SIFROL ER 0.375 mg

Israel - English - Ministry of Health

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Active ingredient:
PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE
Available from:
BOEHRINGER INGELHEIM ISRAEL LTD.
ATC code:
N04BC05
Pharmaceutical form:
TABLETS EXTENDED RELEASE
Composition:
PRAMIPEXOLE DIHYDROCHLORIDE MONOHYDRATE 0.375 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG, GERMANY
Therapeutic group:
PRAMIPEXOLE
Therapeutic area:
PRAMIPEXOLE
Therapeutic indications:
Treatment of signs and symptoms of idiopathic Parkinson's disease, as monotherapy or in combination with levodopa.
Authorization number:
144 95 33088 00
Authorization date:
2015-11-30

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

26-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

15-06-2020

Sifrol ER

Updated Patient Information Leaflet

0.375,0.75,1.5 mg

April 2020

Patient leaflet in accordance with the Pharmacists' Regulations (preparations) - 1986

This medicine is to be supplied upon physician’s prescription only

Sifrol

®

ER 0.375

Sifrol

®

ER 0.75

Sifrol

®

ER 1.5

Extended-release tablets

Each tablet of Sifrol ER 0.375 contains pramipexole dihydrochloride monohydrate 0.375 mg

Each tablet of Sifrol ER 0.75 contains pramipexole dihydrochloride monohydrate 0.75 mg

Each tablet of Sifrol ER 1.5 contains pramipexole dihydrochloride monohydrate 1.5 mg

*For the list of inactive ingredients and allergens in the medicine - see section 6, "Additional information".

Read the entire leaflet carefully before using this medicine. This leaflet contains essential information about

this medicine. If you have any further questions, refer to the physician or the pharmacist.

This medicine has been prescribed for your treatment. 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 this medicine intended for?

This medicine is indicated for the treatment of the signs and symptoms of Parkinson's disease (alone or

combination with levodopa).

Therapeutic group: medicines that activate the dopamine receptor (dopaminergic medicines).

2.

Before using this medicine

Do not use this medicine if:

You are sensitive (allergic) to the active ingredient or to any of the other ingredients that this medicine

contains (for the list of inactive ingredients, see section 6).

You are breastfeeding.

Special warnings regarding the use of the medicine

Before taking Sifrol ER, tell your physician if you have (had) or if you develop any symptoms or medical

conditions, especially any of the following:

Kidney disease.

Hallucinations (seeing, hearing or feeling things that are not there). Most hallucinations are visual.

You suffer from dyskinesia (e.g. abnormal, uncontrolled movements of the limbs). If you have advanced

Parkinson’s disease and are taking levodopa, you might develop dyskinesia during the up-titration of Sifrol

You experience difficulty keeping your body and neck straight and upright (dystonia). In particular, you may

experience forward bending of the head and neck, the lower back, or sideward bending of the back.

Sleepiness and episodes of suddenly falling asleep.

Psychosis (comparable with symptoms of schizophrenia).

Vision impairment. You should have regular eye examinations during treatment with Sifrol ER.

Severe heart or blood vessels disease. You will need to monitor your blood pressure regularly, especially at

the beginning of treatment. This is to avoid postural hypotension (a fall in blood pressure on standing up).

Tell your physician if you or your family notices that you are developing urges or cravings to behave in ways that

are unusual for you and you cannot resist the impulse or temptation to carry out certain activities that could harm

yourself or others. These are called impulse control disorders and can include behaviors such as addictive

gambling, excessive eating, spending, an abnormally high sex drive or preoccupation with an increase in sexual

thoughts. Your physician may need to adjust or stop your dose

Also, tell your physician if you or your family notices that you are developing mania (agitation, feeling extremely

elated and over-excited) or delirium (decreased awareness, confusion, loss of contact with reality). Your

physician may need to adjust or stop your dose.

Tell your physician if you experience symptoms such as depression, apathy, anxiety, fatigue, sweating or pain

after stopping or reducing your Sifrol ER dose. If the symptoms persist more than a few weeks, your physician

may need to adjust your dose.

Sifrol ER

Updated Patient Information Leaflet

0.375,0.75,1.5 mg

April 2020

Sifrol ER tablets is a specially designed tablet from which the active ingredient is gradually released, once the

tablet has been ingested. Parts of the tablets may show up in your stool and may even look like whole tablets.

Tell your physician if you notice tablet pieces in your stool (faeces).

Tell your physician if you develop difficulty keeping your body and neck straight and upright. Your physician may

need to adjust your dose or change your treatment.

Children and adolescents

Sifrol ER is not intended for use in children and adolescents under the age of 18.

Tests and follow-up

Use of the medicine may cause blurred vision. You should have regular eye examinations during treatment with

Sifrol ER. You will also need to have your blood pressure checked regularly, especially at the beginning of

treatment (see section 2 "Special warnings regarding the use of the medicine").

Other medicines and Sifrol ER

If you are taking or have recently taken other medicines, including non-prescription medicines and food

supplements, tell the physician or the pharmacist. Particularly if you are taking:

Cimetidine (to treat excess stomach acid and stomach ulcers).

Amantadine (to treat Parkinson’s disease).

Mexiletine (to treat irregular heartbeats - a condition known as ventricular arrhythmia).

Zidovudine (to treat the acquired immune deficiency syndrome, AIDS/HIV).

Cisplatin (to treat various types of cancers).

Quinidine (used for the prevention of painful night-time leg cramps and for the treatment of a type of malaria

known as falciparum malaria).

Procainamide (to treat irregular heart beat).

Do not take Sifrol ER together with antipsychotic medicines.

If you are taking levodopa - the dose of levodopa is recommended to be reduced before you start treatment with

Sifrol ER.

Take care if you are using any medicines that calm you down (have a sedative effect) or if you are drinking

alcohol. In these cases this medicine may affect your ability to drive and operate machinery.

Using the medicine and food

Sifrol ER can be taken with or without food.

Using the medicine and alcohol consumption

You should be cautious while drinking alcohol during treatment with this medicine.

Pregnancy, breastfeeding, and fertility

If you are pregnant, think you may be pregnant, planning to have a baby or are breastfeeding, you should consult

a physician before starting to take this medicine. Your physician will discuss with you if you should continue to

take Sifrol ER.

The effect of Sifrol ER on the unborn child is not known. Therefore, do not take this medicine unless your

physician tells you to do so.

Do not use this medicine during breast-feeding. Sifrol ER can reduce the production of breast milk. Also, the

medicine can pass into the breast milk and can reach the breast-fed child. If use of Sifrol ER is unavoidable,

breast-feeding should be stopped.

Driving and using machines

The medicine can cause hallucinations (hearing, seeing or feeling things that are not there). If affected by the

medicine in this manner, do not drive or use dangerous machines.

Sifrol ER can cause sleepiness and episodes of suddenly falling asleep, particularly in patients with Parkinson’s

disease. If you experience these side effects, you must not drive or operate dangerous machines. You should tell

your physician if this occurs.

3.

How should you use the medicine?

Always use according to the physician's instructions. You should check with the physician or the pharmacist if you

are not sure about your dose or about how to take this medicine.

The dosage and treatment will be determined only by the physician.

The usually recommended dose is:

Take the medicine once a day,

at about the same time.

You can take Sifrol ER with or without food. Swallow the tablet whole with water.

Sifrol ER

Updated Patient Information Leaflet

0.375,0.75,1.5 mg

April 2020

Do not chew, divide or crush the extended-release tablets. Chewing/crushing or dividing the tablet may cause an

overdose, because the medicine may be released into your body too quickly.

During the first week, the usual daily dose is 0.375 mg Sifrol ER. The dose will be increased every 5-7 days as

directed by your doctor until your symptoms are controlled (maintenance dose).

Ascending dose schedule of Sifrol ER

Week

Dose (mg)

Number of tablets

0.375

one Sifrol ER

0.375

mg tablet

0.75

one Sifrol

ER 0.75

mg tablet

two Sifrol

0.375

mg tablets

one Sifrol ER 1.5 mg tablet

four Sifrol ER

0.375

mg tablets

The usual maintenance dose is 1.5 mg per day. However, your dose may have to be increased even further. If

necessary, your dose may be increased up to a maximum of 4.5 mg of pramipexole (the active ingredient) a day.

A lower maintenance dose of 0.375 mg a day is also possible.

Patients with kidney disease:

If you have kidney disease, your doctor may advise you to take the usual starting dose of 0.375 mg Sifrol ER only

every other day for the first week. After that, your doctor may increase the dosing frequency to one 0.375 mg

Sifrol ER tablet every day. If a further dose increase is necessary, your doctor will adjust it in increments of 0.375

mg pramipexole (the active ingredient) at a time.

If you have serious kidney problems, your physician may need to switch you to a different pramipexole medicine.

If during treatment your kidney problems get worse, you should contact your physician as soon as possible.

If you are switching from Sifrol immediate release tablets - Your physician will base your dose of Sifrol ER

extended-release tablets on the dose of Sifrol immediate release tablets you were taking.

Take your Sifrol (immediate release) tablets as normal the day before you switch. Then take your Sifrol ER

extended-release tablets next morning. Do not take any more Sifrol (immediate release) tablets.

Do not exceed the recommended dose.

If you have accidentally taken a higher dose or if a child has accidentally swallowed the medicine, go

immediately to a physician or a hospital emergency room and bring the medicine package with you.

Taking an overdose may cause vomiting, restlessness, or any of the side effects as described in section 4, Side

effects section.

If you forget to take the medicine at the scheduled time, but remember within 12 hours of your usual time,

take your tablet straightaway and then take your next tablet at the usual time.

If you forget for more than 12

hours, skip the forgotten dose and take the next dose at the usual time.

Do not take a double dose to make up for a forgotten tablet dose.

Persist with the treatment as recommended by the physician.

Even if there is an improvement in your health, do not stop treatment with this medicine without consulting the

physician. If you have to stop taking this medicine, your physician will reduce the dose gradually to reduce the

risk of worsening symptoms.

If you stop taking the medicine

Do not stop taking Sifrol ER without first talking to your physician. If you have to stop taking this medicine, your

physician will reduce the dose gradually. This reduces the risk of worsening symptoms.

Sifrol ER

Updated Patient Information Leaflet

0.375,0.75,1.5 mg

April 2020

If you suffer from Parkinson’s disease you should not stop treatment with this medicine abruptly. A sudden stop

could cause to a

severe medical condition called neuroleptic malignant syndrome. The symptoms of the

syndrome include: akinesia (loss of muscle movement), rigid muscles, fever, unstable blood pressure,

tachycardia (increased heart rate), confusion,

depressed level of consciousness (e.g. coma).

If you stop or reduce your Sifrol ER dose you may develop a medical condition called dopamine agonist

withdrawal syndrome (

DAWS)

. The symptoms include depression, apathy, anxiety, fatigue, sweating or pain. If

you experience these symptoms you should contact your physician.

Do not take medicines in the dark! Check the label and the dose each time you take the medicine. Wear

glasses if you need them.

If you have any further questions regarding the use of this medicine, consult the physician or the

pharmacist.

4.

Side Effects

As with any medicine, use of Sifrol ER may cause side effects in some users. Do not be alarmed by reading the

list of side effects. You may not experience any of them.

Very common side effects: may affect more than 1 in 10 users:

Movement disorders - Dyskinesia (e.g. abnormal, uncontrolled movements of the limbs).

Sleepiness.

Dizziness.

Nausea (sickness).

Common side effects: may affect up to 1 in 10 users:

Urge to behave in an unusual way.

Hallucinations (hearing, seeing or feeling things that are not there).

Confusion.

Tiredness (fatigue).

Sleeplessness (insomnia).

Excess of fluid, usually in the legs (peripheral oedema).

Headache.

Hypotension (low blood pressure).

Abnormal dreams.

Constipation.

Visual impairment.

Vomiting (being sick).

Weight loss including decreased appetite.

Uncommon side effects: may affect up to 1 in 100 users:

Paranoia.

Delusion.

Excessive daytime sleepiness or suddenly falling asleep.

Memory disturbance.

Increased movements and inability to keep still (hyperkinesia).

Weight increase.

Allergic reactions (e.g. rash, itching, hypersensitivity).

Fainting.

*Cardiac failure (heart problems which can cause shortness of breath or ankle swelling).

*Syndrome of inappropriate antidiuretic hormone (ADH) secretion.

Restlessness.

Difficulties to breathe (Dyspnoea).

Hiccups.

Pneumonia (infection of the lungs).

Inability to resist the impulse to perform an action that could be harmful to you or others, which may include:

Strong impulse to gamble excessively despite serious personal or family consequences.

Altered or increased sexual interest and behavior of significant concern to you or to others, for example,

an increased sexual drive.

Uncontrollable excessive shopping or spending.

*Binge eating (eating large amounts of food in a short time period) or compulsive eating (eating more

food than normal and more than is needed to satisfy your hunger).

Delirium (decreased awareness, confusion, loss of reality).

Sifrol ER

Updated Patient Information Leaflet

0.375,0.75,1.5 mg

April 2020

Rare side effects: may affect up to 1 in 1,000 users:

Mania (agitation, feeling extremely elated or over-excited).

Side effects with unknown frequency (the frequency of these effects has not been established yet):

After stopping or reducing your Sifrol ER treatment: Depression, apathy, anxiety, fatigue, sweating or pain

may occur (also known as dopamine agonist withdrawal syndrome or DAWS).

* The precise frequency is not known, since these side effects were not observed in clinical studies among 2,762

patients treated with pramipexole. The frequency category for these side effects is probably not greater than

“uncommon side effects".

If a side effect occurs, if any of the side effects gets worse, or if you suffer from a side effect not

mentioned in the leaflet, you should consult your physician.

Side effects can be reported to the Ministry of Health (MoH) by clicking on the "Report on side effects due to

medication therapy" link on the MoH home page (www.health.gov.il

) which refers to the online form for side

effects reporting, or by entering the link:

https://sideeffects.health.gov.il

5.

How to store the medicine?

Avoid poisoning! This medicine and any other medicine should be kept in a closed place out of the reach

and sight of children and/or infants in order to avoid poisoning. Do not induce vomiting without an explicit

instruction from your physician.

Do not use the medicine after the expiration date (exp. date) that appears on the box. The expiration date

refers to the last day of that month.

Storage conditions: Store in the original package to protect from moisture. Store below 25°C.

Do not discard the medicine to the wastewater or household waste. Consult the pharmacist about how to

throw away medicines you no longer use. These measures will help in environmental protection.

6.

Additional information

In addition to the active ingredient the medicine also contains –

maize starch, hypromellose 2208, carbomer 941, silica colloidal

anhydrous, magnesium stearate.

What does the medicine look like and what is the content of the package -

Sifrol ER 0.375 and Sifrol ER 0.75 are white to off-white tablets of round shape, convex on both sides.

side is debossed with the Boehringer Ingelheim company symbol, "BI"; and the other side is debossed with

"P1" (Sifrol ER 0.375) and "P2" (Sifrol ER 0.75).

Sifrol ER 1.5 are white to off-white tablets of oval shape, convex on both sides. One side is debossed with

the Boehringer Ingelheim company symbol, "BI"; and the other side is debossed with "P3".

The tablets are packed in blister strip. Each package containing 10 or 30 Extended-release tablets. Not all

pack sizes may be marketed.

Registration holder: Boehringer Ingelheim Israel Ltd., 89 Medinat Ha-Yehudim, P.O.B. 4124, Hertzliya-

Pituach 4676672.

Manufacturer name: Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.

This leaflet was revised in April 2020.

Registration number of the medicine in the National Drug Registry of the Ministry of Health:

Sifrol ER 0.375 - 144-95-33088-00

Sifrol ER 0.75 -

33089

Sifrol ER 1.5 -

33090

Sifrol ER

Updated Prescribing Information

0.375,0.75,1.5 mg

April 2020

Product Information

Sifrol ER

Pramipexole

Extended-release tablets

1.

NAME OF THE MEDICINAL PRODUCT

SIFROL ER 0.375 mg extended-release tablets

SIFROL ER 0.75 mg extended-release tablets

SIFROL ER 1.5 mg extended-release tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Sifrol ER 0.375 extended-release tablet contains 0.375 mg pramipexole dihydrochloride

monohydrate equivalent to 0.26 mg pramipexole.

Each Sifrol ER 0.75 extended-release tablet contains 0.75 mg pramipexole dihydrochloride

monohydrate equivalent to 0.52 mg pramipexole.

Each Sifrol ER 1.5 extended-release tablet contains 1.5 mg pramipexole dihydrochloride monohydrate

equivalent to 1.05 mg pramipexole.

Please note:

Pramipexole doses as published in the literature refer to the salt form.

Therefore, doses will be expressed in terms of both pramipexole base and pramipexole salt (in

brackets).

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Extended-release tablets.

The tablets are white to off-white and have a code embossed.

Strength (mg salt)

Appearance

Sifrol ER 0.375

round, with bevelled edges, code embossed (one side with code P1 and one

side with the Boehringer Ingelheim company symbol).

Sifrol ER 0.75

round, with bevelled edges, code embossed (one side with code P2 and one

side with the Boehringer Ingelheim company symbol).

Sifrol ER 1.5

oval, code embossed (one side with code P3 and one side with the Boehringer

Ingelheim company symbol).

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

SIFROL is indicated for treatment of signs and symptoms of idiopathic Parkinson’s disease, as

monotherapy or in combination with levodopa.

Sifrol ER

Updated Prescribing Information

0.375,0.75,1.5 mg

April 2020

4.2

Posology and method of administration

Posology

SIFROL extended-release tablets are a once-a-day oral formulation of pramipexole.

Initial treatment

Doses should be increased gradually from a starting dose of 0.375 mg of salt (0.26 mg of base) per day

and then increased every 5 - 7 days. Providing patients do not experience intolerable undesirable

effects, the dose should be titrated to achieve a maximal therapeutic effect.

Ascending dose schedule of SIFROL extended-release tablets

Week

Daily dose (mg of salt)

Daily dose (mg of base)

0.375

0.26

0.75

0.52

1.05

If a further dose increase is necessary the daily dose should be increased by 0.75 mg of salt (0.52 mg

of base) at weekly intervals up to a maximum dose of 4.5 mg of salt (3.15 mg of base) per day.

However, it should be noted that the incidence of somnolence is increased at doses higher than 1.5 mg

of salt (1.05 mg of base) per day (see section 4.8).

Patients already taking SIFROL tablets may be switched to SIFROL extended-release tablets

overnight, at the same daily dose. After switching to SIFROL extended-release tablets, the dose may

be adjusted depending on the patient’s therapeutic response (see section 5.1).

Maintenance treatment

The individual dose of pramipexole should be in the range of 0.375 mg of salt (0.26 mg of base) to a

maximum of 4.5 mg of salt (3.15 mg of base) per day. During dose escalation in pivotal studies,

efficacy was observed starting at a daily dose of 1.5 mg of salt (1.05 mg of base). Further dose

adjustments should be done based on the clinical response and the occurrence of adverse reactions. In

clinical trials approximately 5% of patients were treated at doses below 1.5 mg of salt (1.05 mg of

base). In advanced Parkinson’s disease, pramipexole doses higher than 1.5 mg of salt (1.05 mg of

base) per day can be useful in patients where a reduction of the levodopa therapy is intended. It is

recommended that the dose of levodopa is reduced during both the dose escalation and the

maintenance treatment with SIFROL, depending on reactions in individual patients (see section 4.5).

Missed dose

When the intake of a dose is missed, SIFROL extended-release tablets should be taken within 12

hours after the regularly scheduled time. After 12 hours, the missed dose should be left out and the

next dose should be taken on the following day at the next regularly scheduled time.

Treatment discontinuation

Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic

malignant syndrome or a dopamine agonist withdrawal syndrome. Pramipexole should be tapered off

at a rate of 0.75 mg of salt (0.52 mg of base) per day until the daily dose has been reduced to 0.75 mg

of salt (0.52 mg of base). Thereafter the dose should be reduced by 0.375 mg of salt (0.26 mg of base)

per day (see section 4.4). Dopamine agonist withdrawal syndrome could still appear while tapering

and a temporary increase of the dose could be necessary before resuming tapering (see section 4.4)

Renal impairment

The elimination of pramipexole is dependent on renal function. The following dose schedule is

suggested:

Sifrol ER

Updated Prescribing Information

0.375,0.75,1.5 mg

April 2020

Patients with a creatinine clearance above 50 ml/min require no reduction in daily dose or dosing

frequency.

In patients with a creatinine clearance between 30 and 50 ml/min, treatment should be started with

0.375 mg SIFROL extended-release tablets every other day. Caution should be exercised and careful

assessment of therapeutic response and tolerability should be made before increasing to daily dosing

after one week. If a further dose increase is necessary, doses should be increased by 0.375 mg

pramipexole salt at weekly intervals up to a maximum dose of 2.25 mg of salt (1.57 mg pramipexole

base) per day.

The treatment of patients with a creatinine clearance below 30 ml/min with SIFROL extended-release

tablets is not recommended as no data are available for this patient population. The use of SIFROL

tablets should be considered.

If renal function declines during maintenance therapy, the recommendations given above should be

followed.

Hhepatic impairment

Dose adjustment in patients with hepatic failure is probably not necessary, as approx. 90% of absorbed

active substance is excreted through the kidneys. However, the potential influence of hepatic

insufficiency on SIFROL pharmacokinetics has not been investigated.

Paediatric population

The safety and efficacy of SIFROL in children below 18 years has not been established. There is no

relevant use of SIFROL extended-release tablets in the paediatric population in Parkinson’s Disease.

Method of administration

The tablets should be swallowed whole with water, and must not be chewed, divided or crushed. The

tablets may be taken either with or without food and should be taken each day at about the same time.

4.3

Contraindications

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

4.4

Special warnings and precautions for use

When prescribing SIFROL in a patient with Parkinson’s disease with renal impairment a reduced dose

is suggested in line with section 4.2.

Hallucinations

Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients

should be informed that (mostly visual) hallucinations can occur.

Dyskinesia

In advanced Parkinson’s disease, in combination treatment with levodopa, dyskinesia can occur during

the initial titration of SIFROL. If they occur, the dose of levodopa should be decreased.

Dystonia

Axial dystonia including antecollis, camptocormia and pleurothotonus (Pisa Syndrome) has

occasionally been reported in patients with Parkinson’s disease following initiation or incremental

dose increase of pramipexole. Although dystonia may be a symptom of Parkinson’s disease, the

symptoms in these patients have improved after reduction or withdrawal of pramipexole. If dystonia

occurs, the dopaminergic medication regimen should be reviewed and an adjustment in the dose of

pramipexole considered.

Sifrol ER

Updated Prescribing Information

0.375,0.75,1.5 mg

April 2020

Sudden onset of sleep and somnolence

Pramipexole has been associated with somnolence and episodes of sudden sleep onset, particularly in

patients with Parkinson’s disease. Sudden onset of sleep during daily activities, in some cases without

awareness or warning signs, has been reported uncommonly. Patients must be informed of this and

advised to exercise caution while driving or operating machines during treatment with SIFROL.

Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from

driving or operating machines. Furthermore a reduction of the dose or termination of therapy may be

considered. Because of possible additive effects, caution should be advised when patients are taking

other sedating medicinal products or alcohol in combination with pramipexole (see sections 4.5, 4.7

and section 4.8).

Impulse control disorders

Patients should be regularly monitored for the development of impulse control disorders. Patients and

carers should be made aware that behavioural symptoms of impulse control disorders including

pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating

and compulsive eating can occur in patients treated with dopamine agonists including SIFROL. Dose

reduction/tapered discontinuation should be considered if such symptoms develop.

Mania and delirium

Patients should be regularly monitored for the development of mania and delirium. Patients and carers

should be made aware that mania and delirium can occur in patients treated with pramipexole. Dose

reduction/tapered discontinuation should be considered if such symptoms develop.

Patients with psychotic disorders

Patients with psychotic disorders should only be treated with dopamine agonists if the potential

benefits outweigh the risks. Co-administration of antipsychotic medicinal products with pramipexole

should be avoided (see section 4.5).

Ophthalmologic monitoring

Ophthalmologic monitoring is recommended at regular intervals or if vision abnormalities occur.

Severe cardiovascular disease

In case of severe cardiovascular disease, care should be taken. It is recommended to monitor blood

pressure, especially at the beginning of treatment, due to the general risk of postural hypotension

associated with dopaminergic therapy.

Neuroleptic malignant syndrome

Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal

of dopaminergic therapy (see section 4.2).

Dopamine agonist withdrawal syndrome (DAWS)

DAWS has been reported with dopamine agonists, including pramipexole (see section 4.8). To

discontinue treatment in patients with Parkinson’s disease, pramipexole should be tapered off (see

section 4.2). Limited data suggests that patients with impulse control disorders and those receiving

high daily dose and/or high cumulative doses of dopamine agonists may be at higher risk for

developing DAWS. Withdrawal symptoms may include apathy, anxiety, depression, fatigue, sweating

and pain and do not respond to levodopa. Prior to tapering off and discontinuing pramipexole, patients

should be informed about potential withdrawal symptoms. Patients should be closely monitored during

tapering and discontinuation. In case of severe and/or persistent withdrawal symptoms, temporary re-

administration of pramipexole at the lowest effective dose may be considered.

Sifrol ER

Updated Prescribing Information

0.375,0.75,1.5 mg

April 2020

Remnants in stool

Some patients have reported the occurrence of remnants in faeces which may resemble intact SIFROL

extended-release tablets. If patients report such an observation, the physician should reassess patient’s

response to therapy.

4.5

Interaction with other medicinal products and other forms of interaction

Plasma protein binding

Pramipexole is bound to plasma proteins to a very low (< 20%) extent, and little biotransformation is

seen in man. Therefore, interactions with other medicinal products affecting plasma protein binding or

elimination by biotransformation are unlikely. As anticholinergics are mainly eliminated by

biotransformation, the potential for an interaction is limited, although an interaction with

anticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline and

levodopa.

Inhibitors/competitors of active renal elimination pathway

Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by

inhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal products

that are inhibitors of this active renal elimination pathway or are eliminated by this pathway, such as

cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine, and procainamide, may interact

with pramipexole resulting in reduced clearance of pramipexole. Reduction of the pramipexole dose

should be considered when these medicinal products are administered concomitantly with SIFROL.

Combination with levodopa

When SIFROL is given in combination with levodopa, it is recommended that the dose of levodopa is

reduced and the dose of other anti-parkinsonian medicinal products is kept constant while increasing

the dose of SIFROL.

Because of possible additive effects, caution should be advised when patients are taking other sedating

medicinal products or alcohol in combination with pramipexole (see sections 4.4, 4.7 and 4.8).

Antipsychotic medicinal products

Co-administration of antipsychotic medicinal products with pramipexole should be avoided (see

section 4.4), e.g. if antagonistic effects can be expected.

4.6

Fertility, pregnancy and lactation

Pregnancy

The effect on pregnancy and lactation has not been investigated in humans. Pramipexole was not

teratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses (see section 5.3).

SIFROL should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit

justifies the potential risk to the foetus.

Breast-feeding

As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected.

The excretion of pramipexole into breast milk has not been studied in women. In rats, the

concentration of active substance-related radioactivity was higher in breast milk than in plasma.

In the absence of human data, SIFROL should not be used during breast-feeding. However, if its use is

unavoidable, breast-feeding should be discontinued.

Fertility

No studies on the effect on human fertility have been conducted. In animal studies, pramipexole

affected oestrous cycles and reduced female fertility as expected for a dopamine agonist. However,

these studies did not indicate direct or indirect harmful effects with respect to male fertility.

Sifrol ER

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4.7

Effects on ability to drive and use machines

SIFROL can have a major influence on the ability to drive and use machines.

Hallucinations or somnolence can occur.

Patients being treated with SIFROL 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 such recurrent

episodes and somnolence have resolved (see also sections 4.4, 4.5 and 4.8).

4.8

Undesirable effects

Based on the analysis of pooled placebo-controlled trials, comprising a total of 1,778 Parkinson’s

disease patients on pramipexole and 1,297 patients on placebo, adverse drug reactions were frequently

reported for both groups. 67% of patients on pramipexole and 54% of patients on placebo reported at

least one adverse drug reaction.

The majority of adverse drug reactions usually start early in therapy and most tend to disappear even

as therapy is continued.

Within the system organ classes, adverse reactions are listed under headings of frequency (number of

patients expected to experience the reaction), using the following categories: 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).

The most commonly (≥ 5%) reported adverse drug reactions in patients with Parkinson’s disease more

frequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension,

dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence of

somnolence is increased at doses higher than 1.5 mg pramipexole salt per day (see section 4.2). A

more frequent adverse drug reaction in combination with levodopa was dyskinesia. Hypotension may

occur at the beginning of treatment, especially if pramipexole is titrated too fast.

Body System

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)

Not known

Infections and

infestations

pneumonia

Endocrine

disorders

inappropriate

antidiuretic

hormone

secretion

Psychiatric

disorders

Insomnia,

Hallucinations,

abnormal

dreams,

confusion

behavioural

symptoms of

impulse control

disorders and

compulsive

shopping,

pathological

gambling,

restlessness,

hypersexuality,

delusion,

libido disorder,

paranoia,

delirium,

mania

Sifrol ER

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0.375,0.75,1.5 mg

April 2020

compulsions

binge eating

hyperphagia

Nervous system

disorders

somnolence

dizziness

dyskinesia

headache

sudden onset of

sleep,

amnesia,

hyperkinesia,

syncope

Eye disorders

visual

impairment

including

diplopia,

vision blurred,

visual acuity

reduced

Cardiac

disorders

cardiac failure

Vascular

disorders

hypotension

Respiratory,

thoracic, and

mediastinal

disorders

Dyspnoea,

Hiccups

Gastrointestinal

disorders

nausea

Constipation,

vomiting

Skin and

subcutaneous

tissue disorders

Hypersensitivity,

Pruritus,

rash

General

disorders and

administration

site conditions

Fatigue,

peripheral

oedema

Dopamine

agonist

withdrawal

syndrome

including

apathy,

anxiety,

depression,

fatigue,

sweating

and pain.

Investigations

weight decrease

including

decreased

appetite

weight increase

Urinary

retention

1 This side effect has been observed in post-marketing experience. With 95 % certainty, the frequency

category is not greater than uncommon, but might be lower. A precise frequency estimation is not

possible as the side effect did not occur in a clinical trial database of 2,762 patients with Parkinson’s

Disease treated with pramipexole.

Description of selected adverse reactions

Somnolence

Pramipexole is commonly associated with somnolence and has been associated uncommonly with

excessive daytime somnolence and sudden sleep onset episodes (see also section 4.4).

Libido disorders

Pramipexole may uncommonly be associated with libido disorders (increased or decreased).

Sifrol ER

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Impulse control disorders

Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating

and compulsive eating can occur in patients treated with dopamine agonists including SIFROL (see

section 4.4).

In a cross-sectional, retrospective screening and case-control study including 3,090 Parkinson’s

disease patients, 13.6% of all patients receiving dopaminergic or non-dopaminergic treatment had

symptoms of an impulse control disorder during the past six months. Manifestations observed include

pathological gambling, compulsive shopping, binge eating, and compulsive sexual behaviour

(hypersexuality). Possible independent risk factors for impulse control disorders included

dopaminergic treatments and higher doses of dopaminergic treatment, younger age ( ≤ 65 years), not

being married and self-reported family history of gambling behaviours.

Dopamine agonist withdrawal syndrome

Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including

pramipexole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain (see section

4.4).

Cardiac failure

In clinical studies and post-marketing experience cardiac failure has been reported in patients with

pramipexole. In a pharmacoepidemiological study pramipexole use was associated with an increased

risk of cardiac failure compared with non-use of pramipexole (observed risk ratio 1.86; 95% CI, 1.21-

2.85).

You can report side effects to the Ministry of Health by following the link ‘Reporting Side Effects of Drug

Treatment' on the Ministry of Health home page (www.health.gov.il) which links to an online form for reporting

side effects. You can also use this link:

https://sideeffects.health.gov.il

4.9

Overdose

There is no clinical experience with massive overdose. The expected adverse reactions would be those

related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting,

hyperkinesia, hallucinations, agitation and hypotension. There is no established antidote for overdose

of a dopamine agonist. If signs of central nervous system stimulation are present, a neuroleptic agent

may be indicated. Management of the overdose may require general supportive measures, along with

gastric lavage, intravenous fluids, administration of activated charcoal and electrocardiogram

monitoring.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: anti-Parkinson drugs, dopamine agonists, ATC code: N04BC05.

Mechanism of action

Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily

of dopamine receptors of which it has a preferential affinity to D3 receptors, and has full intrinsic

activity.

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Pramipexole alleviates parkinsonian motor deficits by stimulation of dopamine receptors in the

striatum. Animal studies have shown that pramipexole inhibits dopamine synthesis, release, and

turnover.

Pharmacodynamic effects

In human volunteers, a dose-dependent decrease in prolactin was observed. In a clinical trial with

healthy volunteers, where SIFROL extended-release tablets were titrated faster (every 3 days) than

recommended up to 3.15 mg pramipexole base (4.5 mg of salt) per day, an increase in blood pressure

and heart rate was observed. Such effect was not observed in patient studies.

Clinical efficacy and safety in Parkinson’s disease

In patients pramipexole alleviates signs and symptoms of idiopathic Parkinson’s disease. Placebo-

controlled clinical trials included approximately 1,800 patients of Hoehn and Yahr stages I – V treated

with pramipexole. Out of these, approximately 1,000 were in more advanced stages, received

concomitant levodopa therapy, and suffered from motor complications.

In early and advanced Parkinson’s disease, efficacy of pramipexole in controlled clinical trials was

maintained for approximately six months. In open continuation trials lasting for more than three years

there were no signs of decreasing efficacy.

In a controlled double blind clinical trial of 2 year duration, initial treatment with pramipexole

significantly delayed the onset of motor complications, and reduced their occurrence compared to

initial treatment with levodopa. This delay in motor complications with pramipexole should be

balanced against a greater improvement in motor function with levodopa (as measured by the mean

change in UPDRS-score). The overall incidence of hallucinations and somnolence was generally

higher in the escalation phase with the pramipexole group. However, there was no significant

difference during the maintenance phase. These points should be considered when initiating

pramipexole treatment in patients with Parkinson’s disease.

The safety and efficacy of SIFROL extended-release tablets in the treatment of Parkinson's disease

was evaluated in a multinational drug development program consisting of three randomized,

controlled trials. Two trials were conducted in patients with early Parkinson's disease and one trial was

conducted in patients with advanced Parkinson's disease.

Superiority of SIFROL extended-release tablets over placebo was demonstrated after 18 weeks of

treatment on both the primary (UPDRS Parts II+III score) and the key secondary (CGI-I and PGI-I

responder rates) efficacy endpoints in a double-blind placebo-controlled trial including a total of 539

patients with early Parkinson’s disease. Maintenance of efficacy was shown in patients treated for

33 weeks. SIFROL extended-release tablets were non-inferior to pramipexole immediate release

tablets as assessed on the UPDRS Parts II+III score at week 33.

In a double-blind placebo-controlled trial including a total of 517 patients with advanced Parkinson’s

disease who were on concomitant levodopa therapy superiority of SIFROL extended-release tablets

over placebo was demonstrated after 18 weeks of treatment on both the primary (UPDRS Parts II+III

score) and the key secondary (off-time) efficacy endpoints.

The efficacy and tolerability of an overnight switch from SIFROL tablets to SIFROL extended-release

tablets at the same daily dose were evaluated in a double-blind clinical study in patients with early

Parkinson’s disease.

Efficacy was maintained in 87 of 103 patients switched to SIFROL extended-release tablets. Out of

these 87 patients, 82.8% did not change their dose, 13.8% increased and 3.4% decreased their dose.

In half of the 16 patients who did not meet the criterion for maintained efficacy on UPDRS Part II+III

score, the change from baseline was considered not clinically relevant.

Only one patient switched to SIFROL extended-release tablets experienced a drug-related adverse

event leading to withdrawal.

Sifrol ER

Updated Prescribing Information

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5.2

Pharmacokinetic properties

Absorption

Pramipexole is completely absorbed following oral administration. The absolute bioavailability is

greater than 90%.

In a Phase I trial, where pramipexole immediate release and extended-release tablets were assessed in

fasted state, the minimum and peak plasma concentration (C

) and exposure (AUC) of the same

daily dose of SIFROL extended-release tablets given once daily and SIFROL tablets given three times

a day were equivalent.

The once daily administration of SIFROL extended-release tablets causes less frequent fluctuations in

the pramipexole plasma concentration over 24 hours compared to the three times daily administration

of pramipexole immediate release tablets.

The maximum plasma concentrations occur at about 6 hours after administration of SIFROL

extended-release tablets once daily. Steady state of exposure is reached at the latest after 5 days of

continuous dosing.

Concomitant administration with food does generally not affect the bioavailability of pramipexole.

Intake of a high fat meal induced an increase in peak concentration (C

) of about 24% after a single

dose administration and about 20% after multiple dose administrations and a delay of about 2 hours in

time to reach peak concentration in healthy volunteers. Total exposure (AUC) was not affected by

concomitant food intake. The increase in C

is not considered clinically relevant. In the Phase III

studies that established safety and efficacy of SIFROL extended-release tablets, patients were

instructed to take study medication without regard to food intake.

While body weight has no impact on the AUC, it was found to influence the volume of distribution

and therefore the peak concentrations C

. A decreased body weight by 30 kg results in an increase in

of 45%. However, in Phase III trials in Parkinson’s disease patients no clinically meaningful

influence of body weight on the therapeutic effect and tolerability of SIFROL extended-release tablets

was detected.

Pramipexole shows linear kinetics and a small inter-patient variation of plasma levels.

Distribution

In humans, the protein binding of pramipexole is very low (< 20%) and the volume of distribution is

large (400 l). High brain tissue concentrations were observed in the rat (approx. 8-fold compared to

plasma).

Biotransformation

Pramipexole is metabolised in man only to a small extent.

Elimination

Renal excretion of unchanged pramipexole is the major route of elimination. Approximately 90% of

C-labelled dose is excreted through the kidneys while less than 2% is found in the faeces. The total

clearance of pramipexole is approximately 500 ml/min and the renal clearance is approximately

400 ml/min. The elimination half-life (t½) varies from 8 hours in the young to 12 hours in the elderly.

5.3

Preclinical safety data

Repeated dose toxicity studies showed that pramipexole exerted functional effects, mainly involving

the CNS and female reproductive system, and probably resulting from an exaggerated

pharmacodynamic effect of pramipexole.

Sifrol ER

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Decreases in diastolic and systolic pressure and heart rate were noted in the minipig, and a tendency to

a hypotensive effect was discerned in the monkey.

The potential effects of pramipexole on reproductive function have been investigated in rats and

rabbits. Pramipexole was not teratogenic in rats and rabbits but was embryotoxic in the rat at

maternally toxic doses. Due to the selection of animal species and the limited parameters investigated,

the adverse effects of pramipexole on pregnancy and male fertility have not been fully elucidated.

A delay in sexual development (i.e., preputial separation and vaginal opening) was observed in rats.

The relevance for humans is unknown.

Pramipexole was not genotoxic. In a carcinogenicity study, male rats developed Leydig cell

hyperplasia and adenomas, explained by the prolactin-inhibiting effect of pramipexole. This finding is

not clinically relevant to man. The same study also showed that, at doses of 2 mg/kg (of salt) and

higher, pramipexole was associated with retinal degeneration in albino rats. The latter finding was not

observed in pigmented rats, nor in a 2-year albino mouse carcinogenicity study or in any other species

investigated.

6.

PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Maize starch

Hypromellose 2208

Carbomer 941

Colloidal anhydrous silica

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Special precautions for storage

Store below 25

C in the original package in order to protect from moisture.

6.4 Nature and contents of container

Aluminium/PVC-aluminium blisters.

Each blister strip contains 10 extended-release tablets.

Cartons containing 1or 3 blister strips (10 or 30 extended-release tablets).

6.5 Special precautions for disposal

No special requirements.

7. Manufacturer

Boehringer Ingelheim International GmbH

D-55216 Ingelheim am Rhein

Germany

8. Marketing authorisation holder

Boehringer Ingelheim Israel LTD

Medinat Ha-Yehudim 89 St.

P.O. Box 4124

Herzliya Pituach 4676672

Marketing authorisation numbers:

Sifrol ER 0.375 mg

144 95 33088

Sifrol ER

Updated Prescribing Information

0.375,0.75,1.5 mg

April 2020

Sifrol ER 0.75 mg

144 96 33089

Sifrol ER 1.5 mg

144 97 33090

Revised in April 2020

אפורל ןולעב )תוחיטב עדימ( הרמחה לע העדוה אפורל ןולעב )תוחיטב עדימ( הרמחה לע העדוה אפורל ןולעב )תוחיטב עדימ( הרמחה לע העדוה

ןכרצלו ןכרצלו ןכרצלו

ןכדועמ( ןכדועמ( ןכדועמ(

05.2013

05.2013

05.2013

:ךיראת

42

רבמצד

5

402

:תילגנאב רישכת םש

blets 0.375mg,0.75mg,1.5mg

SIFROL ER Ta

:םושיר ירפסמ

33090

-

97

-

33089, 144

-

96

-

33088,144

-

95

-

144

:םושירה לעב םש

Boehringer Ingelheim

לארשי

ונמוסמ תורמחהה עקר לע ת .בוהצ

תושקובמה תורמחהה

אפורל ןולעב

ןולעב קרפ

יחכונ טסקט

שדח טסקט

Special

Warnings

and

Precautions

----

Mania and delirium

Patients should be regularly monitored for the

development of mania and delirium. Patients and

carers should be made aware that mania and

delirium can occur in patients treated with

pramipexole. Dose reduction/tapered

discontinuation should be considered if such

symptoms develop.

Undesirable

Effects

Expected adverse reactions

The following adverse reactions are

expected under the use of SIFROL:

abnormal dreams, amnesia, behavioural

symptoms of impulse control disorders

and compulsions such as binge eating,

compulsive shopping, hypersexuality and

pathological gambling; cardiac failure,

confusion, constipation, delusion,

dizziness, dyskinesia, dyspnoea, fatigue,

hallucinations, headache, hiccups,

hyperkinesia, hyperphagia, hypotension,

inappropriate antidiuretic hormone

secretion, insomnia, libido disorders,

nausea, paranoia, peripheral oedema,

pneumonia, pruritus, rash and other

hypersensitivity; restlessness,

somnolence, sudden onset of sleep,

syncope, visual impairment including

diplopia, vision blurred and visual acuity

reduced, vomiting, weight decrease

including decreased appetite, weight

increase.

....

Psychiatric Disorders:

Uncommon: binge eating1,

compulsive shopping, delusion,

hyperphagia1, hypersexuality, libido

disorder, paranoia, pathological

gambling, restlessness

Expected adverse reactions

The following adverse reactions are expected

under the use of SIFROL: abnormal dreams,

amnesia, behavioural symptoms of impulse

control disorders and compulsions such as binge

eating, compulsive shopping, hypersexuality and

pathological gambling; cardiac failure, confusion,

constipation, delirium, delusion, dizziness,

dyskinesia, dyspnoea, fatigue, hallucinations,

headache, hiccups, hyperkinesia, hyperphagia,

hypotension, inappropriate antidiuretic hormone

secretion, insomnia, libido disorders, mania,

nausea, paranoia, peripheral oedema, pneumonia,

pruritus, rash and other hypersensitivity;

restlessness, somnolence, sudden onset of sleep,

syncope, visual impairment including diplopia,

vision blurred and visual acuity reduced,

vomiting, weight decrease including decreased

appetite, weight increase.

....

Psychiatric Disorders:

Uncommon: binge eating1, compulsive

shopping, delusion, hyperphagia1, hypersexuality,

libido disorder, paranoia, pathological gambling,

restlessness

delirium

Rare: mania

ןכרצל ןולעב תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

קט שדח טס

תורהזא תודחוימ תועגונה שומישל :הפורתב

:דוקפתב יוקילמ רבעב תלבס וא לבוס ךניה םא /הילכה ,םייניעה ,םדה ילכ וא/ו בלה תכרעמ םיבצעה תכרעמ ,ןתשה

וא לבוס ךניה םא וא רבעב תלבס תויטוכיספ תויעבמ ,תויזה ,

םייוניש תוינק תכירע ,םייגולותפ םירומיה( םייתוגהנתה ןפואב

יפקתה ,הגירח תינימ תוגהנתה ,יתייפכ תזרפומ הליכא

שי םא אפורל רפס .לורפיס תליטנ ינפל אפורב ץעוויהל שי ,םייאופר םיבצמ וא םינימסת חתפמ ךנה םא וא ךל )היה וא( :הלאמ דחא לכ טרפב

ךנה

לבוס

יוקילמ

העונתב

dyskinesia,

תועונת

אל

תוטלשנ

אלו

לש תוניקת

.)םייפגה ה םא לבוס ךנ ,הפודובל לטונ ךנהו ןוסניקרפ לש תמדקתמ הלחממ לש ןונימה תאלעה ןמזב העונתב יוקיל חתפתו ןכתיי .לורפיס

....

בל תלחמ הרומח

.םד ילכ תלחמ וא

תליחתב דוחייב ,םדה ץחל תא עובק ןפואב רטנל שי לופיטה הדימעב םד ץחל תת עונמל תנמ לע תאזו

הדימעל רבעמב םדה ץחל תליפנ(

שי

ןכדעל

תא

אפורה

םא

התא

וא

דחא

ינבמ

ךתחפשמ

םש

בל

התאש

ףחד חתפמ

וא

הקושת

גהנתהל

ןפואב

וניאש

ינייפוא

ךל

ךניאו

לוכי

דומעל

ףחד ינפב

וא

יותיפ

עצבל

תויוליעפ

תולולעש

םורגל

ךל

וא

םירחאל

קזנ

הלאכ תויוגהנתה

תוארקנ

תוערפה

הטילש

ףחדב

תולוכיו

לולכל

רומיהל תורכמתה ומכ תויוגהנתה םי

זובזב ,תזרפומ הליכא

ףסכ

ףחד

ליגר אל

םויקל

יסחי

ןימ

וא

היילע

תורידתב

לש תובשחמ

לע

ןימ

אפורהו ןכתיי

ךלש

ךרטצי

םיאתהל

.לופיטה תא קיספהל וא ןונימה תא

שי ,ןכ ומכ

ןכדעל

תא

אפורה

םא

התא

וא

דחא

ינבמ

ךתחפשמ

םש

בל

התאש

חתפמ לש השוחת ,שפנ תרעס( הינאמ לש בצמ

וא )רתי שוגירו תולוכי לכ ,תולעתה .)תואיצמה םע רשק דוביא ,לובלב ,תונרעב הדירי( םוירלד

אפורהו ןכתיי

ךלש

ךרטצי

קיספהל וא ןונימה תא םיאתהל .לופיטה תא

....

תונוכמב שומישו הגיהנ

( תויזהל םורגל הלולע הפורתה תשוחת וא הייאר ,העימש םימייק םניאש םירבד ןפואב ךילע העיפשה הפורתה םא .) ,הז תונכוסמ תונוכמ ליעפהל וא גוהנל ןיא

תויונונשיל םורגל הלולע לורפיס םיבצמו

לש

תומדרה

.ןוסניקרפ ילוחב דוחייב ,תוימואתפ

הווח ךנה םא

.תונכוסמ תונוכמ ליעפהל וא גוהנל ןיא ,ולא יאוול תועפות .ולא תועפות לע אפורל רפסל ךילע

ןיב תובוגת :תויתופורת

רידס וניאש בל בצקב לופיטל( ןיטלסיקמ

תוערפה .)תוירדח בצק

:הקנהו ןוירה

ינפל אפורב ץעוויהל ילבמ הפורתב שמתשהל ןיא :םיאבה םירקמב לופיטה תלחתה

.ןוירה תננכתמ וא ןוירהב ךניה םא

וא ןוירה תננכתמ ,ןוירהב ךניהש תבשוח ,ןוירהב ךניה םא .הפורתב שומישה ינפל אפורב ץעוויהל שי הקינמ אפורה .לורפיס לוטיל ךישמהל ךילע םא ךמע חחושי

ןיא ןכל העודי הניא רבועה לע לורפיס לש העפשהה .תרחא הרוה אפורה םא אלא ,הפורתב שמתשהל

.הקינמ ךניה רשאכ הפורתב ישמתשת לא הלולע לורפיס הפורתה ,ןכ ומכו בלחה רוציי תא תיחפהל רובעל הלוכי

ו םא בלחל הלולע

שומישה םא .קנויה קוניתל עיגהל הקנהה תא קיספהל שי ,ענמנ יתלב אוה לורפיסב

שמתשת דציכ :הפורתב

:שומישה ןפוא

ל ,סועלל ןיא שותכ

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הפורתה תא עולבל התומלשב .םימ סוכ םע

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הילבט

התומלשב

ינמזל רשק אלל הפורתה תא לוטיל ןתינ .תוחוראה

שורדה ןמזל רבעמ הפב הפורתה תא קיזחהל ןיא התעילבל

שומישה ןפוא

רוסא ורחשב תוילבטה תא שותכל וא ,תוצחל ,סועלל

ךשוממ

םורגל הלולע הילבטה תיצח וא השיתכ/הסיעל ידמ רהמ ררחתשהל הלולע הפורתהש ןוויכמ ,רתי תנמל .ףוגב

הובג ןונימ תועטב תלטנ םא

...

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...

הילכ תלחמ םע םילפוטמ

,הילכ תלחממ לבוס ךנה םא .ךל המיאתמה ןונימ תאלעה לע ץילמי ךלש אפורה

ךלש אפורהו ןכתיי ,הילכב תורומח תויעבמ לבוס ךנה םא םא .לוסקפימרפ הליכמש תרחא הפורתל הפורתה תא הנשי ח לופיטה ךלהמב רשק רוציל שי ,הילכב תויעבב הרמחה הל .ירשפאה םדקהב אפורה םע

:יאוול תועפות

(

יפל הגצהל הנתשה יאוולה תועפות תגצה ןפוא שדחה טמרופל םאתהב,תויוחיכש

.)

דע לע עיפשהל תולולע :תוחיכש ןניאש יאוול תועפות

:םישמתשמ

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כי רסוחו רתי תויתעונת ביצי ראשיהל תלו

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תואצות תורמל תמזגומ הרוצב רמהל קזח ףחד .תויניצר תויתפשמ וא תוישיא

תמזגומ הליכא*

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םע רשק ןדבא ,לובלב ,תונרעב הדירי( םוירילד .)תואיצמה

דע לע עיפשהל תולולע : תורידנ יאוול תועפות

1000

:םישמתשמ

לש השוחת ,שפנ תרעס( הינאמ לש בצמ

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