Pramipeksol Synthon

Pramipeksol Synthon 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).

Pramipeksol Synthon 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).

Pramipeksol Synthon is indicated 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).

Pramipeksol SynthonIN 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).

Pramipeksol SynthonIN 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).

Pramipeksol Synthon® tablets are indicated for the treatment of Parkinson's disease.

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.

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.

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 Pramipeksol Synthon, depending on reactions in individual patients.

Treatment discontinuation

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

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 Pramipeksol Synthon 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 Pramipeksol Synthon 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 Pramipeksol Synthon 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 Pramipeksol Synthon 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 Pramipeksol Synthon pharmacokinetics has not been investigated.

Paediatric population

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

Restless Legs Syndrome

The recommended starting dose of Pramipeksol Synthon 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).

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) Pramipeksol Synthon 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 Pramipeksol Synthon 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

Pramipeksol Synthon 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

Pramipeksol Synthon is not recommended for use in children and adolescents below 18 years since the efficacy and safety has not been established in this population. Pramipeksol Synthon should not be used in children or adolescents with Tourette Disorder because of a negative benefit-risk balance for this disorder.

Method of administration

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

Posology

Parkinson's disease

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

Initial treatment

Dosages 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 dosage should be titrated to achieve a maximal therapeutic effect.

If a further dose increase is necessary the daily dose should be increased by 0.54 mg base (0.75 mg 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/day.

Maintenance treatment

The individual dose 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 three 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 (1.5 mg of salt). In advanced Parkinson's disease, doses higher than 1.1 mg (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 dosage of levodopa is reduced during both the dose escalation and the maintenance treatment with Pramipeksol Synthon, depending on reactions in individual patients.

Treatment discontinuation

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

Patients with renal impairment

The elimination of pramipexole is dependent on renal function. The following dosage 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 Pramipeksol Synthon 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 Pramipeksol Synthon 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 reduce Pramipeksol Synthon daily dose by the same percentage as the decline in creatinine clearance, i.e. if creatinine clearance declines by 30%, then reduce the Pramipeksol Synthon daily dose 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.

Patients with 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 Pramipeksol Synthon pharmacokinetics has not been investigated.

Paediatric population

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

Tourette Disorder

Paediatric population

Pramipeksol Synthon is not recommended for use in children and adolescents below 18 years since the efficacy and safety has not been established in this population. Pramipeksol Synthon should not be used in children or adolescents with Tourette Disorder because of a negative benefit-risk balance for this disorder.

Method of administration

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

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.

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.

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 Pramipeksol SynthonIN, depending on reactions in individual patients.

Treatment discontinuation

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

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 Pramipeksol SynthonIN 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 Pramipeksol SynthonIN 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 Pramipeksol SynthonIN 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 Pramipeksol SynthonIN 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 Pramipeksol SynthonIN pharmacokinetics has not been investigated.

Paediatric population

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

Restless Legs Syndrome

The recommended starting dose of Pramipeksol SynthonIN 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).

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) Pramipeksol SynthonIN 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 Pramipeksol SynthonIN 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

Pramipeksol SynthonIN 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

Pramipeksol SynthonIN is not recommended for use in children and adolescents below 18 years since the efficacy and safety has not been established in this population. Pramipeksol SynthonIN should not be used in children or adolescents with Tourette Disorder because of a negative benefit-risk balance for this disorder.

Method of administration

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

General Dosing Considerations

Pramipeksol Synthon tablets are taken orally once daily, with or without food.

Pramipeksol Synthon tablets must be swallowed whole and must not be chewed, crushed, or divided.

If a significant interruption in therapy with Pramipeksol Synthon tablets has occurred, re-titration of therapy may be warranted.

Dosing For Parkinson's Disease

The starting dose is 0.375 mg given once per day. Based on efficacy and tolerability, dosages may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day.

In clinical trials, dosage was initiated at 0.375 mg/day and gradually titrated based on individual therapeutic response and tolerability. Doses greater than 4.5 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment.

Due to the flexible dose design used in clinical trials, specific dose-response information could not be determined.

Pramipeksol Synthon tablets may be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter, the dose may be reduced by 0.375 mg per day.

Dosing in Patients with Renal Impairment

In patients with moderate renal impairment (creatinine clearance between 30 and 50 mL/min), Pramipeksol Synthon tablets should initially be taken every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after one week, and before any additional titration in 0.375 mg increments up to 2.25 mg per day. Dose adjustment should occur no more frequently than at weekly intervals.

Pramipeksol Synthon tablets have not been studied in patients with severe renal impairment (creatinine clearance < 30 mL/min) or patients on hemodialysis, and are not recommended in these patients.

Switching From Immediate-Release Pramipexole Tablets To MIRAPEX ER

Patients may be switched overnight from immediate-release pramipexole tablets to Pramipeksol Synthon tablets at the same daily dose. When switching between immediate-release pramipexole tablets and Pramipeksol Synthon tablets, patients should be monitored to determine if dosage adjustment is necessary.

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 Pramipeksol Synthon. 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

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 Pramipeksol Synthon. 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.

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.

Dopamine agonist withdrawal syndrome

To discontinue treatment in patients with Parkinson's disease, pramipexole should be tapered off. Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including pramipexole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain which may be severe. Patients should be informed about this before tapering the dopamine agonist, and monitored regularly thereafter. In case of persistent symptoms, it may be necessary to increase the pramipexole dose temporarily.

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.

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.

Dyskinesias

In advanced Parkinson's disease, in combination treatment with levodopa, dyskinesias can occur during the initial titration of Pramipeksol Synthon. If they occur, the dose of levodopa should be decreased.

Sudden onset of sleep and somnolence

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.

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.

Augmentation

Reports in the literature indicate that treatment of another indication with dopaminergic medicinal products can result in augmentation. Augmentation refers to the earlier onset of symptoms in the evening (or even 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.

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 Pramipeksol SynthonIN. 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

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 Pramipeksol SynthonIN. 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.

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.

Dopamine agonist withdrawal syndrome

To discontinue treatment in patients with Parkinson's disease, pramipexole should be tapered off. Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including pramipexole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain which may be severe. Patients should be informed about this before tapering the dopamine agonist, and monitored regularly thereafter. In case of persistent symptoms, it may be necessary to increase the pramipexole dose temporarily.

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.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Falling Asleep During Activities Of Daily Living And Somnolence

Patients treated with pramipexole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on pramipexole tablets, some perceived that they had no warning signs (sleep attack) such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment. In placebo-controlled clinical trials in Parkinson's disease, the sudden onset of sleep or sleep attacks were reported in 8 of 387 (2%) patients treated with Pramipeksol Synthon tablets compared to 2 of 281 (1%) patients on placebo.

In early Parkinson's disease, somnolence was reported in 36% of 223 patients treated with Pramipeksol Synthon, median dose 3.0 mg/day, compared to 15% of 103 patients on placebo. In advanced Parkinson's disease, somnolence was reported in 15% of 164 patients treated with Pramipeksol Synthon tablets, median dose 3 mg/day, compared to 16% of 178 patients on placebo. It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with Pramipeksol Synthon tablets, advise patients of the potential to develop drowsiness, and specifically ask about factors that may increase the risk for somnolence such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine). If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), MIRAPEX ER tablets should ordinarily be discontinued. If a decision is made to continue Pramipeksol Synthon tablets, advise patients not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Symptomatic Orthostatic Hypotension

Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, Parkinson's disease patients being treated with dopaminergic agonists, including Pramipeksol Synthon, ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk. In placebo-controlled clinical trials in Parkinson's disease, symptomatic orthostatic hypotension was reported in 10 of 387 (3%) patients treated with Pramipeksol Synthon tablets compared to 3 of 281 (1%) patients on placebo. One patient of 387 on Pramipeksol Synthon tablets discontinued treatment due to hypotension.

Impulse Control/Compulsive Behaviors

Case reports and the results of cross-sectional studies suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including Pramipeksol Synthon, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with Pramipeksol Synthon. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Pramipeksol Synthon.

A total of 1056 patients with Parkinson's disease who participated in two Pramipeksol Synthon placebo-controlled studies of up to 33 weeks duration were specifically asked at each visit about the occurrence of these symptoms. A total of 14 of 387 (4%) treated with Pramipeksol Synthon tablets, 12 of 388 (3%) treated with immediate-release pramipexole tablets, and 4 of 281 (1%) treated with placebo reported compulsive behaviors, including pathological gambling, hypersexuality, and/or compulsive buying.

Hallucinations And Psychotic-like Behavior

In placebo-controlled clinical trials in Parkinson's disease, hallucinations (visual or auditory or mixed) were reported in 25 of 387 (6%) patients treated with Pramipeksol Synthon tablets compared to 5 of 281 (2%) patients receiving placebo. Hallucinations led to discontinuation of treatment in 5 of 387 (1%) patients on Pramipeksol Synthon tablets.

Age appears to increase the risk of hallucinations attributable to pramipexole. In placebo-controlled clinical trials in Parkinson's disease, hallucinations were reported in 15 of 162 (9%) SDWLHQWV. \HDUV RI DJH WDNLQJ Pramipeksol Synthon tablets compared to 10 of 225 (4%) patients < 65 years of age taking Pramipeksol Synthon tablets.

Postmarketing reports with dopamine agonists, including Pramipeksol Synthon, indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with Pramipeksol Synthon or after starting or increasing the dose of Pramipeksol Synthon. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.

Patients with a major psychotic disorder should ordinarily not be treated with dopamine agonists, including Pramipeksol Synthon, because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of Pramipeksol Synthon.

Dyskinesia

Pramipeksol Synthon tablets may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia.

Renal Impairment

The elimination of pramipexole is dependent on renal function. Patients with mild renal impairment (a creatinine clearance above 50 mL/min) require no reduction in daily dose. Pramipeksol Synthon tablets have not been studied in patients with moderate to severe renal impairment (creatinine clearance < 50 mL/min) or on hemodialysis.

Rhabdomyolysis

In the clinical development program for immediate-release pramipexole tablets, a single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson's disease. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.

Advise patients to contact a physician if they experience any unexplained muscle pain, tenderness, or weakness, as these may be symptoms of rhabdomyolysis.

Retinal Pathology

Human Data

A two-year open-label, randomized, parallel-group safety study of retinal deterioration and vision compared immediate-release pramipexole tablets and immediate-release ropinirole. Two hundred thirty four Parkinson's disease patients (115 on pramipexole, mean dose 3.0 mg/day and 119 on ropinirole, mean dose 9.5 mg/day) were evaluated using a panel of clinical ophthalmological assessments. Of 234 patients who were evaluable, 196 had been treated for two years and 29 were judged to have developed clinical abnormalities that were considered meaningful (19 patients in each treatment arm had received treatment for less than two years). There was no statistical difference in retinal deterioration between the treatment arms; however, the study was only capable of detecting a very large difference between treatments. In addition, because the study did not include an untreated comparison group (placebo treated), it is unknown whether the findings reported in patients treated with either drug are greater than the background rate in an aging population.

Animal Data

Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in a 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect for humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.

Events Reported With Dopaminergic Therapy

Although the events enumerated below may not have been reported with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date.

Hyperpyrexia and Confusion

Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. If possible, avoid sudden discontinuation or rapid dose reduction in patients taking Pramipeksol Synthon tablets. If the decision is made to discontinue Pramipeksol Synthon tablets, the dose should be tapered to reduce the risk of hyperpyrexia and confusion.

Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, non-ergot derived dopamine agonists can cause them is unknown.

Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the postmarketing experience with immediate-release pramipexole tablets. While the evidence is not sufficient to establish a causal relationship between pramipexole and these fibrotic complications, a contribution of pramipexole cannot be completely ruled out.

Melanoma

Epidemiologic studies have shown that patients with Parkinson's disease have a higher risk (2-to approximately 6-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Pramipeksol Synthon tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Dosing Instructions

Instruct patients to take Pramipeksol Synthon tablets only as prescribed. If a dose is missed, Pramipeksol Synthon tablets should be taken as soon as possible, but no later than 12 hours after the regularly scheduled time. After 12 hours, the missed dose should be skipped and the next dose should be taken on the following day at the regularly scheduled time.

Pramipeksol Synthon tablets can be taken with or without food. If patients develop nausea, advise that taking Pramipeksol Synthon tablets with food may reduce the occurrence of nausea.

Pramipeksol Synthon tablets should be swallowed whole. They should not be chewed, crushed, or divided.

Pramipexole is the active ingredient that is in both Pramipeksol Synthon tablets and immediate-release pramipexole tablets. Ensure that patients do not take both immediate-release pramipexole and Pramipeksol Synthon.

Sedating Effects

Alert patients to the potential sedating effects of Pramipeksol Synthon tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with Pramipeksol Synthon tablets to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., conversations or eating) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, advise caution when patients are taking other sedating medications or alcohol in combination with Pramipeksol Synthon and when taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine).

Impulse Control Symptoms Including Compulsive Behaviors

Alert patients and their caregivers to the possibility that they may experience intense urges to spend money, intense urges to gamble, increased sexual urges, binge eating and/or other intense urges and the inability to control these urges while taking Pramipeksol Synthon.

Hallucinations and Psychotic-like Behavior

Inform patients that hallucinations and other psychotic-like behavior can occur and that the elderly are at a higher risk than younger patients with Parkinson's disease.

Postural (Orthostatic) Hypotension

Advise patients that they may develop postural (orthostatic) hypotension, with or without symptoms such as dizziness, nausea, fainting, or blackouts, and sometimes, sweating. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with Pramipeksol Synthon.

Pregnancy

Because the teratogenic potential of pramipexole has not been completely established in laboratory animals, and because experience in humans is limited, advise women to notify their physicians if they become pregnant or intend to become pregnant during therapy.

Nursing Mothers

Because of the possibility that pramipexole may be excreted in breast milk, advise women to notify their physicians if they intend to breast-feed or are breast-feeding an infant.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Two-year carcinogenicity studies with pramipexole have been conducted in mice and rats. Pramipexole was administered in the diet to mice at doses up to 10 mg/kg/day [or approximately 10 times the maximum recommended human dose (MRHD) of 1.5 mg TID on a mg/m² basis]. Pramipexole was administered in the diet to rats at doses up to 8 mg/kg/day. These doses were associated with plasma AUCs up to approximately 12 times that in humans at the MRHD. No significant increases in tumors occurred in either species.

Pramipexole was not mutagenic or clastogenic in a battery of in vitro (bacterial reverse mutation, V79/HGPRT gene mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) assays.

In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day (5 times the MRHD on a mg/m² basis) prolonged estrus cycles and inhibited implantation. These effects were associated with reductions in serum levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. Pramipeksol Synthon should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/day [5 times the maximum recommended human dose (MRHD) on a mg/m² basis]. Administration of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of organogenesis (gestation days 7 through 16) resulted in a high incidence of total resorption of embryos. The plasma AUC in rats at this dose was 4 times the AUC in humans at the MRHD. These findings are thought to be due to the prolactin-lowering effect of pramipexole, since prolactin is necessary for implantation and maintenance of early pregnancy in rats (but not rabbits or humans). Because of pregnancy disruption and early embryonic loss in these studies, the teratogenic potential of pramipexole could not be adequately evaluated. There was no evidence of adverse effects on embryo-fetal development following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis (plasma AUC was 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day (approximately equivalent to the MRHD on a mg/m² basis) or greater during the latter part of pregnancy and throughout lactation.

Nursing Mothers

A single-dose, radio-labeled study showed that drug-related material was present in rat milk at concentrations three to six times higher than in plasma at equivalent time points.

Studies have shown that pramipexole treatment resulted in an inhibition of prolactin secretion in humans and rats.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from pramipexole, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of Pramipeksol Synthon tablets in pediatric patients have not been evaluated.

Geriatric Use

Pramipexole total oral clearance is approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours. In a placebo-controlled clinical trial of Pramipeksol Synthon tablets in early Parkinson's disease, 47% of the 259 patients ZHUH. \HDUV RI DJH Among patients receiving Pramipeksol Synthon tablets, hallucinations were more common in the elderly, occurring in 13 RI WKH SDWLHQWV. \HDUV RI DJH FRPSDUHG WR RI WKH SDWLHQWV \HDUV RI DJH

Renal Impairment

The elimination of pramipexole is dependent upon renal function. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis.

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

Hallucinations or somnolence can occur.

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

Hallucinations or somnolence can occur.

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. 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

¹ This side effect has been observed in post-marketing experience. With 95 % certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 2,762 patients with Parkinson's Disease treated with pramipexole.

Restless Legs Syndrome, most common adverse reactions

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

Table 2: Restless Legs Syndrome

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

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 Pramipeksol Synthon.

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.

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:

United Kingdom

Yellow Card Scheme

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

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

Expected adverse effects

The following adverse reactions are expected under the use of pramipexole: abnormal dreams, amnesia, behavioural symptoms of impulse control disorders and compulsions such as binge eating, compulsive shopping, hypersexuality and pathological gambling; cardiac failure, confusion, constipation, delusion, dizziness, dyskinesia, dyspnoea, fatigue, hallucinations, headache, hiccups, hyperkinesia, hyperphagia, hypotension, inappropriate antidiuretic hormone secretion, insomnia, libido disorders, nausea, paranoia, peripheral oedema, pneumonia, pruritus, rash and other hypersensitivity; restlessness, somnolence, sudden onset of sleep, syncope, visual impairment including diplopia, vision blurred and visual acuity reduced, vomiting, weight decrease including decreased appetite, weight increase.

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.

Tables 1 and 2 display the frequency of adverse reactions from placebo-controlled clinical trials. The adverse reactions reported in these tables are those events that occurred in 0,1% or more of patients treated with pramipexole and were reported significantly more often in patients taking pramipexole than placebo, or where the event was considered clinically relevant. However, the majority of common adverse reactions were mild to moderate, they usually start early in therapy, and most tended to disappear even as therapy was 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, < 1/10); uncommon (> 1/1,000, < 1/100); rare (> 1/10,000, < 1/1,000); very rare (< 1/10,000).

Parkinson's disease, most common adverse effects

The most commonly (>5%) reported adverse 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/day. 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

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.

Other indication, most common adverse effects

The most commonly (> 5%) reported adverse drug reactions in patients with other indication 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: Other indication

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 other indication treated with pramipexole.

Somnolence

Libido disorders

Pramipexole may 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 Pramipeksol Synthon.

In a cross-sectional, retrospective screening and case-control study including 3090 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.

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 1,923 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. 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

¹ This side effect has been observed in post-marketing experience. With 95 % certainty, the frequency category is not greater than uncommon, but might be lower. A precise frequency estimation is not possible as the side effect did not occur in a clinical trial database of 2,762 patients with Parkinson's Disease treated with pramipexole.

Restless Legs Syndrome, most common adverse reactions

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

Table 2: Restless Legs Syndrome

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

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 Pramipeksol SynthonIN.

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.

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:

United Kingdom

Yellow Card Scheme

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

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Falling Asleep During Activities of Daily Living and Somnolence
• Symptomatic Orthostatic Hypotension
• Impulse Control/Compulsive Behaviors
• Hallucinations and Psychotic-like Behavior
• Dyskinesia
• Rhabdomyolysis
• Retinal Pathology
• Events Reported with Dopaminergic Therapy

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.

During the premarketing development of Pramipeksol Synthon tablets, patients with early Parkinson's disease were treated with Pramipeksol Synthon tablets, placebo, or immediate-release pramipexole tablets. In addition, a randomized, double-blind, parallel group trial was conducted in 156 early Parkinson's disease patients (Hoehn & Yahr Stages I-III) to assess overnight switching of immediate-release pramipexole tablets to Pramipeksol Synthon tablets. In this latter study, concomitant treatment with stable doses of levodopa, monoamine oxidase B inhibitor (MAOB-I) drugs, anticholinergics, or amantadine, individually or in combination, was allowed. In a third trial, advanced Parkinson's disease patients received Pramipeksol Synthon tablets, placebo, or immediate-release pramipexole tablets as adjunctive therapy to levodopa.

Early Parkinson's Disease

The most common adverse reactions ( ≥ 5% and more frequent than placebo) after 33 weeks of treatment with Pramipeksol Synthon tablets in the trial of early Parkinson's disease patients were somnolence, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle spasms, and peripheral edema.

Twenty four of 223 (11%) patients treated with Pramipeksol Synthon tablets for 33 weeks discontinued treatment due to adverse reactions compared to 4 of 103 (4%) patients who received placebo and approximately 20 of 213 (9%) patients who received immediate-release pramipexole tablets. The adverse reaction most commonly causing discontinuation of treatment with Pramipeksol Synthon tablets was nausea (2%).

Table 1 lists adverse reactions that occurred with a frequency of at least 2% with Pramipeksol Synthon and were more frequent than with placebo during 33 weeks of treatment in a double-blind, placebo-controlled study in early Parkinson's disease. In this study, patients did not receive concomitant levodopa; however, levodopa was permitted as rescue medication.

Table 1 : Adverse-Reactions in a 33-Week Double-Blind, Placebo-Controlled Trial with Pramipeksol Synthon in Early Parkinson's Disease

Because this study used a flexible dose titration design, it was not possible to assess the effects of dose on the incidence of adverse reactions.

Adverse reactions can initially occur in either the titration or maintenance phase. Some adverse reactions developed in Pramipeksol Synthon-treated patients during the titration phase and SHUVLVWHG.7 days) into the maintenance phase (i.e., Pramipeksol Synthon % -SODFHER WUHDWPHQW GLIIHUHQFH. SHUVLVWHQW DGYHUVH reactions were somnolence, nausea, constipation, fatigue, and dry mouth.

A double-blind, randomized, parallel group trial evaluated the tolerability of an overnight switch from immediate-release pramipexole tablets to Pramipeksol Synthon tablets at the same daily dose in 156 early Parkinson's disease patients with or without levodopa. One of 104 patients switched from immediate-release pramipexole tablets to Pramipeksol Synthon tablets discontinued due to adverse reactions (vertigo and nausea).

Advanced Parkinson's Disease

The most common adverse reactions. DQG JUHDWHU IUHTXHQF\ WKDQ LQ SODFHER GXULQJ ZHHNV RI WUHDWPHQW with Pramipeksol Synthon tablets in the trial of advanced Parkinson's disease patients with concomitant levodopa were dyskinesia, nausea, constipation, hallucinations, headache, and anorexia.

Eight of 164 (5%) patients treated with Pramipeksol Synthon tablets for 18 weeks discontinued treatment due to adverse reactions compared to 7 of 178 (4%) patients who received placebo and 8 of 175 (5%) patients who received immediate-release pramipexole tablets. The most common adverse reactions leading to discontinuation of treatment with Pramipeksol Synthon tablets were nausea (1%) and hallucination (1%).

Table 2 lists adverse reactions that occurred with a frequency of at least 2% with Pramipeksol Synthon and were more frequent than with placebo during 18 weeks of treatment in patients with advanced Parkinson's disease treated with Pramipeksol Synthon tablets. In this study, Pramipeksol Synthon tablets, immediate-release pramipexole tablets, or placebo was administered to patients who were also receiving concomitant levodopa.

Table 2 : Adverse-Reactions in an 18-Week Double-Blind, Placebo-Controlled Trial with Pramipeksol Synthon in Advanced Parkinson's Disease

Because this flexible dose study used a titration design, it was not possible to assess the effects of dose on the incidence of adverse reactions.

Adverse reactions can initially occur in either the titration or maintenance phase. Some adverse reactions developed in Pramipeksol Synthon-treated patients during the titration phase and pHUVLVWHG. GD\V LQWR WKH maintenance phase (i.e., Pramipeksol Synthon % -SODFHER WUHDWPHQW GLIIHUHQFH. SHUVLVWHQW DGYHUVH reactions were dyskinesia and insomnia.

Laboratory Tests

During the development of Pramipeksol Synthon tablets, no systematic abnormalities on routine laboratory testing were noted.

Other adverse reactions observed during clinical trials of MIRAPEX immediate-release or Pramipeksol Synthon in early and advanced Parkinson's disease

Other adverse reactions in clinical studies involving MIRAPEX immediate-release or Pramipeksol Synthon tablets include abnormal dreams, akathisia, amnesia, decreased libido, decreased weight, dyspnea, pneumonia, and vision abnormalities.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of MIRAPEX immediate-release or Pramipeksol Synthon tablets, primarily in Parkinson's disease patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to pramipexole tablets. Similar types of reactions were grouped into a smaller number of standardized categories using the MedDRA terminology: cardiac failure, inappropriate antidiuretic hormone secretion (SIADH), skin reactions (including erythema, rash, pruritus, urticaria), syncope, vomiting, and weight increase.

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 Pramipeksol Synthon 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

Clinical efficacy and safety in Restless Legs Syndrome

The efficacy of pramipexole was evaluated in four placebo-controlled clinical trials in approximately 1,000 patients with moderate to very severe idiopathic Restless Legs Syndrome.

The mean change from baseline in the Restless Legs Syndrome Rating Scale (IRLS) and the Clinical Global Impression-Improvement (CGI-I) were the primary efficacy outcome measures. For both primary endpoints statistically significant differences have been observed for the pramipexole dose groups 0.25 mg, 0.5 mg and 0.75 mg pramipexole salt in comparison to placebo. After 12 weeks of treatment the baseline IRLS score improved from 23.5 to 14.1 points for placebo and from 23.4 to 9.4 points for pramipexole (doses combined). The adjusted mean difference was -4.3 points (CI 95% -6.4; -2.1 points, p-value <0.0001). CGI-I responder rates (improved, very much improved) were 51.2% and 72.0% for placebo and pramipexole, respectively (difference 20% CI 95%: 8.1%; 31.8%, p<0.0005). Efficacy was observed with 0.088 mg of base (0.125 mg of salt) per day after the first week of treatment.

In a placebo-controlled polysomnography study over 3 weeks Pramipeksol Synthon significantly reduced the number of periodic limb movements during time in bed.

Longer term efficacy was evaluated in a placebo-controlled clinical trial. After 26 weeks of treatment, there was an adjusted mean reduction in IRLS total score of 13.7 and 11.1 points in the pramipexole and placebo group, respectively, with a statistically significant (p = 0.008) mean treatment difference of -2.6. CGI-I responder rates (much improved, very much improved) were 50.3% (80/159) and 68.5% (111/162) for placebo and pramipexole, respectively (p = 0.001), corresponding to a number needed to treat (NNT) of 6 patients (95%CI: 3.5, 13.4).

Paediatric population

Clinical efficacy and safety in Tourette Disorder

The efficacy of pramipexole (0.0625-0.5 mg/day) with paediatric patients aged 6-17 years with Tourette Disorder was evaluated in a 6-week, double-blind, randomised, placebo-controlled flexible dose study. A total of 63 patients were randomised (43 on pramipexole, 20 on placebo). The primary endpoint was change from baseline on the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS). No difference was observed for pramipexole as compared to placebo for either the primary endpoint or for any of the secondary efficacy endpoints including YGTSS total score, Patient Global Impression of Improvement (PGI-I), Clinical Global Impression of Improvement (CGI-I), or Clinical Global Impressions of Severity of Illness (CGI-S). Adverse events occurring in at least 5% of patients in the pramipexole group and more common in the pramipexole-treated patients than in patients on placebo were: headache (27.9%, placebo 25.0%), somnolence (7.0%, placebo 5.0%), nausea (18.6%, placebo 10.0%), vomiting (11.6%, placebo 0.0%), upper abdominal pain (7.0%, placebo 5.0%), orthostatic hypotension (9.3%, placebo 5.0%), myalgia (9.3%, placebo 5.0%), sleep disorder (7.0%, placebo 0.0%), dyspnoea (7.0%, placebo 0.0%) and upper respiratory tract infection (7.0%, placebo 5.0%). Other significant adverse events leading to discontinuation of study medication for patients receiving pramipexole were confusional state, speech disorder and aggravated condition.

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.

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 1800 patients of Hoehn and Yahr stages stages I - IV. Out of these, approximately 1000 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 the 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

Clinical efficacy and safety in Tourette Disorder

The efficacy of pramipexole (0.0625-0.5 mg/day) with paediatric patients aged 6-17 years with Tourette Disorder was evaluated in a 6-week, double-blind, randomised, placebo-controlled flexible dose study. A total of 63 patients were randomised (43 on pramipexole, 20 on placebo). The primary endpoint was change from baseline on the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS). No difference was observed for pramipexole as compared to placebo for either the primary endpoint or for any of the secondary efficacy endpoints including YGTSS total score, Patient Global Impression of Improvement (PGI-I), Clinical Global Impression of Improvement (CGI-I), or Clinical Global Impressions of Severity of Illness (CGI-S). Adverse events occurring in at least 5% of patients in the pramipexole group and more common in the pramipexole-treated patients than in patients on placebo were: headache (27.9%, placebo 25.0%), somnolence (7.0%, placebo 5.0%), nausea (18.6%, placebo 10.0%), vomiting (11.6%, placebo 0.0%), upper abdominal pain (7.0%, placebo 5.0%), orthostatic hypotension (9.3%, placebo 5.0%), myalgia (9.3%, placebo 5.0%), sleep disorder (7.0%, placebo 0.0%), dyspnoea (7.0%, placebo 0.0%) and upper respiratory tract infection (7.0%, placebo 5.0%). Other significant adverse events leading to discontinuation of study medication for patients receiving pramipexole were confusional state, speech disorder and aggravated condition.

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 Pramipeksol SynthonIN 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

Clinical efficacy and safety in Restless Legs Syndrome

The efficacy of pramipexole was evaluated in four placebo-controlled clinical trials in approximately 1,000 patients with moderate to very severe idiopathic Restless Legs Syndrome.

The mean change from baseline in the Restless Legs Syndrome Rating Scale (IRLS) and the Clinical Global Impression-Improvement (CGI-I) were the primary efficacy outcome measures. For both primary endpoints statistically significant differences have been observed for the pramipexole dose groups 0.25 mg, 0.5 mg and 0.75 mg pramipexole salt in comparison to placebo. After 12 weeks of treatment the baseline IRLS score improved from 23.5 to 14.1 points for placebo and from 23.4 to 9.4 points for pramipexole (doses combined). The adjusted mean difference was -4.3 points (CI 95% -6.4; -2.1 points, p-value <0.0001). CGI-I responder rates (improved, very much improved) were 51.2% and 72.0% for placebo and pramipexole, respectively (difference 20% CI 95%: 8.1%; 31.8%, p<0.0005). Efficacy was observed with 0.088 mg of base (0.125 mg of salt) per day after the first week of treatment.

In a placebo-controlled polysomnography study over 3 weeks Pramipeksol SynthonIN significantly reduced the number of periodic limb movements during time in bed.

Longer term efficacy was evaluated in a placebo-controlled clinical trial. After 26 weeks of treatment, there was an adjusted mean reduction in IRLS total score of 13.7 and 11.1 points in the pramipexole and placebo group, respectively, with a statistically significant (p = 0.008) mean treatment difference of -2.6. CGI-I responder rates (much improved, very much improved) were 50.3% (80/159) and 68.5% (111/162) for placebo and pramipexole, respectively (p = 0.001), corresponding to a number needed to treat (NNT) of 6 patients (95%CI: 3.5, 13.4).

Paediatric population

Clinical efficacy and safety in Tourette Disorder

The efficacy of pramipexole (0.0625-0.5 mg/day) with paediatric patients aged 6-17 years with Tourette Disorder was evaluated in a 6-week, double-blind, randomised, placebo-controlled flexible dose study. A total of 63 patients were randomised (43 on pramipexole, 20 on placebo). The primary endpoint was change from baseline on the Total Tic Score (TTS) of the Yale Global Tic Severity Scale (YGTSS). No difference was observed for pramipexole as compared to placebo for either the primary endpoint or for any of the secondary efficacy endpoints including YGTSS total score, Patient Global Impression of Improvement (PGI-I), Clinical Global Impression of Improvement (CGI-I), or Clinical Global Impressions of Severity of Illness (CGI-S). Adverse events occurring in at least 5% of patients in the pramipexole group and more common in the pramipexole-treated patients than in patients on placebo were: headache (27.9%, placebo 25.0%), somnolence (7.0%, placebo 5.0%), nausea (18.6%, placebo 10.0%), vomiting (11.6%, placebo 0.0%), upper abdominal pain (7.0%, placebo 5.0%), orthostatic hypotension (9.3%, placebo 5.0%), myalgia (9.3%, placebo 5.0%), sleep disorder (7.0%, placebo 0.0%), dyspnoea (7.0%, placebo 0.0%) and upper respiratory tract infection (7.0%, placebo 5.0%). Other significant adverse events leading to discontinuation of study medication for patients receiving pramipexole were confusional state, speech disorder and aggravated condition.

The effect of pramipexole on the QT interval of the ECG was investigated in a clinical study in 60 healthy male and female volunteers. All subjects initiated treatment with 0.375 mg Pramipeksol Synthon tablets administered once daily, and were up-titrated every 3 days to 2.25 mg and 4.5 mg daily, a faster rate of titration than recommended in the label. No dose-or exposure-related effect on mean QT intervals was observed; however, the study did not have a valid assessment of assay sensitivity. The effect of pramipexole on QTc intervals at higher exposures achieved either due to drug interactions (e.g., with cimetidine), renal impairment, or at higher doses has not been systematically evaluated.

Although mean values remained within normal reference ranges throughout the study, supine systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate for subjects treated with pramipexole generally increased during the rapid up-titration phase, by 10 mmHg, 7 mmHg, and 10 bpm higher than placebo, respectively. Higher SBP, DBP, and pulse rates compared to placebo were maintained until the pramipexole doses were tapered; values on the last day of tapering were generally similar to baseline values. Such effects have not been observed in clinical studies with Parkinson's disease patients, who were titrated according to labeled recommendations.