Mirapex

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIRAPEX® (MIRAPEX®)

Composition:

Active substance: pramipexole;

1 tablet contains 0.25 mg of pramipexole dihydrochloride monohydrate, equivalent to 0.18 mg of pramipexole, or 1 mg, equivalent to 0.7 mg of pramipexole;

Excipients: mannitol (E 421), maize starch, colloidal anhydrous silicon dioxide, povidone, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

0.25 mg tablets – white, oval, flat tablets on both sides with bevelled edges and marking: P7 / deep break line / P7 on one side, company logo of Boehringer Ingelheim / break line / company logo of Boehringer Ingelheim on the other side. Tablets can be divided into equal halves;

1 mg tablets – white, round, flat tablets with bevelled edges and marking: P9 / deep break line / P9 on one side, company logo of Boehringer Ingelheim / break line / company logo of Boehringer Ingelheim on the other side. Tablets can be divided into equal halves.

Pharmacotherapeutic group.

Antiparkinson drugs. Dopaminergic agents. Dopamine agonists.

ATC code N04BC05.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

Pramipexole is a dopamine agonist with high selectivity and specificity for dopamine receptors of the D2 subtype, with preferential affinity for D3 receptors and full intrinsic activity at these receptors.

Pramipexole alleviates parkinsonian motor disturbances by stimulating dopamine receptors in the striatum. Animal studies have demonstrated that pramipexole inhibits the synthesis, release, and reuptake of dopamine.

The precise mechanism of action of MIRAPEX in the treatment of restless legs syndrome is unknown. Neuropharmacological data suggest involvement of the dopaminergic system.

Pharmacodynamic effects

In volunteers, a dose-dependent decrease in prolactin was observed. In a clinical study involving healthy volunteers, rapid dose titration of MIRAPEX PD (every 3 days) up to 4.5 mg pramipexole as salt (3.15 mg pramipexole) per day resulted in increased arterial blood pressure and heart rate. This effect was not observed in studies conducted in patients.

Pharmacokinetics.

Absorption

Pramipexole is rapidly and completely absorbed after oral administration. Absolute bioavailability exceeds 90%. Maximum plasma concentration is reached between 1 and 3 hours after administration. The rate of absorption is not reduced by concomitant food intake, but overall absorption extent is decreased. Pramipexole exhibits linear kinetics and low interindividual variability in plasma levels.

Distribution

In humans, pramipexole has very low protein binding (< 20%) and a large volume of distribution (400 L). High concentrations were observed in rat brain tissue (approximately 8 times higher than in plasma).

Metabolism

Pramipexole is metabolized in humans to only a negligible extent.

Elimination

Renal excretion of unchanged pramipexole is the main elimination pathway. Approximately 90% of a radiolabeled 14C dose is excreted renally, while less than 2% is recovered in feces. Total clearance of pramipexole is approximately 500 ml/min, and renal clearance is approximately 400 ml/min. The elimination half-life (t½) ranges from 8 hours in young individuals to 12 hours in elderly subjects.

Clinical characteristics.

Indications.

MIRAPEX is indicated in adults for the treatment of signs and symptoms of idiopathic Parkinson’s disease, either as monotherapy (without levodopa) or in combination with levodopa, throughout the course of the disease up to the later stages when the effect of levodopa diminishes or becomes unstable and fluctuations in therapeutic response occur (end-of-dose wearing-off or on-off fluctuations).

MIRAPEX is indicated in adults for symptomatic treatment of moderate to severe idiopathic restless legs syndrome at doses not exceeding 0.75 mg of pramipexole dihydrochloride monohydrate (0.54 mg pramipexole) (see section "Dosage and administration").

Contraindications.

Hypersensitivity to the active substance or to any of the other components of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Plasma protein binding.

Pramipexole is minimally bound to plasma proteins (< 20 %), and negligible biotransformation occurs in males. Therefore, interactions with other medicinal products affecting protein binding or elimination via biotransformation are unlikely. Since anticholinergic agents are primarily eliminated via biotransformation, potential interaction is unlikely, although interactions with anticholinergic agents have not been studied. There is no pharmacokinetic interaction with selegiline and levodopa.

Inhibitors/competitors of the active renal excretion pathway.

Cimetidine reduced the renal clearance of pramipexole by approximately 34 %, likely by inhibiting the cationic secretory transport system in the renal tubules. Therefore, medicinal products that are inhibitors of this active renal excretion pathway or are themselves eliminated via this pathway—such as cimetidine, amantadine, mexiletine, zidovudine, cisplatin, quinine, and procainamide—may interact with pramipexole, leading to reduced pramipexole clearance. When coadministering these medicinal products with MIRAPEX, consideration should be given to reducing the dose of pramipexole.

Combination with levodopa.

When increasing the dose of MIRAPEX in combination with levodopa, it is recommended to reduce the dose of levodopa, while doses of other antiparkinsonian medicinal products should remain unchanged.

Due to possible additive effects, patients should be advised to exercise caution when taking other sedative medicinal products or alcohol in combination with pramipexole (see sections "Special precautions", "Effect on ability to drive and use machines", and "Adverse reactions").

Antipsychotic medicinal products.

Concomitant use of antipsychotic medicinal products with pramipexole should be avoided (see section "Special precautions"), for example, when antagonistic effects can be expected.

Special precautions for use.

When prescribing MIRAPEX to patients with Parkinson's disease and impaired renal function, dose reduction is recommended according to the section "Dosage and administration".

Hallucinations. Hallucinations are known as an adverse effect of dopamine agonists and levodopa therapy. Patients should be informed that hallucinations (predominantly visual) may occur.

Disorders of dyskinesia. During combination therapy with levodopa in progressive Parkinson’s disease, dyskinesia may develop during initial titration of MIRAPEX. If this occurs, the levodopa dose should be reduced.

Dystonia.

Axial dystonia, including antecollis, camptocormia, and pleurothotonus (Pisa syndrome), has been occasionally reported in patients with Parkinson’s disease after initiation or gradual dose increase of pramipexole. Although dystonia may be a symptom of Parkinson’s disease, symptoms of dystonia in patients with Parkinson’s disease improved after dose reduction or discontinuation of pramipexole.

If dystonia occurs, reassessment of the treatment regimen with dopaminergic agents and adjustment of pramipexole dosage should be considered.

Sudden sleep attacks and somnolence. The use of pramipexole has been associated with somnolence and sudden onset of sleep episodes, particularly in patients with Parkinson’s disease. Rare cases of sudden sleep attacks during daytime activities, sometimes occurring without awareness or warning signs, have been reported. Patients should be informed about this risk. They should be advised to exercise caution when driving or operating machinery during treatment with MIRAPEX. Patients who experience somnolence and/or sudden sleep attacks should refrain from driving or operating machinery. In addition, dose reduction or discontinuation of treatment should be considered. Due to possible additive effects, caution is recommended if patients are using other sedative medicinal products in combination with pramipexole or consuming alcohol (see sections "Interaction with other medicinal products and other forms of interaction", "Ability to affect reaction speed when driving or operating machinery", and "Adverse reactions").

Impulse control disorders. Patients should be closely monitored for the development of impulse control disorders. Patients and caregivers should be aware that, during treatment with dopamine agonists, including MIRAPEX, symptoms of impulse control disorders may occur, such as pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating. If such symptoms develop, dose reduction or discontinuation of the drug should be considered.

Mania and delirium. Patients should be closely monitored for the development of mania and delirium. Patients and caregivers should be aware that mania and delirium may occur in patients receiving pramipexole therapy. If such symptoms occur, dose reduction or discontinuation of the drug should be considered.

Patients with psychiatric disorders. Patients with psychiatric disorders should be treated with dopamine agonists only if the potential benefit outweighs the risks. Concomitant use of antipsychotic medicinal products with pramipexole should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Ophthalmological monitoring. Regular ophthalmological examinations at consistent intervals or whenever visual disturbances occur are recommended.

Severe cardiovascular disease. Caution should be exercised in patients with severe cardiovascular disease. Blood pressure should be monitored, especially at the beginning of treatment, due to the general risk of postural hypotension associated with dopaminergic therapy.

Malignant neuroleptic syndrome. Symptoms suggestive of malignant neuroleptic syndrome have been observed after abrupt discontinuation of dopaminergic therapy (see section "Dosage and administration").

Dopamine agonist withdrawal syndrome (DAWS).

Dopamine agonist withdrawal syndrome has been observed with the use of dopamine agonists, including pramipexole (see section "Adverse reactions"). To discontinue treatment, the pramipexole dose in patients with Parkinson’s disease should be tapered gradually (see section "Dosage and administration"). Limited data suggest that patients with impulse control disorders and those receiving high daily doses and/or high cumulative doses of dopamine agonists may be at higher risk of developing dopamine agonist withdrawal syndrome. Withdrawal syndrome may include apathy, anxiety, depression, fatigue, sweating, pain, and lack of response to levodopa. Before reducing the dose or discontinuing pramipexole, patients should be informed about possible withdrawal symptoms. Close monitoring is required during dose reduction and discontinuation of pramipexole. In cases of severe and/or persistent dopamine agonist withdrawal syndrome symptoms, temporary re-initiation of pramipexole at the lowest effective dose may be considered.

Augmentation in restless legs syndrome. Treatment of restless legs syndrome with pramipexole may lead to augmentation. Augmentation is characterized by earlier onset of symptoms in the evening (or even during daytime), worsening of symptoms, and spread of symptoms to other limbs.

The risk of augmentation may increase with higher doses. Before initiating treatment, patients should be informed about the risk of augmentation and should consult their physician if symptoms of augmentation occur. If augmentation is suspected, dose adjustment to the lowest effective dose should be considered, or discontinuation of pramipexole should be evaluated (see sections "Dosage and administration" and "Adverse reactions").

Use during pregnancy or breastfeeding.

Pregnancy. The effects on pregnancy and lactation in humans have not been studied. Pramipexole was not teratogenic in studies in rats and rabbits, but showed embryotoxic effects in rats at doses that were toxic to pregnant females. MIRAPEX should not be used during pregnancy unless clearly necessary, i.e., when the potential benefit outweighs the potential risk to the fetus.

Breastfeeding. Since pramipexole treatment suppresses prolactin secretion in humans, inhibition of lactation is expected. Excretion of pramipexole into human breast milk has not been studied. In rats, the concentration of radiolabeled active substance in breast milk was higher than in plasma. Due to the lack of adequate human data, MIRAPEX is not recommended during breastfeeding. However, if use of this medicinal product cannot be avoided, breastfeeding should be discontinued.

Fertility. Studies on effects on human fertility have not been conducted. In animal studies, pramipexole affected the oestrous cycle and reduced fertility in females, as expected for a dopamine agonist. However, these studies did not reveal direct or indirect harmful effects on male fertility.

Ability to affect reaction speed when driving or operating machinery.

MIRAPEX may have a significant influence on the ability to drive and operate machinery. Hallucinations or somnolence may occur.

Patients treated with MIRAPEX who develop somnolence and/or sudden sleep attacks should be advised to refrain from driving or engaging in activities where reduced alertness may place themselves or others at risk of serious injury or death (e.g., operating machinery) until recurrent episodes and somnolence cease. (See sections "Special precautions for use", "Interaction with other medicinal products and other forms of interaction", and "Adverse reactions").

Dosage and administration.

Parkinson's disease.

The daily dose should be administered in three equal divided doses.

Initial treatment.

The dose should be increased gradually, starting at 0.375 mg pramipexole dihydrochloride monohydrate (0.264 mg pramipexole) per day, and then increased every 5–7 days. If patients do not experience intolerable adverse effects, the dose should be titrated upward until the maximum therapeutic effect is achieved (see Table 1).

Table 1

If further dose escalation is necessary, the daily dose should be increased by 0.75 mg pramipexole dihydrochloride monohydrate (0.54 mg pramipexole) weekly up to the maximum dose of 4.5 mg pramipexole dihydrochloride monohydrate (3.3 mg pramipexole) per day. However, it should be noted that the incidence of somnolence increases with doses above 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole) per day (see section "Adverse Reactions").

Maintenance therapy.

The individual dose ranges from 0.375 mg pramipexole dihydrochloride monohydrate (0.264 mg pramipexole) to the maximum of 4.5 mg pramipexole dihydrochloride monohydrate (3.3 mg pramipexole) per day. In clinical trials, therapeutic efficacy was observed starting from a daily dose of 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole). Further dose adjustments should be made according to the clinical response and taking into account the occurrence of adverse reactions. Approximately 5% of patients were treated with doses below 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole) in clinical trials. For patients with progressive Parkinson's disease, doses exceeding 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole) per day may be beneficial, especially if a reduction in levodopa dosage is planned. It is recommended to reduce the levodopa dose when increasing the dose of MIRAPLEX and also during maintenance therapy with this drug, depending on the individual patient's response (see section "Interaction with other medicinal products and other forms of interaction").

Discontinuation of treatment.

Sudden withdrawal of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome or dopamine agonist withdrawal syndrome. The dose of pramipexole should be gradually reduced by 0.75 mg pramipexole dihydrochloride monohydrate (0.54 mg pramipexole) per day until the daily dose is reduced to 0.75 mg pramipexole dihydrochloride monohydrate (0.54 mg pramipexole). After that, the dose should be further reduced to 0.375 mg pramipexole dihydrochloride monohydrate (0.264 mg pramipexole) per day (see section "Special precautions for use"). Dopamine agonist withdrawal syndrome may occur during gradual dose reduction. Therefore, temporary dose increases may be necessary before resuming dose reduction (see section "Special precautions for use").

Dosing in patients with renal impairment.

Elimination of pramipexole depends on renal function. The following dosing regimen is recommended for initial therapy:

• Patients with creatinine clearance above 50 ml/min do not require dose reduction or adjustment of dosing frequency;
• Patients with creatinine clearance of 20–50 ml/min should start initial daily dose of MIRAPLEX in two divided doses, beginning with 0.125 mg pramipexole dihydrochloride monohydrate (0.088 mg pramipexole) twice daily (0.25 mg/day pramipexole dihydrochloride monohydrate / 0.176 mg pramipexole/day). The maximum daily dose should not exceed 2.25 mg pramipexole dihydrochloride monohydrate (1.57 mg pramipexole);
• Patients with creatinine clearance below 20 ml/min should receive the daily dose of MIRAPLEX as a single dose, starting with 0.125 mg/day pramipexole dihydrochloride monohydrate (0.088 mg pramipexole/day). The maximum daily dose of pramipexole should not exceed 1.5 mg pramipexole dihydrochloride monohydrate (1.1 mg pramipexole);
• In case of worsening renal function during maintenance therapy, the daily dose of MIRAPLEX should be reduced by the same percentage by which creatinine clearance has decreased. For example, if creatinine clearance decreases by 30%, the daily dose of MIRAPLEX should be reduced by 30%. The daily dose can be administered in two divided doses if creatinine clearance is within 20–50 ml/min, and as a single dose if creatinine clearance is below 20 ml/min.

Dosing in patients with hepatic impairment.

Dose adjustment is probably not necessary in patients with hepatic impairment, since approximately 90% of the absorbed active substance is excreted by the kidneys. However, the potential impact of hepatic impairment on the pharmacokinetics of MIRAPLEX has not been studied.

Restless legs syndrome.

The recommended initial dose of MIRAPLEX is 0.125 mg pramipexole dihydrochloride monohydrate (0.088 mg pramipexole) once daily, taken 2–3 hours before bedtime. For patients requiring additional symptom relief, the dose may be increased every 4–7 days up to the maximum dose of 0.75 mg pramipexole dihydrochloride monohydrate (0.54 mg pramipexole) per day (see Table 2). The lowest effective dose should be used (see section "Special precautions for use, Restless legs syndrome").

Table 2

* If necessary

The patient's response to treatment should be evaluated after 3 months, and the need for continuing therapy should be reviewed. If treatment is interrupted for more than a few days, dose titration should be restarted as described above.

Discontinuation of treatment.

Since the daily dose for the treatment of restless legs syndrome does not exceed 0.75 mg pramipexole dihydrochloride monohydrate (0.54 mg pramipexole), MIRAPEX can be discontinued without tapering the dose. In a 26-week placebo-controlled clinical trial, symptom rebound of restless legs syndrome (worsening of symptoms compared to baseline levels) was observed in 10% of patients (14 out of 135 patients) after abrupt discontinuation of pramipexole. This effect was similar across all doses.

Dosing in patients with renal impairment.

Elimination of MIRAPEX from the body depends on renal function. Patients with a creatinine clearance above 20 mL/min do not require a reduction in daily dose.

The use of MIRAPEX has not been studied in patients undergoing hemodialysis or in patients with severe renal impairment.

Dosing in patients with hepatic impairment.

Dose reduction is not considered necessary for patients with hepatic impairment, as nearly 90% of the absorbed active substance is excreted by the kidneys.

Method of administration.

Tablets should be taken orally with water, with or without food.

Children.

Parkinson’s disease. The safety and efficacy of MIRAPEX in children (under 18 years of age) have not been established. There is no justification for the use of MIRAPEX in children with Parkinson’s disease.

Restless legs syndrome. The use of MIRAPEX is not recommended in children (under 18 years of age) due to insufficient data on safety and efficacy.

Tourette’s syndrome. MIRAPEX is not recommended for use in children (under 18 years of age) with Tourette’s syndrome due to insufficient data on safety and efficacy and due to an unfavorable benefit-risk ratio for this condition.

Overdose.

There is no clinical experience with significant overdose. Expected adverse reactions may include those related to the pharmacodynamic profile of a dopamine agonist, including nausea, vomiting, hyperkinesia, hallucinations, anxiety, and arterial hypotension. There is no established antidote for dopamine agonist overdose. In cases of central nervous system stimulation, administration of a neuroleptic agent may be indicated. Management of overdose may require general supportive measures, including gastric lavage, intravenous fluid administration, activated charcoal, and electrocardiographic monitoring.

Adverse Reactions

An analysis of pooled placebo-controlled trials involving a total of 1,923 patients treated with pramipexole and 1,354 patients treated with placebo showed that adverse reactions were commonly reported in both groups. At least one adverse reaction was reported in 63% of patients receiving pramipexole and in 52% of patients receiving placebo.

Most adverse reactions are usually observed at the beginning of therapy, and a significant proportion of them resolve even if treatment continues.

Adverse reactions are listed by system organ class and frequency of occurrence (number of patients in whom the reaction is expected to occur), 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), and not known (cannot be estimated from available data).

Parkinson’s disease.

The most frequently reported adverse reactions (≥ 5%) in patients with Parkinson’s disease treated with pramipexole (occurring more frequently than with placebo) were nausea, dyskinesia, hypotension, dizziness, somnolence, insomnia, constipation, hallucinations, headache, and fatigue. The incidence of somnolence increases with doses exceeding 1.5 mg of pramipexole dihydrochloride monohydrate per day (see section "Dosage and administration"). The most common adverse reaction when administered in combination with levodopa was dyskinesia. Hypotension may occur at the beginning of treatment, particularly if titration of pramipexole is too rapid.

Table 3. Parkinson’s disease

1 This adverse reaction was observed during the post-marketing period. With 95 % certainty, the frequency category was defined as uncommon, but it could be lower. Determination of the exact frequency is not possible because the adverse reaction was not observed during clinical studies in 2,762 Parkinson's disease patients treated with pramipexole.

Restless legs syndrome, most common adverse reactions

In patients with restless legs syndrome treated with pramipexole, the most common adverse reactions (≥ 5 %) were nausea, headache, dizziness, and increased fatigue. Nausea and increased fatigue were observed more frequently in women (20.8 % and 10.5 %, respectively) compared to men (6.7 % and 7.3 %, respectively) during treatment with MIRAPLEX.

Table 4. Restless legs syndrome

1 This adverse reaction was observed during the post-marketing period. With 95 % certainty, the frequency category was determined as uncommon, but it may be lower. Determining the exact frequency is not possible, since this adverse reaction was not observed during clinical trials among 1,395 patients with restless legs syndrome treated with pramipexole.

Description of selected adverse reactions

Somnolence. Pramipexole administration is frequently associated with somnolence and uncommonly with excessive daytime sleepiness and episodes of sudden sleep attacks (see section "Special warnings and precautions for use").

Libido disorders. The use of pramipexole may uncommonly be associated with libido disorders (increased or decreased libido).

Impulse control disorders. When treating with dopamine agonists, including MIRAPEX, symptoms of impulse control disorders may occur, including pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating (see section "Special warnings and precautions for use").

During a cross-sectional retrospective screening and a case-control study involving 3,090 patients with Parkinson's disease, 13.6 % of all patients receiving dopaminergic or non-dopaminergic therapy experienced symptoms of impulse control disorders within the past six months. Observed manifestations included pathological gambling, irresistible urge to shop, excessive eating, and compulsive sexual behavior (hypersexuality). Possible independent risk factors for developing impulse control disorders included dopaminergic therapy and higher doses of dopaminergic therapy, younger age (≤ 65 years), unmarried status, and a family history of pathological gambling as reported by the patient.

Dopamine agonist withdrawal syndrome. Non-motor adverse reactions may occur when reducing the dose or discontinuing dopamine agonists (including pramipexole). Symptoms include apathy, anxiety, depression, fatigue, sweating, and pain (see section "Special warnings and precautions for use").

Heart failure. During clinical trials and the post-marketing period, heart failure has been observed in patients taking pramipexole. In a pharmacoe pidemiological study, the use of pramipexole was associated with an increased risk of heart failure compared to non-use (risk ratio 1.86; 95 % CI, 1.21–2.85).

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister; 3 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Boehringer Ingelheim Pharma GmbH & Co. KG.

Manufacturer's address and location of operations.

Binger Strasse 173, 55216 Ingelheim am Rhein, Germany.