).

In study II, the mean difference in the number of hours spent in the “OFF” state compared to placebo

was -0.78 h, 95% CI [-1.18, -0.39], p = 0.0001. The mean total daily decrease in the OFF time was

similar in the entacapone group (-0.80 h, 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 -0.94 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 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

) in approximately 0.5 hours.

The absolute bioavailability of a single rasagiline dose is about 36%. Food does not affect the T

rasagiline, although C

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

C-labelled rasagiline is approximately 60 to 70%.

Biotransformation

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.

Ex vivo

in vitro

experiments demonstrate that rasagiline is neither inhibitor nor inducer of major

CYP450 enzymes (see section 4.5).

Elimination

After oral administration of

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 in Parkinson’s disease

patients. Its terminal half-life is 0.6-2 hours.

Hepatic impairment

In subjects with mild hepatic impairment, AUC and C

were increased by 80% and 38%,

respectively. In subjects with moderate hepatic impairment, AUC and C

were increased by 568%

and 83%, respectively (see section 4.4).

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.

Elderly

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

5.3

Preclinical safety data

Non-clinical data reveal no special hazard for humans based on the standard studies of safety

pharmacology, repeated-dose toxicity, genotoxicity, carcinogenicity, reproduction toxicity and

development.

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

Calcium sulfate dehydrate

Starch, pregelatinised (maize)

Maize starch

Stearic acid 50

Talc

Citric acid anhydrous

Silica, colloidal anhydrous

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years.

6.4

Special precautions for storage

Store in the original package in order to protect from light.

6.5

Nature and contents of container

Blisters: Aluminium (OPA/Al/PVC) / Aluminium blisters blister packs of 10, 28, 30, 56, 60 or

100 tablets.

Bottles: White, round HDPE container with a snap-on neck and a white cylindrical desiccant with the

inscription in blue: “DO NOT EAT”. The LDPE cap is white, round push-fit tamper-evident cap with

a short opening tear-band and frangible connection bridges. Bottles contain 30, 100 or 112 tablets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements

7.

MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

{Name and address}

<{tel}>

<{fax}>

<{e-mail}>

8.

MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<Date of first authorisation: {DD month YYYY}>

<Date of latest renewal: {DD month YYYY}>

<[To be completed nationally]>

10.

DATE OF REVISION OF THE TEXT

2019-10-09

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