pramipexole: prescribing information – dosing, contraindications, interactions, side effects

MIRAPEXIN 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).

MIRAPEXIN 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).

MIRAPEXIN 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).

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 MIRAPEXIN
Week
Dose
(mg of base)
Total Daily Dose
(mg of base)
Dose
(mg of salt)
Total Daily Dose
(mg of salt)
3 × 0.088
0.264
3 × 0.125
0.375
3 × 0.18

Posology

MIRAPEXIN 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 MIRAPEXIN prolonged-release tablets
Week
Daily dose (mg of base)
Daily dose (mg of salt)

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

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.

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

Reproductive system and breast disorders

spontaneous penile erection

General disorders and administration site conditions

fatigue peripheral oedema

dopamine agonist withdrawal syndrome including apathy, anxiety,

depression, fatigue, sweating and pain.
Investigations

weight decrease including decreased appetite weight increase

This side effect has been observed in post-marketing experience. With 95% certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 2 762 patients with Parkinson’s Disease treated with pramipexole.

Restless Legs Syndrome, most common adverse reactions
The most commonly (≥ 5%) reported adverse drug reactions in patients with Restless Legs Syndrome treated with pramipexole were nausea, headache, dizziness and fatigue. Nausea and fatigue were more often reported in female patients treated with MIRAPEXIN (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)
Rare
(≥ 1/10 000 to
< 1/1 000)
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
Restless legs augmentation syndrome headache dizziness somnolance sudden onset of sleep syncope dyskinesia amnesia1 hyperkinesia1

Eye disorders

visual impairment including visual acuity reduced diplopia vision blurred

Cardiac

cardiac failure1

disorders
Vascular disorders

hypotension

Respiratory, thoracic, and mediastinal disorders

dyspnoea hiccups

Gastrointestinal disorders nausea constipation vomiting

Skin and subcutaneous tissue disorders

hypersensitivity pruritus rash

Reproductive system and breast disorders

spontaneous penile erection

General disorders and administration site conditions

fatigue peripheral oedema

dopamine agonist withdrawal syndrome including apathy, anxiety, depression, fatigue, sweating and pain Investigations

weight decrease including decreased appetite weight increase

This side effect has been observed in post-marketing experience. With 95% certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 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 MIRAPEXIN (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.

Based on the analysis of pooled placebo-controlled trials, comprising a total of 1 778 Parkinson’s disease patients on pramipexole and 1 297 patients on placebo, adverse drug reactions were frequently reported for both groups. 67% of patients on pramipexole and 54% of patients on placebo reported at least one adverse drug reaction.

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

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (≥ 1/10);
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data).

The most commonly (≥ 5%) reported adverse drug reactions in patients with Parkinson’s disease more frequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence of somnolence is increased at doses higher than 1.5 mg pramipexole salt per day (see section 4.2). A more frequent adverse drug reaction in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too fast.

Body System
Very common
(≥ 1/10)
Common
(≥ 1/100 to
< 1/10)
Uncommon
(≥ 1/1 000 to
< 1/100)
Rare
(≥ 1/10 000 to
< 1/1 000)
Not known
Infections and infestations

pneumonia

Endocrine disorders

inappropriate antidiuretic hormone 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

Reproductive system and breast disorders

spontaneous penile erection

General disorders and administration site conditions

fatigue peripheral oedema

dopamine agonist withdrawal syndrome including apathy, anxiety,

depression, fatigue, sweating and pain.
Investigations

weight decrease including decreased appetite weight increase

This side effect has been observed in post-marketing experience. With 95% certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 2 762 patients with Parkinson’s Disease treated with pramipexole.

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 MIRAPEXIN (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.

When prescribing MIRAPEXIN 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 MIRAPEXIN. 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 MIRAPEXIN.
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 MIRAPEXIN.
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.

Restless legs augmentation syndrome
Treatment of Restless Legs Syndrome with pramipexole 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.
The risk of augmentation may increase with higher dose. Prior to treatment, patients should be informed that augmentation may occur and should be advised to contact their physician if they

experience symptoms of augmentation. If augmentation is suspected, dose adjustment to the lowest effective dose, or discontinuation of pramipexole should be considered (see section 4.2 and 4.8).

When prescribing MIRAPEXIN 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 MIRAPEXIN. 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 MIRAPEXIN.
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 MIRAPEXIN.
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.

Remnants in stool
Some patients have reported the occurrence of remnants in faeces which may resemble intact MIRAPEXIN prolonged-release tablets. If patients report such an observation, the physician should reassess patient’s response to therapy.

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 MIRAPEXIN.

Combination with levodopa
When MIRAPEXIN 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 MIRAPEXIN.

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.

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).
MIRAPEXIN 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, MIRAPEXIN 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.

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

Hallucinations or somnolence can occur.

Patients being treated with MIRAPEXIN 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).

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

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 MIRAPEXIN 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.

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with MIRAPEXIN 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.

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 MIRAPEXIN 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 MIRAPEXIN 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.

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.

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 MIRAPEXIN prolonged-release tablets given once daily and MIRAPEXIN tablets given three times a day were equivalent.

The once daily administration of MIRAPEXIN 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 MIRAPEXIN 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 MIRAPEXIN prolonged-release tablets, patients were instructed to take study medication without regard to food intake.

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).

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).

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)
3 × 0.088
0.264
3 × 0.125
0.375
3 × 0.18

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)

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

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.

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

Reproductive system and breast disorders

spontaneous penile erection

General disorders and administration site conditions

fatigue peripheral oedema

dopamine agonist withdrawal syndrome including apathy, anxiety,

depression, fatigue, sweating and pain.
Investigations

weight decrease including decreased appetite weight increase

This side effect has been observed in post-marketing experience. With 95% certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 2 762 patients with Parkinson’s Disease treated with pramipexole.

Restless Legs Syndrome, most common adverse reactions
The most commonly (≥ 5%) reported adverse drug reactions in patients with Restless Legs Syndrome treated with pramipexole were nausea, headache, dizziness and fatigue. Nausea and fatigue were more often reported in female patients treated with SIFROL (20.8% and 10.5%, respectively) compared to males (6.7% and 7.3%, respectively).

Table 2: Restless Legs Syndrome
Body System
Very common
(≥ 1/10)
Common
(≥ 1/100 to
< 1/10)
Uncommon
(≥ 1/1 000 to < 1/100)
Rare
(≥ 1/10 000 to
< 1/1 000)
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
Restless legs augmentation syndrome headache dizziness somnolance sudden onset of sleep syncope dyskinesia amnesia1 hyperkinesia1

Eye disorders

visual impairment including visual acuity reduced diplopia vision blurred

Cardiac

cardiac failure1

disorders
Vascular disorders

hypotension

Respiratory, thoracic, and mediastinal disorders

dyspnoea hiccups

Gastrointestinal disorders nausea constipation vomiting

Skin and subcutaneous tissue disorders

hypersensitivity pruritus rash

Reproductive system and breast disorders

spontaneous penile erection

General disorders and administration site conditions

fatigue peripheral oedema

dopamine agonist withdrawal syndrome including apathy, anxiety, depression, fatigue, sweating and pain Investigations

weight decrease including decreased appetite weight increase

This side effect has been observed in post-marketing experience. With 95% certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 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).

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.

Based on the analysis of pooled placebo-controlled trials, comprising a total of 1 778 Parkinson’s disease patients on pramipexole and 1 297 patients on placebo, adverse drug reactions were frequently reported for both groups. 67% of patients on pramipexole and 54% of patients on placebo reported at least one adverse drug reaction.

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

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (≥ 1/10);
common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000); not known (cannot be estimated from the available data).

The most commonly (≥ 5%) reported adverse drug reactions in patients with Parkinson’s disease more frequent with pramipexole treatment than with placebo were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucination, headache and fatigue. The incidence of somnolence is increased at doses higher than 1.5 mg pramipexole salt per day (see section 4.2). A more frequent adverse drug reaction in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of treatment, especially if pramipexole is titrated too fast.

Body System
Very common
(≥ 1/10)
Common
(≥ 1/100 to
< 1/10)
Uncommon
(≥ 1/1 000 to
< 1/100)
Rare
(≥ 1/10 000 to
< 1/1 000)
Not known
Infections and infestations

pneumonia

Endocrine disorders

inappropriate antidiuretic hormone 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

Reproductive system and breast disorder

spontaneous penile erection

General disorders and administration site conditions

fatigue peripheral oedema

dopamine agonist withdrawal syndrome including apathy, anxiety, depression,

fatigue, sweating and pain.
Investigations

weight decrease including decreased appetite weight increase

This side effect has been observed in post-marketing experience. With 95% certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 2 762 patients with Parkinson’s Disease treated with pramipexole.

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.

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.

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.

Restless legs augmentation syndrome
Treatment of Restless Legs Syndrome with pramipexole 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.
The risk of augmentation may increase with higher dose. Prior to treatment, patients should be informed that augmentation may occur and should be advised to contact their physician if they experience symptoms of augmentation. If augmentation is suspected, dose adjustment to the lowest effective dose, or discontinuation of pramipexole should be considered (see section 4.2 and 4.8).

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.

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.

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.

Pregnancy
The effect on pregnancy and lactation has not been investigated in humans. Pramipexole was not teratogenic in rats and rabbits, but was embryotoxic in the rat at maternotoxic doses (see section 5.3).
SIFROL should not be used during pregnancy unless clearly necessary, i.e. if the potential benefit justifies the potential risk to the foetus.

Breast-feeding
As pramipexole treatment inhibits secretion of prolactin in humans, inhibition of lactation is expected.
The excretion of pramipexole into breast milk has not been studied in women. In rats, the concentration of active substance-related radioactivity was higher in breast milk than in plasma.
In the absence of human data, SIFROL should not be used during breast-feeding. However, if its use is unavoidable, breast-feeding should be discontinued.

Fertility
No studies on the effect on human fertility have been conducted. In animal studies, pramipexole affected oestrous cycles and reduced female fertility as expected for a dopamine agonist. However, these studies did not indicate direct or indirect harmful effects with respect to male fertility.

SIFROL 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).

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

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 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.

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.

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.

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 influence of body weight on the therapeutic effect and tolerability of SIFROL prolonged-release tablets was detected.