4.1. Therapeutic indications

Pramipexole 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).

Pramipexole 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 PRAMIPEXOLE

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 Pramipexole, 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).

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 Pramipexole 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 Pramipexole 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 Pramipexole 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 Pramipexole 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 Pramipexole pharmacokinetics has not been investigated.

Paediatric population

The safety and efficacy of Pramipexole in children below 18 years has not been established. There is no relevant use of Pramipexole in the paediatric population for the indication of Parkinson's Disease.

Restless Legs Syndrome

The recommended starting dose of Pramipexole 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 Pramipexole

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) Pramipexole can be discontinued without tapering off. In a 26 week placebo controlled trial, rebound of RLS symptoms (worsening of symptom severity as compared to baseline) was observed in 10% of patients (14 out of 135) after abrupt discontinuation of treatment. This effect was found to be similar across all doses.

Renal impairment

The elimination of pramipexole is dependent on renal function. Patients with a creatinine clearance above 20 ml/min require no reduction in daily dose.

The use of pramipexole 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

Pramipexole 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

Pramipexole is not recommended for use in children and adolescents below 18 years since the efficacy and safety has not been established in this population. Pramipexole 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 Pramipexole 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 Pramipexole. 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 Pramipexole. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore a reduction of 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 pramipexole. 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.

Coadministration 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 readministration of pramipexole at the lowest effective dose may be considered.

Augmentation

Reports in the literature indicate that treatment of Restless Legs Syndrome with dopaminergic medicinal products can result in augmentation. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. Augmentation was specifically investigated in a controlled clinical trial over 26 weeks. Augmentation was observed in 11.8% of patients in the pramipexole group (N = 152) and 9.4% of patients in the placebo group (N = 149). Kaplan-Meier analysis of time to augmentation showed no significant difference between pramipexole and placebo groups.

4.5. Interaction with other medicinal products and other forms of interaction

Plasma protein binding

Pramipexole is bound to plasma proteins to a very low (< 20%) extent, and little biotransformation is seen in man. Therefore, interactions with other medicinal products affecting plasma protein binding or elimination by biotransformation are unlikely. As anticholinergics are mainly eliminated by biotransformation, the potential for an interaction is limited, although an interaction with anticholinergics has not been investigated. There is no pharmacokinetic interaction with selegiline and levodopa.

Inhibitors/competitors of active renal elimination pathway

Cimetidine reduced the renal clearance of pramipexole by approximately 34%, presumably by inhibition of the cationic secretory transport system of the renal tubules. Therefore, medicinal products that are inhibitors of this 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 Pramipexole.

Combination with levodopa

When Pramipexole 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 Pramipexole.

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). Pramipexole 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, Pramipexole 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

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

Hallucinations or somnolence can occur.

Patients being treated with Pramipexole 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.

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

somnolence

headache

sudden onset of

system disorders

dizziness dyskinesia

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.

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 (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 disorders

nausea

constipation vomiting

Skin and subcutaneous tissue disorders

hypersensitivity pruritus rash

General disorders and administration site conditions

fatigue

peripheral oedema

Dopamine agonist withdrawal syndrome including apathy, anxiety, depression, fatigue, sweating and

pain

Investigations

weight decrease including decreased appetite weight increase

1 This side effect has been observed in post-marketing experience. With 95 % certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 1,395 patients with Restless Legs Syndrome treated with pramipexole.

Description of selected adverse reactions

Somnolence

Pramipexole is commonly associated with somnolence and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes (see also section 4.4).

Libido disorders

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

Impulse control disorders

Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including Pramipexole (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, 1.212.85).

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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

There is no clinical experience with massive overdose. The expected adverse drug 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.