SIFROL TABLETS 1 MG

Sifrol IR

Updated Patient Information Leaflet

0.25, 1 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

®

0.25 mg

Sifrol

®

1 mg

Tablets

Each tablet of Sifrol 0.25 mg contains pramipexole dihydrochloride monohydrate 0.25 mg.

Each tablet of Sifrol 1 mg contains pramipexole dihydrochloride monohydrate 1 mg.

*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?

Sifrol 0.25 mg and Sifrol 1 mg are indicated for the treatment of the signs and symptoms of Parkinson's

disease (alone or

combination with levodopa).

Sifrol 0.25 mg is also indicated for treating moderate to severe symptoms of idiopathic restless legs

syndrome.

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.

You are breastfeeding.

Special warnings regarding the use of the medicine

Before taking Sifrol, tell your physician if you have (or 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 (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.

Severe heart or blood vessels disease. You should monitor your blood pressure regularly,

especially at the beginning of treatment, and this is to avoid postural hypotension (a fall in blood

pressure on standing up).

Symptoms augmentation. You may feel that your disease symptoms start earlier in the day than

usual, are more intense, and involve other limbs.

Tell your physician if you or your family or relatives notice 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 your dose or

stop the treatment.

Also, tell your physician if you or your family or relatives notice 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 your dose or stop the treatment.

Sifrol IR

Updated Patient Information Leaflet

0.25, 1 mg

April 2020

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

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

physician may need to adjust your dose.

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 is not intended for 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. 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

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 heartburn 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 together with antipsychotic medicines.

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

treatment with Sifrol.

Take care if you are using any medicines that calm you down or if you are drinking alcohol. In these

cases, the medicine may affect your ability to drive and operate dangerous machines.

Using the medicine and food

Sifrol can be taken with or without food.

Using the medicine and alcohol consumption

You should be cautious while drinking alcohol during treatment with the medicine. See above in the section "If

you are taking other medicines".

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.

The effect of Sifrol 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 breastfeeding. Sifrol can reduce the production of breast milk. Also, the

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

breastfeeding 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 operate dangerous machines.

Sifrol 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. Do not exceed the recommended

dose.

Sifrol can be taken with or without food.

Swallow the tablet with water. There is no information about

crushing, grinding or chewing the tablet. You can cut the tablets in half, on the score line and take both

halves at the same time to make swallowing easier or according to the dosage prescribed for you by the

physician.

The usually recommended dose is:

Sifrol IR

Updated Patient Information Leaflet

0.25, 1 mg

April 2020

Parkinson’s disease:

The daily dose must be divided into 3 equal doses.

During the first week, the usual daily dose is 0.125 mg SIFROL three times a day (equivalent to 0.375

mg daily):

week

Number of tablets

Half a tablet of SIFROL 0.25 mg three times a day

Daily dose (mg)

0.375

This dose will be increased every 5-7 days as directed by your physician until your symptoms are

controlled (maintenance dose).

week

week

Number of tablets

1 tablet SIFROL 0.25 mg

three times a day

2 tablets SIFROL 0.25 mg

three times a day

Total daily dose (mg)

0.75 mg

1.5 mg

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

Patients with kidney disease:

If you have moderate or severe kidney disease, your physician will prescribe a lower dose. In this case,

you will have to take the tablets once or twice a day. If you have moderate kidney disease, the usual

starting dose is half a tablet of Sifrol 0.25 mg twice a day. In severe kidney disease, the usual starting

dose is half a tablet Sifrol 0.25 mg once a day.

Restless Legs Syndrome

The usual dose is taken once a day, in the evening, 2-3 hours before bedtime.

During the first week, the usual dose is half a tablet of Sifrol 0.25 mg once a day (equivalent to 0.125 mg

daily):

week

Number of tablets

Half a tablet of Sifrol 0.25 mg once a day

Daily dose (mg)

0.125 mg

This dose will be increased every 4-7 days as directed by your physician until your symptoms are

controlled (maintenance dose).

week

week

week

Number of

tablets

1 tablet Sifrol 0.25 mg

2 tablets Sifrol 0.25 mg

3 tablets Sifrol 0.25 mg

Total daily

dose (mg)

0.25

0.50

0.75

The maximum daily dose should not exceed 0.75 mg of the active ingredient pramipexole.

If you stop taking your medicine for more than a few days, you must start again at the lowest dose. You

can then build up the dose again, as you did the first time. Ask your physician for advice.

Your physician will review your treatment after 3 months to decide whether or not to continue the

treatment.

Patients with kidney disease:

If you have severe kidney disease, Sifrol may not be a suitable treatment for you.

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

Do not compensate for a forgotten dose.

Sifrol IR

Updated Patient Information Leaflet

0.25, 1 mg

April 2020

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 or the pharmacist.

If you stop taking the medicine

Do not stop taking Sifrol without first talking to your 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 suffer from Parkinson’s disease you should not stop treatment with this medicine abruptly. A

sudden stop could cause a

severe medical condition called neuroleptic malignant syndrome. The

symptoms of the syndrome include: loss of muscle movement (akinesia), rigid muscles, fever, unstable

blood pressure, increased heart rate (tachycardia), confusion,

depressed level of consciousness (e.g.

coma).

If you stop or reduce your Sifrol 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 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.

If you have Parkinson's disease you may experience the following side effects:

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

Movement disorders (e.g. abnormal, uncontrolled movements of the limbs), sleepiness, dizziness,

nausea.

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), edema (mainly in the legs), headache,

hypotension (low blood pressure), abnormal dreams, constipation, visual impairment, vomiting, weight

loss including decreased appetite.

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

Paranoia (excessive fear for your own well-being), delusion, excessive daytime sleepiness or suddenly

falling asleep, forgetfulness, increased movements and inability to keep still (hyperkinesia), weight

increase, allergic reactions (e.g. rash, itching, hypersensitivity), fainting, *heart failure (heart problems

which can cause shortness of breath or leg edema), *syndrome of inappropriate antidiuretic hormone

(ADH) secretion, restlessness, difficulty breathing (dyspnoea), hiccups, pneumonia, delirium (decreased

awareness, confusion, losing touch with reality), inability to resist the impulse to perform an action that

could harm yourself or others. Such acts 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).

Rare side effects: may affect up to 1 in 1000 users:

Mania, for example feeling agitated, elated and overexcited.

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

yet):

After stopping or reducing your Sifrol 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. 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 you have restless legs syndrome you may experience the following side effects:

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

Nausea.

Sifrol IR

Updated Patient Information Leaflet

0.25, 1 mg

April 2020

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

Changes in your sleeping pattern, such as insomnia and drowsiness, fatigue, headache, unusual dreams,

constipation, dizziness, vomiting.

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

*Urge to behave in an unusual way, *heart failure (problems with your heart which can cause shortness

of breath or edema in your ankles), *syndrome of inappropriate antidiuretic hormone (ADH) secretion,

movement disorders (such as uncontrollable and abnormal limb movements), *excessive body

movement and inability to keep still (hyperkinesia), *paranoia (excessive fear for your own well-being),

*delusions, *forgetfulness, hallucination (hearing, seeing or feeling things that are not there), confusion,

increased drowsiness during the day or suddenly falling asleep, weight gain, low blood pressure, edema

(mainly in the legs), allergic reactions (such as rash, itch, hypersensitivity), fainting, restlessness,

disturbed vision, weight loss with loss of appetite, difficulty breathing, hiccups, *pneumonia, mania (for

example feeling agitated, elated and overexcited), delirium (decreased awareness, confusion, losing

touch with reality), inability to resist the impulse to perform an act that may could harm yourself or

others. Such acts include:

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

*Unusual sexual behavior and interests of significant concern to you and your environment, such as

increased sexual drive.

*Excessive, uncontrollable shopping or spending.

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

than usual and more than you need to satisfy your hunger).

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

yet):

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

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

* Precise frequency is unknown. These side effects did not appear in clinical trials conducted in 1,395 patients

taking 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 at a temperature below 25˚C.

6.

Additional information

In addition to the active ingredient the medicine also contains –

mannitol, maize starch dried, maize starch, magnesium stearate, colloidal anhydrous silica,

povidone K25.

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

Sifrol 0.25 mg – white, oval, flat-faced, beveled-edge tablet, with a score line on both sides.

Tablets have P7 on one side, on both sides of the score line, and the symbol of Boehringer

Ingelheim embossed on the other side, on both sides of the score line.

Sifrol 1 mg – white, oval, flat-faced, beveled-edge tablet, with a score line on both sides. Tablets

have P9 on one side, on both sides of the score line, and the symbol of Boehringer Ingelheim on

the other side, on both sides of the score line.

The tablets are packed in a blister strip. Each package containing 100 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, Ingelheim am Rhein,

Germany.

Sifrol IR

Updated Patient Information Leaflet

0.25, 1 mg

April 2020

This leaflet was revised in April 2020.

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

Sifrol 0.25 mg –

30500

Sifrol 1 mg –

30501

Sifrol IR

Updated Prescribing Information

0.25 mg, 1 mg

April 2020

Product Information

Sifrol

Pramipexole

Tablets

1.

NAME OF THE MEDICINAL PRODUCT

Sifrol 0.25 mg tablets

Sifrol 1 mg tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Sifrol 0.25 mg tablet contains 0.25 mg pramipexole dihydrochloride monohydrate (salt form) equivalent to

0.18 mg of pramipexole base.

Each Sifrol 1 mg tablet contains 1 mg pramipexole dihydrochloride monohydrate (salt form) equivalent to 0.7 mg

of pramipexole base.

Please note:

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

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

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Tablets.

The tablets are white, both faces flat with beveled edges, scored on both sides and have a code

embossed.

Strength (mg salt)

Appearance

Sifrol 0.25

Oval, code embossed (one side with code P7 and one side with the Boehringer

Ingelheim company symbol).

Sifrol 1

Round, code embossed (one side with code P9 and one side with the Boehringer

Ingelheim company symbol).

Tablets can be divided into equal halves.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Sifrol 0.25 mg and 1 mg

are indicated for the treatment of signs and symptoms of idiopathic Parkinson's disease,

as monotherapy or in combination with levodopa.

Sifrol 0.25 mg is also indicated

for symptomatic treatment of moderate to severe idiopathic Restless Legs

Syndrome.

4.2

Posology and method of administration

Posology

Sifrol IR

Updated Prescribing Information

0.25 mg, 1 mg

April 2020

Parkinson’s disease:

The daily dose is administered in equally divided doses 3 times a day.

Initial treatment

Doses should be increased gradually from a starting-dose of 0.375 mg salt (0.264 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

Week

Dose

(mg of salt)

Total Daily Dose (mg

of salt)

Dose

(mg of base)

Total Daily Dose (mg

of base)

3 x 0.125

0.375

3 x 0.088

0.264

3 x 0.25

0.75

3 x 0.18

0.54

3 x 0.5

3 x 0.35

If a further dose increase is necessary the daily dose should be increased by 0.75 mg of salt (0.54 mg base) at

weekly intervals up to a maximum dose of 4.5 mg of salt (3.3 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)

per day (see section 4.8).

Maintenance treatment

The individual dose of pramipexole should be in the range of 0.375 mg salt (0.264 mg base) to a maximum of 4.5

mg salt (3.3 mg base) per day. During dose escalation in pivotal studies

,

efficacy was observed starting at a daily

dose of 1.5 mg salt (1.1 mg 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 salt (1.1 mg base). In advanced Parkinson's disease, pramipexole doses higher than 1.5 mg salt (1.1 mg 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).

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

salt (0.54 mg base) per day until the daily dose has been reduced to 0.75 mg salt (0.54 mg base). Thereafter the

dose should be reduced by 0.375 mg salt (0.264 mg 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 for

initiation of therapy:

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 20 and 50 ml/min, the initial daily dose of SIFROL should be

administered in two divided doses, starting at 0.125 mg salt (0.088 mg base) twice a day (0.25 mg salt/0.176 mg

base daily). A maximum daily dose of 2.25 mg salt (1.57 mg base) should not be exceeded.

Sifrol IR

Updated Prescribing Information

0.25 mg, 1 mg

April 2020

In patients with a creatinine clearance less than 20 ml/min, the daily dose of SIFROL should be administered in a

single dose, starting at 0.125 mg salt (0.088 mg base) daily. A maximum daily dose of 1.5 mg salt (1.1 mg base)

should not be exceeded.

If renal function declines during maintenance therapy the SIFROL daily dose should be reduced by the same

percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then the SIFROL

daily dose should be reduced by 30%. The daily dose can be administered in two divided doses if creatinine

clearance is between 20 and 50 ml/min and as a single daily dose if creatinine clearance is less than 20 ml/min.

Hepatic 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 in the paediatric population in Parkinson’s Disease.

Restless Legs Syndrome:

The recommended starting dose of SIFROL is 0.125 mg salt (0.088 mg base) taken once daily 2-3 hours before

bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days to a

maximum of 0.75 mg salt (0.54 mg base) per day (as shown in the table below).

Dose Schedule of SIFROL

Titration Step

Once Daily Evening Dose (mg of

salt)

Once Daily Evening Dose

base)

0.125

0.088

0.25

0.18

0.50

0.35

0.75

0.54

* if needed

Patient´s response should be evaluated after 3 months treatment and the need for treatment continuation should be

reconsidered. If treatment is interrupted for more than a few days it should be re-initiated by dose titration carried

out as above.

Treatment discontinuation

Since the daily dose for the treatment of Restless Legs Syndrome will not exceed 0.75 mg salt (0.54 mg base)

SIFROL can be discontinued without tapering off. In a 26 week placebo controlled trial, rebound of RLS

symptoms (worsening of symptom severity as compared to baseline) was observed in 10% of patients (14 out of

135) after abrupt discontinuation of treatment. This effect was found to be similar across all doses.

Renal impairment

The elimination of pramipexole is dependent on renal function. Patients with a creatinine clearance above 20

ml/min require no reduction in daily dose.

The use of SIFROL has not been studied in haemodialysis patients, or in patients with severe renal impairment.

Hepatic impairment

Dose adjustment in patients with hepatic failure is not required, as approx. 90% of absorbed active substance is

excreted through the kidneys.

Sifrol IR

Updated Prescribing Information

0.25 mg, 1 mg

April 2020

Paediatric population

SIFROL is not recommended for use in children and adolescents below 18 years due to a lack of data on safety

and efficacy.

Tourette Disorder

Paediatric population

SIFROL is not recommended for use in children and adolescents below 18 years since the efficacy and safety has

not been established in this population. SIFROL should not be used in children or adolescents with Tourette

Disorder because of a negative benefit-risk balance for this disorder (see section 5.1).

Method of administration

The tablets should be taken orally, swallowed with water, and can be taken either with or without food.

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.

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.

Sifrol IR

Updated Prescribing Information

0.25 mg, 1 mg

April 2020

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.

Augmentation

Reports in the literature indicate that treatment of Restless Legs Syndrome with dopaminergic medicinal products

can result in augmentation. Augmentation refers to the earlier onset of symptoms in the evening (or even the

afternoon), increase in symptoms, and spread of symptoms to involve other extremities. Augmentation was

specifically investigated in a controlled clinical trial over 26 weeks. Augmentation was observed in 11.8% of

patients in the pramipexole group (N = 152) and 9.4% of patients in the placebo group (N = 149). Kaplan-Meier

analysis of time to augmentation showed no significant difference between pramipexole and placebo groups.

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

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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.

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 1,923 patients on pramipexole and

1,354 patients on placebo, adverse drug reactions were frequently reported for both groups. 63% of patients on

pramipexole and 52% 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.

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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).

Parkinson's disease

, most common adverse reactions

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.

Table 1: Parkinson’s disease

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

compulsions

compulsive

shopping,

pathological

gambling,

restlessness,

hypersexuality,

delusion,

libido disorder,

paranoia,

delirium,

binge eating

hyperphagia

mania

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

Hypersensitivity,

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subcutaneous

tissue disorders

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

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.

Restless Legs Syndrome, most common adverse reactions

The most commonly (

5%) reported adverse drug reactions in patients with Restless Legs Syndrome treated

with Pramipexole were nausea, headache, dizziness and fatigue. Nausea and fatigue were more often reported in

female patients treated with SIFROL (20.8% and 10.5%, respectively) compared to males (6.7% and 7.3%,

respectively).

Table 2: Restless Legs Syndrome

Body

System

Very common

(≥1/10)

Common

(≥1/100 to

<1/10)

Uncommon (≥1/1,000 to <

1/100)

Not known

Infections and

infestations

pneumonia

Endocrine

disorders

inappropriate antidiuretic

hormone secretion

Psychiatric

disorders

Insomnia,

abnormal

dreams

Restlessness, confusion,

hallucinations, libido disorder,

delusion

, hyperphagia

, paranoia

, mania

, delirium

, behavioural

symptoms of impulse control

disorders and compulsions

(such

compulsive shopping,

pathological gambling,

hypersexuality, binge eating)

Nervous

system

disorders

Headache,

dizziness,

somnolence

sudden onset of sleep, syncope,

dyskinesia, amnesia

hyperkinesia

Eye disorders

visual impairment

including visual acuity,

reduced diplopia,

vision blurred

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Cardiac

disorders

cardiac failure

Vascular

disorders

Hypotension

Respiratory,

thoracic, and

mediastinal

disorders

Dyspnoea, hiccups

Gastrointestina

l 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

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 1,395 patients with Restless Legs Syndrome 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).

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

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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 D

receptors, and has full intrinsic activity.

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.

The mechanism of action of pramipexole as treatment for Restless Legs Syndrome is unknown.

Neuropharmacological evidence suggests primary dopaminergic system involvement.

Pharmacodynamic effects

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

volunteers, where SIFROL prolonged-release tablets were titrated faster (every 3 days) than recommended up to

4.5 mg of salt (3.15 mg pramipexole base) 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.

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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.

Clinical efficacy and safety

in Restless Legs Syndrome

The efficacy of pramipexole was evaluated in four placebo-controlled clinical trials in approximately 1,000

patients with moderate to very severe idiopathic Restless Legs Syndrome.

The mean change from baseline in the Restless Legs Syndrome Rating Scale (IRLS) and the Clinical Global

Impression-Improvement (CGI-I) were the primary efficacy outcome measures. For both primary endpoints

statistically significant differences have been observed for the pramipexole dose groups 0.25 mg, 0.5 mg and 0.75

mg pramipexole salt in comparison to placebo. After 12 weeks of treatment the baseline IRLS score improved

from 23.5 to 14.1 points for placebo and from 23.4 to 9.4 points for pramipexole (doses combined). The adjusted

mean difference was -4.3 points (CI 95% -6.4; -2.1 points, p-value <0.0001). CGI-I responder rates (improved,

very much improved) were 51.2% and 72.0% for placebo and pramipexole, respectively (difference 20% CI 95%:

8.1%; 31.8%, p<0.0005). Efficacy was observed with 0.125 mg salt (0.088 mg base) per day after the first week

of treatment.

In a placebo-controlled polysomnography study over 3 weeks SIFROL significantly reduced the number of

periodic limb movements during time in bed.

Longer term efficacy was evaluated in a placebo-controlled clinical trial. After 26 weeks of treatment, there was

an adjusted mean reduction in IRLS total score of 13.7 and 11.1 points in the pramipexole and placebo group,

respectively, with a statistically significant (p = 0.008) mean treatment difference of -2.6. CGI-I responder rates

(much improved, very much improved) were 50.3% (80/159) and 68.5% (111/162) for placebo and pramipexole,

respectively (p = 0.001), corresponding to a number needed to treat (NNT) of 6 patients (95%CI: 3.5, 13.4).

Clinical efficacy and safety

in Tourette Disorder

The efficacy of pramipexole (0.0625-0.5 mg/day) with paediatric patients aged 6-17 years with Tourette Disorder

was evaluated in a 6-week, double-blind, randomised, placebo-controlled flexible dose study. A total of 63

patients were randomised (43 on pramipexole, 20 on placebo). The primary endpoint was change from baseline

on the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS). No difference was observed for

pramipexole as compared to placebo for either the primary endpoint or for any of the secondary efficacy

endpoints including YGTSS total score, Patient Global Impression of Improvement (PGI-I), Clinical Global

Impression of Improvement (CGI-I), or Clinical Global Impressions of Severity of Illness (CGI-S). Adverse

events occurring in at least 5% of patients in the pramipexole group and more common in the pramipexole-treated

patients than in patients on placebo were: headache (27.9%, placebo 25.0%), somnolence (7.0%, placebo 5.0%),

nausea (18.6%, placebo 10.0%), vomiting (11.6%, placebo 0.0%), upper abdominal pain (7.0%, placebo 5.0%),

orthostatic hypotension (9.3%, placebo 5.0%), myalgia (9.3%, placebo 5.0%), sleep disorder (7.0%, placebo

0.0%), dyspnoea (7.0%, placebo 0.0%) and upper respiratory tract infection (7.0%, placebo 5.0%). Other

significant adverse events leading to discontinuation of study medication for patients receiving pramipexole were

confusional state, speech disorder and aggravated condition (see section 4.2).

5.2

Pharmacokinetic properties

Absorption

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

greater than 90% and the maximum plasma concentrations occur between 1 and 3 hours. Concomitant

administration with food did not reduce the extent of pramipexole absorption, but the rate of absorption was

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

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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.

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 (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

Mannitol, maize starch, anhydrous colloidal silica, povidone K25, magnesium stearate

6.2

Incompatibilities

Not applicable

6.3

Special precautions for storage

Store in the original package below 25

6.4

Nature and contents of container

OPA/aluminium/PVC-aluminium blisters.

10 tablets per aluminum blister strips

Cartons containing 10 blister strips (100 tablets)

6.5

Special precautions for disposal and other handling

No special requirements

7.

Manufacturer

Boehringer Ingelheim Pharma

KG, Ingelheim am Rhein, Germany.

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Registration holder

Boehringer Ingelheim Israel Ltd., 89 Medinat Ha-Yehudim St., P.O. Box 4124,

Herzliya Pituach 4676672.

Registration Numbers

Sifrol 0.25 mg

126 17 30500

Sifrol 1 mg

126 16 30501

Revised in April 2020.