Sifrol

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.088 mg tablets
SIFROL 0.18 mg tablets
SIFROL 0.35 mg tablets
SIFROL 0.7 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

SIFROL 0.088 mg tablets
Each tablet contains 0.125 mg pramipexole dihydrochloride monohydrate equivalent to 0.088 mg 
pramipexole.

SIFROL 0.18 mg tablets
Each tablet contains 0.25 mg pramipexole dihydrochloride monohydrate equivalent to 0.18 mg 
pramipexole.

SIFROL 0.35 mg tablets
Each tablet contains 0.5 mg pramipexole dihydrochloride monohydrate equivalent to 0.35 mg 
pramipexole.

SIFROL 0.7 mg tablets
Each tablet contains 1.0 mg pramipexole dihydrochloride monohydrate equivalent to 0.7 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

Tablet

SIFROL 0.088 mg tablets
The tablets are white, flat, of round shape, and have a code embossed (one side with the code P6, and 
one side with the Boehringer Ingelheim company symbol).

SIFROL 0.18 mg tablets
The tablets are white, flat, of oval shape, scored on both sides, and have a code embossed (one side 
with the code P7, and one side with the Boehringer Ingelheim company symbol).
Tablets can be divided into equal halves.

SIFROL 0.35 mg tablets
The tablets are white, flat, of oval shape, scored on both sides, and have a code embossed (one side 
with the code P8, and one side with the Boehringer Ingelheim company symbol).
Tablets can be divided into equal halves.

SIFROL 0.7 mg tablets
The tablets are white, flat, of round shape, scored on both sides, and have a code embossed (one side 
with the code P9, and one side with the Boehringer Ingelheim company symbol).
Tablets can be divided into equal halves.



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4. CLINICAL PARTICULARS

4.1 Therapeutic indications

SIFROL is indicated in adults for treatment of the signs and symptoms of idiopathic Parkinson’s 
disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, 
through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations 
of the therapeutic effect occur (end of dose or “on off” fluctuations).

SIFROL is indicated in adults for symptomatic treatment of moderate to severe idiopathic Restless 
Legs Syndrome in doses up to 0.54 mg of base (0.75 mg of salt) (see section 4.2).

4.2 Posology and method of administration

Posology

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 0.264 mg of base (0.375 mg of salt) 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 base)
Total Daily Dose
(mg of base)

Dose
(mg of salt)

Total Daily Dose
(mg of salt)

1 3 x 0.088 0.264 3 x 0.125 0.375
2 3 x 0.18 0.54 3 x 0.25 0.75
3 3 x 0.35 1.1 3 x 0.5 1.50

If a further dose increase is necessary the daily dose should be increased by 0.54 mg of base (0.75 mg 
of salt) at weekly intervals up to a maximum dose of 3.3 mg of base (4.5 mg of salt) 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 0.264 mg of base (0.375 mg of salt) to a 
maximum of 3.3 mg of base (4.5 mg of salt) per day. During dose escalation in pivotal studies, 
efficacy was observed starting at a daily dose of 1.1 mg of base (1.5 mg of salt). 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 1.1 mg of base (1.5 mg of 
salt). In advanced Parkinson’s disease, pramipexole doses higher than 1.1 mg of base (1.5 mg of salt) 
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 0.54 mg of base (0.75 mg of salt) per day until the daily dose has been reduced to 0.54 mg 
of base (0.75 mg of salt). Thereafter the dose should be reduced by 0.264 mg of base (0.375 mg of 
salt) 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).



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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 0.088 mg of base (0.125 mg of salt) twice a 
day (0.176 mg of base/0.25 mg of salt daily). A maximum daily dose of 1.57 mg pramipexole base 
(2.25 mg of salt) should not be exceeded.

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 0.088 mg of base (0.125 mg of salt) daily. A maximum daily 
dose of 1.1 mg pramipexole base (1.5 mg of salt) 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 for the indication of Parkinson’s Disease.

Restless Legs Syndrome

The recommended starting dose of SIFROL is 0.088 mg of base (0.125 mg of salt) 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 0.54 mg of base (0.75 mg of salt) per day (as shown in the 
table below).

Dose Schedule of SIFROL
Titration Step Once Daily Evening Dose

(mg of base)
Once Daily Evening Dose
(mg of salt)

1 0.088 0.125
2* 0.18 0.25
3* 0.35 0.50
4* 0.54 0.75
* 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 0.54 mg of base 
(0.75 mg of salt) 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 



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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.

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.



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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.

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 



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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 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.



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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.

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.



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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 secretion1

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 eating1

hyperphagia1

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 failure1

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.



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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 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

pneumonia1

Endocrine 
disorders

inappropriate antidiuretic hormone 
secretion1

Psychiatric 
disorders

insomnia
abnormal 
dreams 

restlessness
confusion 
hallucinations
libido disorder
delusion1

hyperphagia1

paranoia1

mania1

delirium1

behavioural symptoms of impulse 
control disorders and compulsions1

(such as:
compulsive shopping,
pathological gambling,
hypersexuality, binge eating)

Nervous 
system 
disorders

headache
dizziness
somnolance

sudden onset of sleep 
syncope
dyskinesia
amnesia1

hyperkinesia1

Eye disorders visual impairment including 
visual acuity reduced
diplopia 
vision blurred 

Cardiac 
disorders

cardiac failure1

Vascular 
disorders

Hypotension

Respiratory, 
thoracic, and 
mediastinal 
disorders

dyspnoea
hiccups

Gastrointestinal nausea constipation



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disorders 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 
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).



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Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

4.9 Overdose

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.

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 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 

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difference during the maintenance phase. These points should be considered when initiating 
pramipexole treatment in patients with Parkinson’s disease.

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with 
SIFROL in all subsets of the paediatric population in Parkinson’s Disease (see section 4.2 for 
information on paediatric use).

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 0.088 mg of base (0.125 mg of salt) 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).

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with 
SIFROL in one or more subsets of the paediatric population in Restless Legs Syndrome (see section 
4.2 for information on paediatric use).

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).



14

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.

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 
14C-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 (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

Mannitol
Maize starch
Anhydrous colloidal silica
Povidone K 25
Magnesium stearate



15

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Do not store above 30°C.
Store in the original package in order to protect from light.

6.5 Nature and contents of container

OPA/aluminium/PVC-aluminium blisters.
Each blister strip contains 10 tablets.
Cartons containing 3 or 10 blister strips (30 or 100 tablets).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

8. MARKETING AUTHORISATION NUMBER(S) 

SIFROL 0.088 mg tablets
EU/1/97/050/001-002

SIFROL 0.18 mg tablets
EU/1/97/050/003-004

SIFROL 0.35 mg tablets
EU/1/97/050/011-012 

SIFROL 0.7 mg tablets
EU/1/97/050/005-006  

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 October 1997
Date of latest renewal: 14 October 2007



16

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

http://www.ema.europa.eu


17

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.26 mg prolonged-release tablets
SIFROL 0.52 mg prolonged-release tablets
SIFROL 1.05 mg prolonged-release tablets
SIFROL 1.57 mg prolonged-release tablets
SIFROL 2.1 mg prolonged-release tablets
SIFROL 2.62 mg prolonged-release tablets
SIFROL 3.15 mg prolonged-release tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

SIFROL 0.26 mg prolonged-release tablets
Each prolonged-release tablet contains 0.375 mg pramipexole dihydrochloride monohydrate
equivalent to 0.26 mg pramipexole.

SIFROL 0.52 mg prolonged-release tablets
Each prolonged-release tablet contains 0.75 mg pramipexole dihydrochloride monohydrate equivalent 
to 0.52 mg pramipexole.

SIFROL 1.05 mg prolonged-release tablets
Each prolonged-release tablet contains 1.5 mg pramipexole dihydrochloride monohydrate equivalent 
to 1.05 mg pramipexole.

SIFROL 1.57 mg prolonged-release tablets
Each prolonged-release tablet contains 2.25 mg pramipexole dihydrochloride monohydrate equivalent 
to 1.57 mg pramipexole.

SIFROL 2.1 mg prolonged-release tablets
Each prolonged-release tablet contains 3 mg pramipexole dihydrochloride monohydrate equivalent to 
2.1 mg pramipexole.

SIFROL 2.62 mg prolonged-release tablets
Each prolonged-release tablet contains 3.75 mg pramipexole dihydrochloride monohydrate equivalent 
to 2.62 mg pramipexole.

SIFROL 3.15 mg prolonged-release tablets
Each prolonged-release tablet contains 4.5 mg pramipexole dihydrochloride monohydrate equivalent 
to 3.15 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

Prolonged-release tablet

SIFROL 0.26 mg prolonged-release tablets
The tablets are white to off-white, of round shape, with bevelled edges, and have a code embossed
(one side with the code P1, and one side with the Boehringer Ingelheim company symbol).



18

SIFROL 0.52 mg prolonged-release tablets
The tablets are white to off-white, of round shape, with bevelled edges, and have a code embossed 
(one side with the code P2, and one side with the Boehringer Ingelheim company symbol).

SIFROL 1.05 mg prolonged-release tablets
The tablets are white to off-white, of oval shape, and have a code embossed (one side with the code 
P3, and one side with the Boehringer Ingelheim company symbol).

SIFROL 1.57 mg prolonged-release tablets
The tablets are white to off-white, of oval shape, and have a code embossed (one side with the code 
P12, and one side with the Boehringer Ingelheim company symbol).

SIFROL 2.1 mg prolonged-release tablets
The tablets are white to off-white, of oval shape, and have a code embossed (one side with the code 
P4, and one side with the Boehringer Ingelheim company symbol).

SIFROL 2.62 mg prolonged-release tablets
The tablets are white to off-white, of oval shape, and have a code embossed (one side with the code 
P13, and one side with the Boehringer Ingelheim company symbol).

SIFROL 3.15 mg prolonged-release tablets
The tablets are white to off-white, of oval shape, and have a code embossed (one side with the code 
P5, and one side with the Boehringer Ingelheim company symbol).

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

SIFROL is indicated in adults for treatment of the signs and symptoms of idiopathic Parkinson’s 
disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, 
through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations 
of the therapeutic effect occur (end of dose or “on off” fluctuations).

4.2 Posology and method of administration

Posology

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

Initial treatment
Doses should be increased gradually from a starting dose of 0.26 mg of base (0.375 mg of salt) 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 prolonged-release tablets
Week Daily dose (mg of base) Daily dose (mg of salt)
1 0.26 0.375
2 0.52 0.75
3 1.05 1.5

If a further dose increase is necessary the daily dose should be increased by 0.52 mg of base (0.75 mg 
of salt) at weekly intervals up to a maximum dose of 3.15 mg of base (4.5 mg of salt) per day.
However, it should be noted that the incidence of somnolence is increased at doses higher than
1.05 mg of base (1.5 mg of salt) per day (see section 4.8).



19

Patients already taking SIFROL tablets may be switched to SIFROL prolonged-release tablets 
overnight, at the same daily dose. After switching to SIFROL prolonged-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 0.26 mg of base (0.375 mg of salt) to a 
maximum of 3.15 mg of base (4.5 mg of salt) per day. During dose escalation in pivotal studies, 
efficacy was observed starting at a daily dose of 1.05 mg of base (1.5 mg of salt). 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 1.05 mg of base (1.5 mg of 
salt). In advanced Parkinson’s disease, pramipexole doses higher than 1.05 mg of base (1.5 mg of salt) 
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 prolonged-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 0.52 mg of base (0.75 mg of salt) per day until the daily dose has been reduced to 0.52 mg 
of base (0.75 mg of salt). Thereafter the dose should be reduced by 0.26 mg of base (0.375 mg of salt) 
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:

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 
0.26 mg SIFROL prolonged-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 0.26 mg 
pramipexole base at weekly intervals up to a maximum dose of 1.57 mg pramipexole base (2.25 mg of 
salt) per day.

The treatment of patients with a creatinine clearance below 30 ml/min with SIFROL prolonged-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.

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.



20

Paediatric population
The safety and efficacy of SIFROL in children below 18 years has not been established. There is no 
relevant use of SIFROL prolonged-release tablets in the paediatric population for the indication of
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.

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.



21

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.

Remnants in stool 
Some patients have reported the occurrence of remnants in faeces which may resemble intact SIFROL
prolonged-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.



22

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 1,778 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).



23

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 secretion1

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 eating1

hyperphagia1

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 failure1

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 



24

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 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).

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).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


25

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.

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 prolonged-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 prolonged-release tablets in the treatment of Parkinson's disease 
was evaluated in a multinational drug development program consisting of three randomised, 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.



26

Superiority of SIFROL prolonged-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 prolonged-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 prolonged-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 prolonged-
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 prolonged-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 prolonged-release tablets experienced a drug-related adverse 
event leading to withdrawal.

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with 
SIFROL in all subsets of the paediatric population in Parkinson’s Disease (see section 4.2 for 
information on paediatric use).

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 prolonged-release tablets were assessed in 
fasted state, the minimum and peak plasma concentration (Cmin, Cmax) and exposure (AUC) of the same 
daily dose of SIFROL prolonged-release tablets given once daily and SIFROL tablets given three 
times a day were equivalent.

The once daily administration of SIFROL prolonged-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
prolonged-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 (Cmax) 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 Cmax is not considered clinically relevant. In the Phase III 
studies that established safety and efficacy of SIFROL prolonged-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 Cmax. A decreased body weight by 30 kg results in an increase in 
Cmax of 45%. However, in Phase III trials in Parkinson’s disease patients no clinically meaningful 



27

influence of body weight on the therapeutic effect and tolerability of SIFROL prolonged-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 
14C-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 (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

Hypromellose 2208
Maize starch
Carbomer 941
Colloidal anhydrous silica
Magnesium stearate

6.2 Incompatibilities

Not applicable.



28

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in the original package in order to protect from moisture.
This medicinal product does not require any special temperature storage conditions.

6.5 Nature and contents of container

OPA/aluminium/PVC-aluminium blisters.
Each blister strip contains 10 prolonged-release tablets.
Cartons containing 1, 3 or 10 blister strips (10, 30 or 100 prolonged-release tablets).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7. MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

8. MARKETING AUTHORISATION NUMBER(S) 

SIFROL 0.26 mg prolonged-release tablets
EU/1/97/050/013-015

SIFROL 0.52 mg prolonged-release tablets
EU/1/97/050/016-018 

SIFROL 1.05 mg prolonged-release tablets
EU/1/97/050/019-021 

SIFROL 1.57 mg prolonged-release tablets
EU/1/97/050/028-030

SIFROL 2.1 mg prolonged-release tablets
EU/1/97/050/022-024 

SIFROL 2.62 mg prolonged-release tablets
EU/1/97/050/031-033 

SIFROL 3.15 mg prolonged-release tablets
EU/1/97/050/025-027 



29

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 14 October 1997
Date of latest renewal: 14 October 2007

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.



30

ANNEX II

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT



31

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturer responsible for batch release

Boehringer Ingelheim Pharma GmbH & Co. KG
Binger Strasse 173
D-55216 Ingelheim am Rhein
Germany

Rottendorf Pharma GmbH
Ostenfelder Strasse 51 – 61
59320 Ennigerloh
Germany

The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached.



32

ANNEX III

LABELLING AND PACKAGE LEAFLET



33

A. LABELLING



34

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Folding box

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.088 mg tablets
Pramipexole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 0.125 mg pramipexole dihydrochloride monohydrate equivalent to 0.088 mg
pramipexole.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 tablets
100 tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C.
Store in the original package in order to protect from light.



35

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/050/001 [30 tablets]
EU/1/97/050/002 [100 tablets]

13. BATCH NUMBER

Lot {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

SIFROL 0.088 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product] 



36

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.088 mg tablets
Pramipexole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP {MM/YYYY}

4. BATCH NUMBER

Lot {number}

5. OTHER



37

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Folding box

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.18 mg tablets
Pramipexole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 0.25 mg pramipexole dihydrochloride monohydrate equivalent to 0.18 mg
pramipexole.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 tablets
100 tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C.
Store in the original package in order to protect from light.



38

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/050/003 [30 tablets]
EU/1/97/050/004 [100 tablets]

13. BATCH NUMBER

Lot {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

SIFROL 0.18 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product] 



39

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.18 mg tablets
Pramipexole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP {MM/YYYY}

4. BATCH NUMBER

Lot {number}

5. OTHER



40

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Folding box

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.35 mg tablets
Pramipexole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 0.5 mg pramipexole dihydrochloride monohydrate equivalent to 0.35 mg 
pramipexole.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 tablets
100 tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C.
Store in the original package in order to protect from light.



41

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/050/011 [30 tablets]
EU/1/97/050/012 [100 tablets]

13. BATCH NUMBER

Lot {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

SIFROL 0.35 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product] 



42

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.35 mg tablets
Pramipexole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP {MM/YYYY}

4. BATCH NUMBER

Lot {number}

5. OTHER



43

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Folding box

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.7 mg tablets
Pramipexole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each tablet contains 1.0 mg pramipexole dihydrochloride monohydrate equivalent to 0.7 mg 
pramipexole.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

30 tablets
100 tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

Do not store above 30°C.
Store in the original package in order to protect from light.



44

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/050/005 [30 tablets]
EU/1/97/050/006 [100 tablets]

13. BATCH NUMBER

Lot {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

SIFROL 0.7 mg

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product] 



45

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.7 mg tablets
Pramipexole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP {MM/YYYY}

4. BATCH NUMBER

Lot {number}

5. OTHER



46

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Folding box

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.26 mg prolonged-release tablets
Pramipexole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains 0.375 mg pramipexole dihydrochloride monohydrate 
equivalent to 0.26 mg pramipexole.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

10 prolonged-release tablets
30 prolonged-release tablets
100 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Once daily.
Swallow whole, do not chew, divide or crush.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

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



47

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/050/013 [10 prolonged-release tablets]
EU/1/97/050/014 [30 prolonged-release tablets]
EU/1/97/050/015 [100 prolonged-release tablets]

13. BATCH NUMBER

Lot {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

SIFROL 0.26 mg prolonged-release tablets

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product] 



48

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.26 mg prolonged-release tablets
Pramipexole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP {MM/YYYY}

4. BATCH NUMBER

Lot {number}

5. OTHER



49

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Folding box

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.52 mg prolonged-release tablets
Pramipexole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains 0.75 mg pramipexole dihydrochloride monohydrate equivalent 
to 0.52 mg pramipexole.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

10 prolonged-release tablets
30 prolonged-release tablets
100 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Once daily.
Swallow whole, do not chew, divide or crush.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

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



50

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/050/016 [10 prolonged-release tablets]
EU/1/97/050/017 [30 prolonged-release tablets]
EU/1/97/050/018 [100 prolonged-release tablets]

13. BATCH NUMBER

Lot {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

SIFROL 0.52 mg prolonged-release tablets

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product] 



51

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 0.52 mg prolonged-release tablets
Pramipexole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP {MM/YYYY}

4. BATCH NUMBER

Lot {number}

5. OTHER



52

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Folding box

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 1.05 mg prolonged-release tablets
Pramipexole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains 1.5 mg pramipexole dihydrochloride monohydrate equivalent 
to 1.05 mg pramipexole.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

10 prolonged-release tablets
30 prolonged-release tablets
100 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Once daily.
Swallow whole, do not chew, divide or crush.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

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



53

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/050/019 [10 prolonged-release tablets]
EU/1/97/050/020 [30 prolonged-release tablets]
EU/1/97/050/021 [100 prolonged-release tablets]

13. BATCH NUMBER

Lot {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

SIFROL 1.05 mg prolonged-release tablets

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product] 



54

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 1.05 mg prolonged-release tablets
Pramipexole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP {MM/YYYY}

4. BATCH NUMBER

Lot {number}

5. OTHER



55

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Folding box

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 1.57 mg prolonged-release tablets
Pramipexole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains 2.25 mg pramipexole dihydrochloride monohydrate equivalent 
to 1.57 mg pramipexole

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

10 prolonged-release tablets
30 prolonged-release tablets
100 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Once daily.
Swallow whole, do not chew, divide or crush.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

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



56

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/050/028 [10 prolonged-release tablets]
EU/1/97/050/029 [30 prolonged-release tablets]
EU/1/97/050/030 [100 prolonged-release tablets]

13. BATCH NUMBER

Lot {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

SIFROL 1.57 mg prolonged-release tablets

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product] 



57

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 1.57 mg prolonged-release tablets
Pramipexole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP {MM/YYYY}

4. BATCH NUMBER

Lot {number}

5. OTHER



58

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Folding box

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 2.1 mg prolonged-release tablets
Pramipexole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains 3 mg pramipexole dihydrochloride monohydrate equivalent to
2.1 mg pramipexole.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

10 prolonged-release tablets
30 prolonged-release tablets
100 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Once daily.
Swallow whole, do not chew, divide or crush.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

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



59

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/050/022 [10 prolonged-release tablets]
EU/1/97/050/023 [30 prolonged-release tablets]
EU/1/97/050/024 [100 prolonged-release tablets]

13. BATCH NUMBER

Lot {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

SIFROL 2.1 mg prolonged-release tablets

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product] 



60

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 2.1 mg prolonged-release tablets
Pramipexole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP {MM/YYYY}

4. BATCH NUMBER

Lot {number}

5. OTHER



61

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Folding box

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 2.62 mg prolonged-release tablets
Pramipexole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains 3.75 mg pramipexole dihydrochloride monohydrate equivalent 
to 2.62 mg pramipexole

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

10 prolonged-release tablets
30 prolonged-release tablets
100 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Once daily.
Swallow whole, do not chew, divide or crush.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

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



62

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/050/031 [10 prolonged-release tablets]
EU/1/97/050/032 [30 prolonged-release tablets]
EU/1/97/050/033 [100 prolonged-release tablets]

13. BATCH NUMBER

Lot {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

SIFROL 2.62 mg prolonged-release tablets

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product] 



63

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 2.62 mg prolonged-release tablets
Pramipexole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP {MM/YYYY}

4. BATCH NUMBER

Lot {number}

5. OTHER



64

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

Folding box

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 3.15 mg prolonged-release tablets
Pramipexole

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each prolonged-release tablet contains 4.5 mg pramipexole dihydrochloride monohydrate equivalent 
to 3.15 mg pramipexole.

3. LIST OF EXCIPIENTS

4. PHARMACEUTICAL FORM AND CONTENTS

10 prolonged-release tablets
30 prolonged-release tablets
100 prolonged-release tablets

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Oral use.
Once daily.
Swallow whole, do not chew, divide or crush.
Read the package leaflet before use.

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP {MM/YYYY}

9. SPECIAL STORAGE CONDITIONS

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



65

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/97/050/025 [10 prolonged-release tablets]
EU/1/97/050/026 [30 prolonged-release tablets]
EU/1/97/050/027 [100 prolonged-release tablets]

13. BATCH NUMBER

Lot {number}

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

SIFROL 3.15 mg prolonged-release tablets

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA

PC: {number} [product code]
SN: {number} [serial number]
NN: {number} [national reimbursement number or other national number identifying the medicinal 
product] 



66

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS

Blister

1. NAME OF THE MEDICINAL PRODUCT

SIFROL 3.15 mg prolonged-release tablets
Pramipexole

2. NAME OF THE MARKETING AUTHORISATION HOLDER

Boehringer Ingelheim (Logo)

3. EXPIRY DATE

EXP {MM/YYYY}

4. BATCH NUMBER

Lot {number}

5. OTHER



67

B. PACKAGE LEAFLET



68

Package leaflet: Information for the user

SIFROL 0.088 mg tablets
SIFROL 0.18 mg tablets
SIFROL 0.35 mg tablets
SIFROL 0.7 mg tablets

Pramipexole

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any of the side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet: 
1. What SIFROL is and what it is used for
2. What you need to know before you take SIFROL
3. How to take SIFROL
4. Possible side effects
5. How to store SIFROL
6. Contents of the pack and other information

1. What SIFROL is and what it is used for

SIFROL contains the active substance pramipexole and belongs to a group of medicines known as 
dopamine agonists, which stimulate dopamine receptors in the brain. Stimulation of the dopamine 
receptors triggers nerve impulses in the brain that help to control body movements.

SIFROL is used to:
- treat the symptoms of primary Parkinson’s disease in adults. It can be used alone or in 

combination with levodopa (another medicine for Parkinson’s disease).
- treat the symptoms of moderate to severe primary Restless Legs Syndrome in adults.

2. What you need to know before you take SIFROL

Do not take SIFROL:
- if you are allergic to pramipexole or to any of the other ingredients of this medicine (listed in

section 6).

Warnings and precautions
Talk to your doctor before taking SIFROL. Tell your doctor if you have (had) or develop any medical 
conditions or symptoms, especially any of the following:
- Kidney disease.
- Hallucinations (seeing, hearing or feeling things that are not there). Most hallucinations are visual.
- Dyskinesia (e.g. abnormal, uncontrolled movements of the limbs). If you have advanced 

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

- Dystonia (inability of keeping your body and neck straight and upright (axial dystonia)). In 
particular, you may experience forward flexion of the head and neck (also called antecollis), 
forward bending of the lower back (also called camptocormia) or sidewards bending of the back 
(also called pleurothotonus or Pisa Syndrome).

- Sleepiness and episodes of suddenly falling asleep.



69

- Psychosis (e.g. comparable with symptoms of schizophrenia).
- Vision impairment. You should have regular eye examinations during treatment with SIFROL.
- Severe heart or blood vessels disease. You will need to have your blood pressure checked 

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

- Augmentation. You may experience that symptoms start earlier than usual, be more intense and 
involve other limbs.

Tell your doctor if you or your family/carer notices that you are developing urges or cravings to 
behave in ways that are unusual for you and you cannot resist the impulse, drive or temptation to carry 
out certain activities that could harm yourself or others. These are called impulse control disorders and 
can include behaviours such as addictive gambling, excessive eating or spending, an abnormally high 
sex drive or preoccupation with an increase in sexual thoughts or feelings. Your doctor may need to 
adjust or stop your dose.

Tell your doctor if you or your family/carer notices that you are developing mania (agitation, feeling 
elated or over-excited) or delirium (decreased awareness, confusion or loss of reality). Your doctor 
may need to adjust or stop your dose.

Tell your doctor if you experience symptoms such as depression, apathy, anxiety, fatigue, sweating or 
pain after stopping or reducing your SIFROL treatment. If the problems persist more than a few 
weeks, your doctor may need to adjust your treatment.

Tell your doctor if you are developing an inability of keeping your body and neck straight and upright 
(axial dystonia). If this happens, your doctor may want to adjust or change your medication.

Children and adolescents
SIFROL is not recommended for use in children or adolescents under 18 years.

Other medicines and SIFROL
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This includes medicines, herbal remedies, health foods or supplements that you have 
obtained without a prescription.

You should avoid taking SIFROL together with antipsychotic medicines.

Take care if you are taking the following medicines:
- cimetidine (to treat excess stomach acid and stomach ulcers)
- amantadine (which can be used to treat Parkinson’s disease)
- mexiletine (to treat irregular heartbeats, a condition known as ventricular arrhythmia)
- zidovudine (which can be used to treat the acquired immune deficiency syndrome (AIDS), a 

disease of the human immune system)
- cisplatin (to treat various types of cancers)
- quinine (which can be used for the prevention of painful night-time leg cramps and for the 

treatment of a type of malaria known as falciparum malaria (malignant malaria))
- procainamide (to treat irregular heart beat)

If you are taking levodopa, the dose of levodopa is recommended to be reduced when you start 
treatment with SIFROL.

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 SIFROL may affect your ability to drive and operate machinery.

SIFROL with food, drink and alcohol
You should be cautious while drinking alcohol during treatment with SIFROL.
SIFROL can be taken with or without food.



70

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor for advice before taking this medicine. Your doctor will then 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 SIFROL if you are 
pregnant unless your doctor tells you to do so.

SIFROL should not be used during breast-feeding. SIFROL can reduce the production of breast milk. 
Also, it can pass into the breast milk and can reach your baby. If use of SIFROL is unavoidable, 
breast-feeding should be stopped.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines
SIFROL can cause hallucinations (seeing, hearing or feeling things that are not there). If affected, do 
not drive or use machines.

SIFROL has been associated with 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 
machinery. You should tell your doctor if this occurs.

3. How to take SIFROL 

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. The doctor will advise you on the right dosing.

You can take SIFROL with or without food. Swallow the tablets with water.

Parkinson’s disease
The daily dose is to be taken divided into 3 equal doses.

During the first week, the usual dose is 1 tablet SIFROL 0.088 mg three times a day (equivalent to 
0.264 mg daily):

1st week
Number of tablets 1 tablet SIFROL 0.088 mg three times a day
Total daily dose (mg) 0.264

This will be increased every 5-7 days as directed by your doctor until your symptoms are controlled 
(maintenance dose).

2nd week 3rd week
Number of tablets 1 tablet SIFROL 0.18 mg 

three times a day
OR
2 tablets SIFROL 0.088 mg 
three times a day

1 tablet SIFROL 0.35 mg 
three times a day
OR
2 tablets SIFROL 0.18 mg 
three times a day

Total daily dose (mg) 0.54 1.1

The usual maintenance dose is 1.1 mg per day. However, your dose may have to be increased even 
further. If necessary, your doctor may increase your tablet dose up to a maximum of 3.3 mg of 
pramipexole a day. A lower maintenance dose of three SIFROL 0.088 mg tablets a day is also 
possible.



71

Lowest maintenance dose Highest maintenance dose
Number of tablets 1 tablet SIFROL 0.088 mg 

three times a day
1 tablet SIFROL 0.7 mg
and 1 tablet SIFROL 0.35 
mg three times a day

Total daily dose (mg) 0.264 3.15

Patients with kidney disease
If you have moderate or severe kidney disease, your doctor will prescribe a lower dose. In this case, 
you will have to take the tablets only once or twice a day. If you have moderate kidney disease, the 
usual starting dose is 1 tablet SIFROL 0.088 mg twice a day. In severe kidney disease, the usual 
starting dose is just 1 tablet SIFROL 0.088 mg a day.

Restless Legs Syndrome
The dose is usually taken once a day, in the evening, 2-3 hours before bedtime.

During the first week, the usual dose is 1 tablet SIFROL 0.088 mg once a day (equivalent to 0.088 mg 
daily):

1st week
Number of tablets 1 tablet SIFROL 0.088 mg
Total daily dose (mg) 0.088

This will be increased every 4-7 days as directed by your doctor until your symptoms are controlled 
(maintenance dose).

2nd week 3rd week 4th week
Number of 
tablets

1 tablet SIFROL 0.18 mg
OR
2 tablets SIFROL
0.088 mg

1 tablet SIFROL 0.35 mg
OR
2 tablets SIFROL 0.18 mg 
OR
4 tablets SIFROL
0.088 mg

1 tablet SIFROL 0.35 mg 
and 1 tablet SIFROL
0.18 mg
OR
3 tablets SIFROL 0.18 mg
OR
6 tablets SIFROL 0.088 mg

Total daily 
dose (mg)

0.18 0.35 0.54

The daily dose should not exceed 6 tablets SIFROL 0.088 mg or a dose of 0.54 mg (0.75 mg 
pramipexole salt).

If you stop taking your tablets for more than a few days and want to restart the treatment, you must 
start again at the lowest dose. You can then build up the dose again, as you did the first time. Ask your 
doctor for advice.

Your doctor 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 take more SIFROL than you should
If you accidentally take too many tablets,
- Contact your doctor or nearest hospital casualty department immediately for advice.
- You may experience vomiting, restlessness, or any of the side effects as described in section 4 

“Possible side effects”.



72

If you forget to take SIFROL
Do not worry. Simply leave out that dose completely and then take your next dose at the right time. 
Do not try to make up for the missed dose.

If you stop taking SIFROL
Do not stop taking SIFROL without first talking to your doctor. If you have to stop taking this 
medicine, your doctor will reduce the dose gradually. This reduces the risk of worsening symptoms.

If you suffer from Parkinson’s disease you should not stop treatment with SIFROL abruptly. A sudden 
stop could cause you to develop a medical condition called neuroleptic malignant syndrome which 
may represent a major health risk. The symptoms 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 SIFROL you may also develop a medical condition called dopamine agonist 
withdrawal syndrome. The symptoms include depression, apathy, anxiety, fatigue, sweating or pain. If 
you experience these symptoms you should contact your physician.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Evaluation 
of these side effects is based on the following frequencies:

Very common may affect more than 1 in 10 people
Common may affect up to 1 in 10 people
Uncommon may affect up to 1 in 100 people
Rare may affect up to 1 in 1,000 people
Very rare may affect up to 1 in 10,000 people
Not known Frequency cannot be estimated from the available data

If you suffer from Parkinson’s disease, you may experience the following side effects:

Very common:
- Dyskinesia (e.g. abnormal, uncontrolled movements of the limbs)
- Sleepiness 
- Dizziness
- Nausea (sickness)

Common:
- Urge to behave in an unusual way
- Hallucinations (seeing, hearing 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



73

- Visual impairment
- Vomiting (being sick)
- Weight loss including decreased appetite

Uncommon:
- Paranoia (e.g. excessive fear for one’s own well-being)
- Delusion
- Excessive daytime sleepiness and suddenly falling asleep
- Amnesia (memory disturbance)
- Hyperkinesia (increased movements and inability to keep still)
- Weight increase
- Allergic reactions (e.g. rash, itching, hypersensitivity)
- Fainting
- Cardiac failure (heart problems which can cause shortness of breath or ankle swelling)*
- Inappropriate antidiuretic hormone secretion*
- Restlessness
- Dyspnoea (difficulties to breathe)
- Hiccups
- Pneumonia (infection of the lungs)
- Inability to resist the impulse, drive or temptation 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 behaviour 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)

Rare:
- Mania (agitation, feeling elated or over-excited)

Not known:
- After stopping or reducing your SIFROL treatment: Depression, apathy, anxiety, fatigue, sweating 

or pain may occur (called dopamine agonist withdrawal syndrome or DAWS).

Tell your doctor if you experience any of these behaviours; he will discuss ways of managing or 
reducing the symptoms.

For the side effects marked with * a precise frequency estimation is not possible, since these side 
effects were not observed in clinical studies among 2,762 patients treated with pramipexole. The 
frequency category is probably not greater than “uncommon”.

If you suffer from Restless Legs Syndrome, you may experience the following side effects:

Very common:
- Nausea (sickness)

Common:
- Changes in sleep pattern, such as sleeplessness (insomnia) and sleepiness
- Tiredness (fatigue)
- Headache
- Abnormal dreams
- Constipation
- Dizziness
- Vomiting (being sick)



74

Uncommon:
- Urge to behave in an unusual way*
- Cardiac failure (heart problems which can cause shortness of breath or ankle swelling)*
- Inappropriate antidiuretic hormone secretion*
- Dyskinesia (e.g. abnormal, uncontrolled movements of the limbs)
- Hyperkinesia (increased movements and inability to keep still)*
- Paranoia (e.g. excessive fear for one’s own well-being)*
- Delusion*
- Amnesia (memory disturbance)*
- Hallucinations (seeing, hearing or feeling things that are not there)
- Confusion
- Excessive daytime sleepiness and suddenly falling asleep 
- Weight increase
- Hypotension (low blood pressure)
- Excess of fluid, usually in the legs (peripheral oedema)
- Allergic reactions (e.g. rash, itching, hypersensitivity)
- Fainting
- Restlessness
- Visual impairment
- Weight loss including decreased appetite
- Dyspnoea (difficulties to breathe)
- Hiccups
- Pneumonia (infection of the lungs)*
- Inability to resist the impulse, drive or temptation 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 behaviour 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)*
- Mania (agitation, feeling elated or over-excited)*
- Delirium (decreased awareness, confusion, loss of reality)*

Not known:
- After stopping or reducing your SIFROL treatment: Depression, apathy, anxiety, fatigue, sweating 

or pain may occur (called dopamine agonist withdrawal syndrome or DAWS).

Tell your doctor if you experience any of these behaviors; he will discuss ways of managing or 
reducing the symptoms.

For the side effects marked with * a precise frequency estimation is not possible, since these side 
effects were not observed in clinical studies among 1,395 patients treated with pramipexole. The 
frequency category is probably not greater than “uncommon”.

Reporting of side effects

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

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

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

this medicine.

5. How to store SIFROL

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

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


75

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 
refers to the last day of that month.

Do not store above 30°C.
Store in the original package to protect the tablets from light.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What SIFROL contains

The active substance is pramipexole.

Each tablet contains 0.088 mg, 0.18 mg, 0.35 mg, or 0.7 mg pramipexole as 0.125 mg, 0.25 mg, 
0.5 mg, or 1 mg pramipexole dihydrochloride monohydrate, respectively.

The other ingredients are mannitol, maize starch, anhydrous colloidal silica, povidone K 25 and
magnesium stearate.

What SIFROL looks like and contents of the pack
SIFROL 0.088 mg tablets are white, of round shape, flat, and without scoring.

SIFROL 0.18 mg tablets and SIFROL 0.35 mg tablets are white, of oval shape, and flat. Tablets are 
scored on both sides and breakable in halves.

SIFROL 0.7 mg tablets are white, of round shape, and flat. Tablets are scored on both sides and 
breakable in halves.

All tablets have the Boehringer Ingelheim company symbol embossed on one side and the codes P6, 
P7, P8, or P9 on the other side, representing the tablet strengths 0.088 mg, 0.18 mg, 0.35 mg, and 
0.7 mg, respectively.

All strengths of SIFROL are available in aluminium blister strips of 10 tablets per strip, in cartons 
containing 3 or 10 blister strips (30 or 100 tablets). Not all pack sizes may be marketed.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
D-55216 Ingelheim am Rhein
Germany



76

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG 
Lietuvos filialas
Tel: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG 
Magyarországi Fióktelepe
Tel: +36 1 299 89 00

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-0

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp.zo.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena - Sucursala Bucureşti
Tel: +40 21 302 28 00

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG 
Podružnica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211



77

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB 
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.



78

Package leaflet: Information for the user

SIFROL 0.26 mg prolonged-release tablets
SIFROL 0.52 mg prolonged-release tablets
SIFROL 1.05 mg prolonged-release tablets
SIFROL 1.57 mg prolonged-release tablets
SIFROL 2.1 mg prolonged-release tablets
SIFROL 2.62 mg prolonged-release tablets
SIFROL 3.15 mg prolonged-release tablets

Pramipexole

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any of the side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4.

What is in this leaflet: 
1. What SIFROL is and what it is used for
2. What you need to know before you take SIFROL
3. How to take SIFROL
4. Possible side effects
5. How to store SIFROL
6. Contents of the pack and other information

1. What SIFROL is and what it is used for

SIFROL contains the active substance pramipexole and belongs to a group of medicines known as 
dopamine agonists, which stimulate dopamine receptors in the brain. Stimulation of the dopamine 
receptors triggers nerve impulses in the brain that help to control body movements.

SIFROL is used to treat the symptoms of primary Parkinson’s disease in adults. It can be used alone or 
in combination with levodopa (another medicine for Parkinson’s disease).

2. What you need to know before you take SIFROL

Do not take SIFROL:
- if you are allergic to pramipexole or to any of the other ingredients of this medicine (listed in 

section 6).

Warnings and precautions
Talk to your doctor before taking SIFROL. Tell your doctor if you have (had) or develop any medical 
conditions or symptoms, especially any of the following:
- Kidney disease
- Hallucinations (seeing, hearing or feeling things that are not there). Most hallucinations are visual.
- Dyskinesia (e.g. abnormal, uncontrolled movements of the limbs). If you have advanced 

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

- Dystonia (inability of keeping your body and neck straight and upright (axial dystonia)). In 
particular, you may experience forward flexion of the head and neck (also called antecollis), 
forward bending of the lower back (also called camptocormia) or sidewards bending of the back 
(also called pleurothotonus or Pisa Syndrome).



79

- Sleepiness and episodes of suddenly falling asleep
- Psychosis (e.g. comparable with symptoms of schizophrenia)
- Vision impairment. You should have regular eye examinations during treatment with SIFROL.
- Severe heart or blood vessels disease. You will need to have your blood pressure checked 

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

Tell your doctor if you or your family/carer notices that you are developing urges or cravings to 
behave in ways that are unusual for you and you cannot resist the impulse, drive or temptation to carry 
out certain activities that could harm yourself or others. These are called impulse control disorders and 
can include behaviours such as addictive gambling, excessive eating or spending, an abnormally high 
sex drive or preoccupation with an increase in sexual thoughts or feelings. Your doctor may need to 
adjust or stop your dose.

Tell your doctor if you or your family/carer notices that you are developing mania (agitation, feeling 
elated or over-excited) or delirium (decreased awareness, confusion, loss of reality). Your doctor may 
need to adjust or stop your dose.

Tell your doctor if you experience symptoms such as depression, apathy, anxiety, fatigue, sweating or 
pain after stopping or reducing your SIFROL treatment. If the problems persist more than a few 
weeks, your doctor may need to adjust your treatment.

Tell your doctor if you are developing an inability of keeping your body and neck straight and upright 
(axial dystonia). If this happens, your doctor may want to adjust or change your medication.

SIFROL prolonged-release tablets is a specially designed tablet from which the active ingredient is 
gradually released, once the tablet has been ingested. Parts of tablets may occasionally be passed and 
seen in the stool (faeces) and may look like whole tablets. Inform your doctor if you find tablet pieces 
in your faeces.

Children and adolescents
SIFROL is not recommended for use in children or adolescents under 18 years.

Other medicines and SIFROL
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This includes medicines, herbal remedies, health foods or supplements that you have 
obtained without a prescription.

You should avoid taking SIFROL together with antipsychotic medicines.

Take care if you are taking the following medicines:
- cimetidine (to treat excess stomach acid and stomach ulcers)
- amantadine (which can be used to treat Parkinson’s disease)
- mexiletine (to treat irregular heartbeats, a condition known as ventricular arrhythmia)
- zidovudine (which can be used to treat the acquired immune deficiency syndrome (AIDS), a 

disease of the human immune system)
- cisplatin (to treat various types of cancers)
- quinine (which can be used for the prevention of painful night-time leg cramps and for the 

treatment of a type of malaria known as falciparum malaria (malignant malaria))
- procainamide (to treat irregular heart beat)

If you are taking levodopa, the dose of levodopa is recommended to be reduced when you start 
treatment with SIFROL.

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 SIFROL may affect your ability to drive and operate machinery.



80

SIFROL with food, drink and alcohol
You should be cautious while drinking alcohol during treatment with SIFROL.
SIFROL can be taken with or without food.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask
your doctor for advice before taking this medicine. Your doctor will then 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 SIFROL if you are 
pregnant unless your doctor tells you to do so.

SIFROL should not be used during breast-feeding. SIFROL can reduce the production of breast milk. 
Also, it can pass into the breast milk and can reach your baby. If use of SIFROL is unavoidable, 
breast-feeding should be stopped.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines
SIFROL can cause hallucinations (seeing, hearing or feeling things that are not there). If affected, do 
not drive or use machines.

SIFROL has been associated with 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 
machinery. You should tell your doctor if this occurs.

3. How to take SIFROL

Always take this medicine exactly as your doctor has told you. Check with your doctor if you are not 
sure. The doctor will advise you on the right dosing.

Take SIFROL prolonged-release tablets only once a day and each day at about the same time.

You can take SIFROL with or without food. Swallow the tablets whole with water. 

Do not chew, divide or crush the prolonged-
release tablets. If you do, there is a danger you 
could overdose, because the medicine may be 
released into your body too quickly.

During the first week, the usual daily dose is 0.26 mg pramipexole. 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 prolonged-release tablets
Week Daily dose (mg) Number of tablets
1 0.26 One SIFROL 0.26 mg prolonged-release tablet.
2 0.52 One SIFROL 0.52 mg prolonged-release tablet,

OR
two SIFROL 0.26 mg prolonged-release tablets.

3 1.05 One SIFROL 1.05 mg prolonged-release tablet,
OR
two SIFROL 0.52 mg prolonged-release tablets,



81

OR
four SIFROL 0.26 mg prolonged-release tablets.

The usual maintenance dose is 1.05 mg per day. However, your dose may have to be increased even 
further. If necessary, your doctor may increase your dose up to a maximum of 3.15 mg of pramipexole 
a day. A lower maintenance dose of one SIFROL 0.26 mg prolonged-release tablet 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 0.26 mg 
prolonged-release tablets only every other day for the first week. After that, your doctor may increase 
the dosing frequency to one 0.26 mg prolonged-release tablet every day. If a further dose increase is 
necessary, your doctor may adjust it in steps of 0.26 mg pramipexole.

If you have serious kidney problems, your doctor may need to switch you to a different pramipexole 
medicine. If during treatment your kidney problems get worse, you should contact your doctor as soon 
as possible.

If you are switching from SIFROL (immediate release) tablets
Your doctor will base your dose of SIFROL prolonged-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 prolonged-release tablets next morning and do not take any more SIFROL (immediate 
release) tablets.

If you take more SIFROL than you should
If you accidentally take too many tablets,
- Contact your doctor or nearest hospital casualty department immediately for advice.
- You may experience vomiting, restlessness, or any of the side effects as described in section 4 

“Possible side effects”.

If you forget to take SIFROL
If you forget to take a dose of SIFROL, 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, simply take the next single dose at the usual time. Do not take a 
double dose to make up for a forgotten tablet dose.

If you stop taking SIFROL
Do not stop taking SIFROL without first talking to your doctor. If you have to stop taking this 
medicine, your doctor will reduce the dose gradually. This reduces the risk of worsening symptoms.

If you suffer from Parkinson’s disease you should not stop treatment with SIFROL abruptly. A sudden 
stop could cause you to develop a medical condition called neuroleptic malignant syndrome which 
may represent a major health risk. The symptoms 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 SIFROL you may also develop a medical condition called dopamine agonist 
withdrawal syndrome. The symptoms include depression, apathy, anxiety, fatigue, sweating or pain. If 
you experience these symptoms you should contact your physician.



82

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Evaluation 
of these side effects is based on the following frequencies:

Very common may affect more than 1 in 10 people
Common may affect up to 1 in 10 people
Uncommon may affect up to 1 in 100 people
Rare may affect up to1 in 1,000 people
Very rare may affect up to 1 in 10,000 people
Not known Frequency cannot be estimated from the available data

You may experience the following side effects:

Very common:
- Dyskinesia (e.g. abnormal, uncontrolled movements of the limbs)
- Sleepiness 
- Dizziness
- Nausea (sickness)

Common:
- Urge to behave in an unusual way
- Hallucinations (seeing, hearing 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:
- Paranoia (e.g. excessive fear for one’s own well-being)
- Delusion
- Excessive daytime sleepiness and suddenly falling asleep
- Amnesia (memory disturbance)
- Hyperkinesia (increased movements and inability to keep still)
- Weight increase
- Allergic reactions (e.g. rash, itching, hypersensitivity)
- Fainting
- Cardiac failure (heart problems which can cause shortness of breath or ankle swelling)*
- Inappropriate antidiuretic hormone secretion*
- Restlessness
- Dyspnoea (difficulties to breathe)
- Hiccups
- Pneumonia (infection of the lungs)
- Inability to resist the impulse, drive or temptation 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.



83

- Altered or increased sexual interest and behaviour 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)

Rare:
- Mania (agitation, feeling elated or over-excited)

Not known:
- After stopping or reducing your SIFROL treatment: Depression, apathy, anxiety, fatigue, sweating 

or pain may occur (called dopamine agonist withdrawal syndrome or DAWS).

Tell your doctor if you experience any of these behaviors; he will discuss ways of managing or 
reducing the symptoms.

For the side effects marked with * a precise frequency estimation is not possible, since these side 
effects were not observed in clinical studies among 2,762 patients treated with pramipexole. The 
frequency category is probably not greater than “uncommon”.

Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine.

5. How to store SIFROL

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

Do not use this medicine after the expiry date which is stated on the carton after EXP. The expiry date 
refers to the last day of that month.

Store in the original package in order to protect from moisture.
This medicinal product does not require any special temperature storage conditions.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What SIFROL contains

The active substance is pramipexole.

Each tablet contains 0.26 mg, 0.52 mg, 1.05 mg, 1.57 mg, 2.1 mg, 2.62 mg, or 3.15 mg pramipexole as 
0.375 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, or 4.5 mg pramipexole dihydrochloride 
monohydrate, respectively.

The other ingredients are hypromellose 2208, maize starch, carbomer 941, colloidal anhydrous silica, 
magnesium stearate.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


84

What SIFROL looks like and contents of the pack
SIFROL 0.26 mg and 0.52 mg prolonged-release tablets are white to off-white, of round shape, and 
have bevelled edges.
SIFROL 1.05 mg, 1.57 mg, 2.1 mg, 2.62 mg and 3.15 mg prolonged-release tablets are white to off-
white and of oval shape.

All tablets have the Boehringer Ingelheim company symbol embossed on one side and the codes P1, 
P2, P3, P12, P4, P13, or P5 on the other side, representing the tablet strengths 0.26 mg, 0.52 mg, 
1.05 mg, 1.57 mg, 2.1 mg, 2.62 mg and 3.15 mg, respectively.

All strengths of SIFROL are available in aluminium blister strips of 10 tablets per strip, in cartons 
containing 1, 3 or 10 blister strips (10, 30 or 100 prolonged-release tablets). Not all pack sizes may be 
marketed.

Marketing Authorisation Holder

Boehringer Ingelheim International GmbH
D-55216 Ingelheim am Rhein
Germany

Manufacturer

Boehringer Ingelheim Pharma GmbH & Co. KG
D-55216 Ingelheim am Rhein
Germany

Rottendorf Pharma GmbH
Ostenfelder Strasse 51 – 61
59320 Ennigerloh
Germany



85

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Lietuva
Boehringer Ingelheim RCV GmbH & Co KG 
Lietuvos filialas
Tel: +370 37 473922

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ -
клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
SCS Boehringer Ingelheim Comm.V
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG 
Magyarországi Fióktelepe
Tel: +36 1 299 89 00

Danmark
Boehringer Ingelheim Danmark A/S
Tlf: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900

Nederland
Boehringer Ingelheim b.v.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Norway KS
Tlf: +47 66 76 13 00

Ελλάδα
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Österreich
Boehringer Ingelheim RCV GmbH & Co KG
Tel: +43 1 80 105-0

España
Boehringer Ingelheim España, S.A.
Tel: +34 93 404 51 00

Polska
Boehringer Ingelheim Sp.zo.o.
Tel: +48 22 699 0 699

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim, Unipessoal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG 
Viena - Sucursala Bucureşti
Tel: +40 21 302 28 00

Ireland
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620

Slovenija
Boehringer Ingelheim RCV GmbH & Co KG 
Podružnica Ljubljana
Tel: +386 1 586 40 00

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
Boehringer Ingelheim RCV GmbH & Co KG
organizačná zložka
Tel: +421 2 5810 1211



86

Italia
Boehringer Ingelheim Italia S.p.A.
Tel: +39 02 5355 1

Suomi/Finland
Boehringer Ingelheim Finland Ky
Puh/Tel: +358 10 3102 800

Κύπρος
Boehringer Ingelheim Ellas A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB 
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

United Kingdom
Boehringer Ingelheim Ltd.
Tel: +44 1344 424 600

This leaflet was last revised in {MM/YYYY}.

Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu.



87

ANNEX IV

SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS 
OF THE MARKETING AUTHORISATION(S)



88

Scientific conclusions

Taking into account the PRAC Assessment Report on the PSUR(s) for pramipexole, the scientific 
conclusions of CHMP are as follows: 

Based on evidence from the scientific literature, inclusion of information regarding risk factors of 
dopamine agonist withdrawal syndrome (DAWS) is considered relevant. Presence of impulse control 
disorders (ICD) has been consistently linked to DAWS in six retrospective chart reviews and one 
prospective observational study. High daily dose and high cumulative doses of dopamine agonists 
(DA) has been inconsistently linked to DAWS. Regardless of the inconsistency, the evidence points to 
an association between DAWS and high daily dose and/or cumulative doses of dopamine agonists. 
Based on these findings it is considered relevant to include the risk factors ICD, high daily dose and/or 
cumulative doses of dopamine agonists (DA) in the product information section 4.4.

DAWS has predominantly been reported in patients with Parkinson’s disease (PD), although there are 
reports of it occurring among patients with Restless Legs Syndrome (RLS). The wording about 
discontinuing pramipexole should therefore not be limited to the PD indication. In consequence 
‘tapering’ should be supplemented by ‘discontinuing’ in section 4.4 regarding DAWS, to make the 
wording also applicable for the RLS indication (tapering is not required in the RLS indication).

As DAWS symptoms occur upon dopamine agonist tapering/discontinuation, it is vital to distinguish 
between undermedication of the underlying medical disorder and DAWS. If the DAWS symptoms are 
mistakenly attributed to PD the clinician might increase the dose of levodopa, however this will not 
alleviate the DAWS symptoms. As combination therapy with DA and levodopa are often used, it is 
considered relevant for healthcare professionals to be informed that withdrawal symptoms do not 
respond to increasing of the levodopa dose, to aid in the differential diagnosis.

Further, updates of SmPC section 4.2 and PIL section 3 to include information regarding treatment 
discontinuation and DAWS, are considered relevant.

The CHMP agrees with the scientific conclusions made by the PRAC.

Grounds for the variation to the terms of the marketing authorisation(s)

On the basis of the scientific conclusions for pramipexole the CHMP is of the opinion that the benefit-
risk balance of the medicinal product(s) containing pramipexole is unchanged subject to the proposed 
changes to the product information.

The CHMP recommends that the terms of the marketing authorisation(s) should be varied.


	SUMMARY OF PRODUCT CHARACTERISTICS
	A.	MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B.	CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C.	OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D.	CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	SCIENTIFIC CONCLUSIONS AND GROUNDS FOR THE VARIATION TO THE TERMS OF THE MARKETING AUTHORISATION(S)