AZILECT

PATIENT PACKAGE INSERT IN

ACCORDANCE WITH THE PHARMACISTS’

REGULATIONS (PREPARATIONS) - 1986

The medicine is dispensed with

a doctor’s prescription only.

AZILECT

®

Tablets

Tablets

Composition

Each tablet contains:

Rasagiline (as mesilate) 1 mg

For the list of inactive ingredients in the preparation, see

section 6 – “Further Information”.

Read this leaflet carefully in its entirety before using

the medicine. This leaflet contains concise information

about the medicine. If you have further questions, refer

to the doctor or pharmacist.

This medicine has been prescribed for the treatment

of your ailment. Do not pass it on to others. It may

harm them, even if it seems to you that their medical

condition is similar.

1. WHAT IS THE MEDICINE INTENDED FOR?

AZILECT is intended for the treatment of Parkinson’s in

adults, and can be used with or without taking levodopa.

Therapeutic group:

Selective monoamine oxidase type B inhibitors.

With Parkinson’s disease, there is a loss of cells that

produce dopamine in the brain. Dopamine is a chemical

substance in the brain involved in movement control.

AZILECT helps increase and sustain levels of dopamine

in the brain.

2. BEFORE USING THE MEDICINE

Do not use the preparation if:

∙ You are sensitive (allergic) to the active ingredient

(rasagiline) or any of the additional ingredients

contained in the medicine (see section 6 – “Further

information”).

∙ You are suffering from severe liver insufficiency.

Do not use AZILECT concomitantly with the following

medicines:

∙ Pethidine (a strong pain killer).

∙ Monoamine oxidase inhibitors (whether given as

medicines for depression, Parkinson’s disease, or

any other indication, including natural or medicinal

preparations given without a doctor’s prescription,

e.g. St. John’s Wort for depression).

You must wait at least 14 days between discontinuing

AZILECT and starting treatment with monoamine

oxidase inhibitors or with pethidine.

Special warnings regarding use of the medicine

Before beginning treatment with AZILECT, tell the

doctor if:

∙ you are suffering from a liver problem.

∙ if you noticed suspicious skin changes.

Notify the doctor if your family/caregiver notice that

you are developing unusual behaviors, where you fail

to resist an impulse, urge or desire to carry out actions

harmful or destructive to yourself or others. This

condition is defined as impulse control disorders. In

patients taking AZILECT together with other medicines

to treat Parkinson’s disease, behavior disorders, such

as compulsive behavior, obsessive thoughts, gambling

addiction, excessive spending, impulse to behave

abnormally, increased sexual drive or increased sexual

thoughts/excitement have been observed. Your doctor

will consider adjusting the dosage or stopping the

medicine (see section 4 – “Side effects”).

AZILECT may cause drowsiness and may cause you to

suddenly fall asleep during day time activities, especially

if you are taking other dopaminergic medicines (used to

treat Parkinson’s disease). For further information, see

“Driving and operating machinery” section.

Use in children and adolescents

The safety and effectiveness of AZILECT in children

and adolescents has not been tested; the medicine

has not been used to treat Parkinson’s in children and

adolescents. Therefore, AZILECT is not intended for use

under 18 years of age.

Smoking

Inform the doctor or pharmacist if you smoke or plan to

stop smoking. Smoking can reduce the levels of AZILECT

in the blood.

If you are taking, have recently taken or plan to

take other medicines, including non-prescription

medicines and nutritional supplements, tell the doctor

or pharmacist.

In particular, inform the doctor if you are taking the

following medicines:

∙ Antidepressants (e.g., tricyclics, tetracyclics,

selective serotonin reuptake inhibitors [SSRIs],

serotonin-norepinephrine reuptake inhibitors [SNRIs]),

monoamine oxidase inhibitors.

∙ Ciprofloxacin (an antibiotic against infections).

∙ Dextromethorphan (cough suppressant).

∙ Sympathomimetics such as those present in eye drops,

oral or nasal decongestants or cold medicines that

contain ephedrine or pseudoephedrine.

Pethidine – see in section 2 “Do not use the preparation”.

Avoid using this medicine concomitantly with

antidepressants that contain fluoxetine or fluvoxamine.

Wait at least a period of 5 weeks between discontinuing

treatment with fluoxetine and starting treatment with

AZILECT. On the other hand, if you start treatment with

fluoxetine or fluvoxamine, do so at least 14 days after

discontinuing treatment with AZILECT.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, suspect that you are

pregnant or are considering becoming pregnant, consult

a doctor or pharmacist before using the medicine.

You must avoid taking AZILECT if you are pregnant, as

the effects of AZILECT on pregnancy and on the fetus

are unknown.

Driving and operating machinery

Consult with your doctor before you drive and operate

machinery, since Parkinson’s disease itself, as well as the

treatment with AZILECT, may influence your ability to do

so. AZILECT can cause dizziness or drowsiness and can

also cause episodes of sudden sleep onset.

The effect can be increased 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 AZILECT.

If you have experienced drowsiness and/or episodes of

sudden sleep onset in the past or while taking AZILECT,

do not drive or operate machinery.

3. HOW SHOULD YOU USE THE MEDICINE?

Always use the medicine according to the doctor’s

instructions. Check with the doctor or pharmacist if you

are uncertain about the dosage and treatment regimen

of the preparation.

The dosage and treatment regimen will be determined

by the doctor only. The usual dosage is generally: one

1 mg tablet per day, with or without food.

Use this medicine at specified time intervals, as

determined by the attending doctor.

Do not exceed the recommended dosage

Do not crush/halve/chew! Swallow the tablet whole,

with water.

If you accidentally take a higher dosage

If you took an overdose, or if a child has accidentally

swallowed the medicine, refer immediately to a doctor

or proceed to a hospital emergency room and bring the

package of the medicine with you.

An AZILECT overdose can manifest in the following

symptoms: slightly euphoric mood (light form of mania),

very high blood pressure and serotonin syndrome (see

section 4 – “Side effects”).

If you forgot to take this medicine at the required time,

do not take two doses together to compensate for the

forgotten dose. Take the next dose at the usual time.

Adhere to the treatment regimen as recommended

by the doctor. Even if there is an improvement in your

health, do not stop treatment with AZILECT without

consulting the doctor.

Do not take medicines in the dark! Check the label and

dose each time you take medicine. Wear glasses if you

need them.

If you have further questions regarding use of the

medicine, consult the doctor or pharmacist.

4. SIDE EFFECTS

As with any medicine, use of this medicine may cause

side effects in some users. Do not be alarmed by the

list of side effects. You may not suffer from any of them.

Contact the doctor immediately if:

∙ you develop unusual behaviors such as compulsive

behavior, obsessive thoughts, gambling addiction,

excessive shopping or spending, impulsive behavior

and an abnormally high sex drive or an increase in

sexual thoughts (impulse control disorders) (see

section 2 – “Before using the medicine”).

∙ you see or hear things that do not exist (hallucinations).

∙ any combination of hallucinations, fever, restlessness,

tremor or sweating (serotonin syndrome).

∙ you notice any suspicious skin changes – consult a

specialist since there is a higher risk of skin cancer

(not exclusively melanoma) in patients with Parkinson’s

disease (see section 2 – “Before using the medicine”).

Additional side effects

Very common side effects – effects that occur in more

than 1 user in 10:

∙ involuntary movements (dyskinesia)

∙ headache

Common side effects – effects that occur in 1-10

in 100 users:

∙ abdominal pain

∙ falling

∙ allergic reactions

∙ fever

∙ flu

∙ general unwell feeling

∙ neck pain

∙ chest pain (angina pectoris)

∙ low blood pressure upon transitioning from sitting to

standing with symptoms such as dizziness

∙ anorexia (lack of appetite)

∙ constipation

∙ dry mouth

∙ nausea and vomiting

∙ abdominal bloating

∙ abnormal blood test results (leucopenia - reduced

number of white blood cells)

∙ joint pain

∙ muscle pain

∙ arthritis

∙ numbness and weakness of the hand muscles (Carpal

Tunnel syndrome)

∙ weight loss

∙ abnormal dreams

∙ difficulty

with

muscle

coordination

(balance

disturbance)

∙ depression

∙ dizziness (vertigo)

∙ prolonged muscle contractions (dystonia)

∙ runny nose (nasal inflammation)

∙ skin irritation (skin inflammation - dermatitis)

∙ rash

∙ red and swollen eyes (conjunctivitis)

∙ urinary urgency

Uncommon side effects – effects that occur in 1-10

in 1,000 users:

∙ stroke

∙ heart attack (myocardial infarction)

∙ a rash that appears in the form of blisters

Side effects whose frequency is unknown (it is not

possible to know the frequency based on the existing

data)

∙ rise in blood pressure

∙ excessive drowsiness

∙ sudden onset of sleep

If a side effect occurs, if one of the side effects worsens

or if you suffer from a side effect not mentioned in

this leaflet, consult with the doctor.

Side effects can be reported to the Ministry of Health

by clicking on the link “Report Side Effects of Drug

Treatment” found on the Ministry of Health homepage

(www.health.gov.il) that directs you to the online form for

reporting side effects, or by entering the link:

https://forms.gov.il/globaldata/getsequence/getsequenc

e.aspx?formType=AdversEffectMedic@moh.gov.il

5. HOW SHOULD THE MEDICINE BE STORED?

∙ Avoid poisoning! This medicine and any other medicine

should be kept in a safe place out of the reach of

children and/or infants in order to avoid poisoning. Do

not induce vomiting unless explicitly instructed to do

so by the doctor.

∙ Do not use the medicine after the expiry date

(exp. date) that appears on the package. The expiry

date refers to the last day of that month.

∙ Store in a cool place, below 25°C. Store in the original

package.

∙ Do not discard medicines in the wastewater or waste

bin. Ask the pharmacist how to dispose of medicines

that are not in use. These measures will help protect

the environment.

6. FURTHER INFORMATION

In addition to the active ingredient, the medicine also

contains:

Mannitol, starch, pregelatinized starch, stearic acid, talc,

colloidal silicon dioxide.

What the medicine looks like and the contents of

the package

A white to off-white, round tablet, debossed with “GIL”

and “1” underneath on one side and plain on the other

side.

The package contains 10 or 30 tablets.

Not all package sizes may be marketed.

Name of Manufacturer and License Holder and its

Address

Teva Pharmaceutical Industries Ltd.,

P.O.B. 3190, Petah-Tikva.

This leaflet was checked and approved by the Ministry of

Health in June 2014 and was updated in February 2018

in accordance with the Ministry of Health guidelines.

Registration number of the medicine in the National

Drug Registry of the Ministry of Health:

132.17.31000

AZIL TAB PL SH 180718

AZIL TAB PL SH 180718

322K101560818

322K101560818

فقوتلا زوجي لا .بيبطلا ةيصوت بسح جلاعلا ىلع ةبظاوملا بجي نسحت أرط ولو ىتح بيبطلا ةراشتسإ نودب تكليزأ ـب جلاعلا نع .ةيحصلا كتلاح ىلع دكأتلاو ءاودلا عباط صيخشت بجي !ةمتعلا يف ةيودأ لوانت زوجي لا ةيبطلا تاراظنلا عض .ءاود اهيف لوانتت ةرم لك يف ةيئاودلا ةعرجلا نم .كلذ رملأا مزل اذإ بيبطلا رشتسإ ،ءاودلا اذه لامعتسإ لوح ةيفاضإ ةلئسأ كيدل ترفوت اذإ .يلديصلا وأ ةيبناجلا ضارعلأا )4 دنع ةيبناج

اضارعأ ببسي دق ءاودلا اذه لامعتسإ نإ ،ءاود لكب امك زئاجلا نم .ةيبناجلا ضارعلأا ةمئاق نم شهدنت لا .نيلمعتسملا ضعب .اهنم

ايأ يناعت لاأ :اذإ بيبطلل

ً

لااح هجوتلا بجي ،ةيساوسو راكفأ ،يرسق كولس لثم ةذاش تايكولس كيدل تروطت ∙ مجان كولس ،هيف غلابم لكشب ءارشلا وأ قافنلإا ،رامقلا ىلع نامدلإا ةيسنج راكفأ وأ داتعملا نع ةدئاز ةيسنج ةبغرو )ةيعافدنإ( عفاد نع لبق« ـ 2 ةرقفلا رظنأ( )عفاودلا يف مكحتلا تابارطضإ( ةديازتم .)»ءاودلا لامعتسإ .)نايذه( ةدوجوم ريغ ءايشأ عمست وأ ىرت تنك ∙ قرعت وأ فاجترإ ،ةحار مدع ،ةنوخس ،نايذه نم جيزم يأ كيدل دجو ∙ .)نينوتوريسلا ةمزلاتم(

ارظن صتخم ةراشتسإ بجي ،كشلل ةريثم ةيدلج تاريغت تظحلا

)امونلايم طقف سيل( دلجلا ناطرس ثودحل ةدئاز ةروطخ دوجول .)»ءاودلا لامعتسإ لبق« ـ 2 ةرقفلا رظنأ( نوسنيكراپلا ىضرم ىدل ةيفاضإ ةيبناج ضارعأ لمعتسم نم رثكأ ىدل رهظت ضارعأ ـ

ً

ادج ةعئاش ةيبناج ضارعأ :ةرشع نيب نم دحاو

dyskinesia

( ةيدارإ لا تاكرح ∙ عادص ∙ نيلمعتسم 10-1 ىدل رهظت ضارعأ ـ ةعئاش ةيبناج ضارعأ :100 نيب نم نطبلا يف ملاآ

طوقس ∙ ةيسسحت لعف دودر ∙ ةنوخس ∙ ازنإولفنإ

ةكعوب ماع روعش ∙ ةبقرلا يف ملاآ

)ةيبلق ةحبذ( ردصلا يف ملأ

فوقولا ىلإ سولجلا ةيعضو نم لاقتنلإا دنع مدلا طغض ضافخنإ

راودلا لثم ضارعأ عم )ماعطلل ةيهشلا ةلق(

anorexia

كاسمإ

مفلا فافج ∙ ؤيقتو نايثغ ∙ نطبلا يف خافتنإ

مدلا ايلاخ ةلق ـ

leucopenia

( مدلا صوحف جئاتن ةملاس مدع ∙ )ءاضيبلا ةيلصفم ملاآ

ةيلضع ملاآ

arthritis

( لصافملا باهتلإ

Carpal Tunnel syndrome

( ديلا ةحار تلاضع يف فعضو ردخ ∙ نزولا صقانت ∙ ةذاش ملاحأ

)نزاوتلا يف بارطضإ( تلاضعلا قسانت يف ةبوعص ∙ بائتكإ

)وغيتريﭬ( راود ∙

dystonia

( تلاضعلل لصاوتم صلقت ∙ )فنلأا باهتلإ( حشر ∙

dermatitis

ـ دلجلا باهتلإ( دلجلا جيهت ∙ حفط ∙ )ةمحتلملا باهتلإ( نينيعلا خافتنإو رارمحإ

لوبتلا ىلع حاحللإا

نيلمعتسم 10-1 ىدل رهظت ضارعأ ـ ةعئاش ريغ ةيبناج ضارعأ :1000 نيب نم ةيغامد ةتكس ∙ )بلقلا ةلضع ءاشتحإ( ةيبلق ةبون ∙ تلاصيوح لكش ىلع رهظي يذلا حفط ∙ عويشلا ةفرعم نكمي لا( فورعم ريغ اهعويش ةيبناج ضارعأ )ةرفوتملا تامولعملا نم مدلا طغض عافترإ

طرفم ساعن ∙ ئجافملا مونلا

وأ ةيبناجلا ضارعلأا ىدحإ تمقافت اذإ ،يبناج ضرع رهظ اذإ كيلع ،ةرشنلا هذه يف ركذي مل يبناج ضرع نم يناعت امدنع .بيبطلا ةراشتسإ طغضلا ةطساوب ةحصلا ةرازول ةيبناج ضارعأ نع غيلبتلا ناكملإاب دوجوملا »يئاود جلاع بقع ةيبناج ضارعأ نع غيلبت« طبارلا ىلع

www.health.gov.il

( ةحصلا ةرازو عقومل ةيسيئرلا ةحفصلا ىلع نع وأ ةيبناج ضارعأ نع غيلبتلل رشابملا جذومنلا ىلإ كهجوي يذلا :طبارلا حفصت قيرط

https://forms.gov.il/globaldata/getsequence/getseq

uence.aspx?formType=AdversEffectMedic@moh.

gov.il

؟ءاودلا نيزخت ةيفيك )5 قلغم ناكم يف رخآ ءاود لكو ءاودلا اذه ظفح بجي !ممستلا بنجت ∙ مهتباصإ يدافتل كلذو عضرلا وأ/و لافطلأا يديأ لوانتم نع

اديعب .بيبطلا نم ةحيرص تاميلعت نودب ؤيقتلا ببست لا .ممستلاب

exp. date

( ةيحلاصلا خيرات ءاضقنإ دعب ءاودلا لامعتسإ زوجي لا ∙ ريخلأا مويلا ىلإ ةيحلاصلا خيرات ريشي .ةبلعلا رهظ ىلع رهظي يذلا .رهشلا سفن نم ءاودلا ظفحي ،ةيوئم ةجرد 25 نود دراب ناكم يف نيزختلا بجي ∙ .ةيلصلأا ةبلعلا يف نع يلديصلا لأسإ .ةمامقلا يف وأ يراجملا يف ةيودلأا يمر زوجي لا ∙ دعاست لئاسولا هذه .لامعتسلإا ديق دعت مل ةيودأ نم صلختلا ةيفيك .ةئيبلا ىلع ظافحلا يف ةيفاضإ تامولعم )6

:

ً

اضيأ ةلاعفلا ةداملل ةفاضلإاب ءاودلا يوتحي

Mannitol, starch, pregelatinized starch, stearic acid, talc,

colloidal silicon dioxide.

ةبلعلا ىوتحم وه امو ءاودلا ودبي فيك بناج يف »

« ةعابطلا عم ركع ضيبأ وأ ضيبأ هنول ريدتسم صرق .صرقلا نم يناثلا بناجلا يف ةعابط نودبو »

« هتحتو صرقلا نم دحاو

اصرق 30 وأ 10 ىلع ةبلعلا يوتحت .بلعلا ماجحأ ةفاك ق

وست لاأ زئاجلا نم هناونعو زايتملإا بحاصو جتنملا مسإ ،.ض.م ةيبطلا تارضحتسملاو ةيودلأل عڤيت .اڤكت ـ حتيپ ،3190 .ب.ص يف صخ

رو صح

ف اهاوتحمو ةرشنلا هذه ةغيص ةحصلا ةرازو ترقأ ةحصلا ةرازو تاميلعت بجومب اهثيدحت متو 2014 ناريزح خيرات 2018 طابش خيراتب :ةحصلا ةرازو يف يموكحلا ةيودلأا لجس يف ءاودلا لجس مقر

132-17-31000

.ركذملا ةغيصب ةرشنلا هذه ةغايص تمت ،ةءارقلا نيوهتو ةلوهس لجأ نم .نيسنجلا لاكل صصخم ءاودلا نإف ،كلذ نم مغرلا ىلع ةمتت

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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 the 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 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 recommended dose of rasagiline is 1 mg (one tablet of AZILECT) once daily, 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 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 AZILECT in children and adolescents have not been established. There is no

relevant use of AZILECT in the paediatric population in the indication Parkinson’s disease.

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Method of administration

For oral use.

AZILECT 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)

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.

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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 should be stopped (see

section

5.2).

4.5

Interaction with other medicinal products and other forms of interaction

MAO Inhibitors

Rasagiline is contraindicated 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.

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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 (see section 5.3).

Levodopa and other Parkinson’s disease medicinal products

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

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

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

Tyramine/rasagiline interaction

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

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Fertility

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

rasagiline has no effect on fertility.

4.7

Effects on ability to drive and use machines

In patients experiencing somnolence/sudden sleep episodes, rasagiline may have major influence on 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 medicinal products, 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) (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:

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

hypotension, fall, abdominal pain, nausea and vomiting, and dry mouth in adjunct to levodopa therapy;

musculoskeletal pain, as back and neck pain, and arthralgia in both regimens. These adverse 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.

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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

nutrition

disorders

Decreased 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

and

administration site

conditions

Fever,

Malaise

*See section description of selected adverse reactions

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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

disorders

Hallucinations*,

Abnormal dreams

Confusion

Impulse control

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

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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. The following were

reported during post-marketing exposure 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 cases 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, 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 medicinal products, 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 medicinal products, 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).

In the post-marketing period, 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.

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. Any suspected adverse events

should be reported to the Ministry of Health according to the National Regulation by using an online

form:

https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh

.gov.il

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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).

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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

) in approximately 0.5 hours.

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

Food does not affect the T

of 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.

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Linearity/non-linearity

Rasagiline pharmacokinetics is 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 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

Mannitol

Starch

Pregelatinised starch

Stearic acid

Talc

colloidal silicon dioxide

6.2

Incompatibilities

Not applicable.

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6.3

Shelf life

The expiry date of the product is indicated on the packaging materials

6.4

Special precautions for storage

Store in a cool place not above 25ºC.

Store in the original package.

6.5

Nature and contents of container

Blisters

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

Aluminium/aluminium perforated unit dose blister packs of 10 x 1, 30 x 1 and 100 x 1 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 for disposal.

7.

MARKETING AUTHORISATION HOLDER

Teva Pharmaceutical Industries Ltd.,

P. O. Box 3190,

Petach Tikva 49131.

8.

REGISTRATION NUMBERS:

132 17 31000

The content of this leaflet was approved by the Ministry of Health in 06.2014 and updated according to

the guidelines of the Ministry of Health in 02.2018