Mirapex® pd

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MIRAPLEX® PD (MIRAPLEX® ER)

Composition:

Active substance: pramipexole;

One prolonged-release tablet contains:

0.375 mg of pramipexole dihydrochloride monohydrate, corresponding to 0.26 mg of pramipexole, or

0.75 mg of pramipexole dihydrochloride monohydrate, corresponding to 0.52 mg of pramipexole, or

1.5 mg of pramipexole dihydrochloride monohydrate, corresponding to 1.05 mg of pramipexole;

Excipients: hypromellose 2208, corn starch, carbomer 941, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Prolonged-release tablets.

Main physicochemical properties:

For 0.375 mg tablets – white or almost white, round, biconvex tablets with bevelled edges, embossed on one side with the company logo «VI», and on the other side – «P1».

For 0.75 mg tablets – white or almost white, round, biconvex tablets with bevelled edges, embossed on one side with the company logo «VI», and on the other side – «P2».

For 1.5 mg tablets – white or almost white, oval, biconvex tablets, embossed on one side with the company logo «VI», and on the other side – «P3».

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, and among these, it has a predominant affinity for D3 receptors, as well as full intrinsic activity at these receptors.

Pramipexole alleviates Parkinsonian motor disturbances by stimulating striatal dopamine receptors. Animal studies have demonstrated that pramipexole inhibits dopamine synthesis, release, and reuptake.

Pharmacodynamic effects

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

Pharmacokinetics.

Absorption

Pramipexole is completely absorbed after oral administration. Absolute bioavailability exceeds 90%. In a Phase I study, in which immediate-release pramipexole and prolonged-release tablets were evaluated under fasting conditions, the minimum and maximum plasma concentrations (Cmin, Cmax), as well as the effect (area under the pharmacokinetic curve [AUC]) of a single daily dose of MIRAPLEX PD prolonged-release tablets administered once daily, were equivalent to those of MIRAPLEX tablets administered three times daily.

Once-daily administration of MIRAPLEX PD prolonged-release tablets results in less fluctuation in plasma pramipexole concentrations over 24 hours compared to administration of immediate-release pramipexole tablets three times daily.

Maximum plasma concentration is reached approximately 6 hours after once-daily administration of MIRAPLEX PD prolonged-release tablets. Steady-state is achieved within at most 5 days of continuous dosing.

Concomitant food intake generally does not affect pramipexole bioavailability. Consumption of a high-fat meal increased the maximum concentration (Cmax) by approximately 24% after a single dose and by approximately 20% after multiple doses, and delayed the time to maximum concentration by approximately 2 hours in healthy volunteers. However, concomitant food intake did not affect the overall exposure (AUC). The increase in maximum concentration (Cmax) is not considered clinically significant. In Phase III trials establishing the efficacy and safety of MIRAPLEX PD, patients were informed that they could take the investigational medicinal product regardless of food intake.

Body weight does not affect the area under the pharmacokinetic curve (AUC), but it has been shown to affect the volume of distribution and thus the maximum concentration (Cmax). A 30 kg reduction in patient body weight leads to a 45% increase in maximum concentration (Cmax). However, in Phase III trials in patients with Parkinson's disease, no clinically significant effect of body weight on the therapeutic effect and tolerability of MIRAPLEX PD prolonged-release tablets was observed. Pramipexole exhibits linear kinetics and low inter-patient 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 plasma concentrations).

Metabolism

Pramipexole is only minimally metabolized in humans.

Elimination

Renal excretion of unchanged pramipexole is the main elimination pathway. Approximately 90% of a 14C-labeled dose is excreted by the kidneys, while less than 2% is detected 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 individuals.

Clinical characteristics.

Indications.

MIRAPEX PD 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 until late 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).

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 is observed in humans. Therefore, interactions with other medicinal products affecting plasma protein binding or elimination via biotransformation are unlikely. Since anticholinergic agents are primarily eliminated by 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 active renal excretion pathways

Cimetidine reduced the renal clearance of pramipexole by approximately 34%, likely by inhibiting the cationic secretory transport system in 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, zidovudin, cisplatin, quinine, and procainamide—may interact with pramipexole, resulting in reduced pramipexole clearance. When co-administering these medicinal products with MIRAPEX PD, consideration should be given to reducing the dose of pramipexole.

Combination with levodopa

When increasing the dose of MIRAPEX PD 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 for use", "Ability to influence reaction rate when driving or operating machinery", and "Adverse reactions").

Antipsychotic medicinal products.

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

Special precautions for use.

When prescribing MIRAPLEX PD to patients with Parkinson's disease and impaired renal function, the dose should be reduced according to the recommendations provided in the section "Dosage and administration".

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

Diskinesia. During combined therapy with levodopa in progressive Parkinson's disease, dyskinesia may develop during initial titration of MIRAPLEX PD. 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 in these patients improved after dose reduction or discontinuation of pramipexole.

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

Sudden sleep attacks or somnolence. The use of pramipexole has been associated with somnolence and sudden sleep attacks, particularly in patients with Parkinson's disease. Sudden onset of sleep during daytime activities, sometimes without prior warning signs or awareness, has been reported infrequently. Patients should be informed about this risk. They should be advised to exercise caution when driving or operating machinery during treatment with MIRAPLEX PD. Patients who experience somnolence and/or sudden sleep attacks should refrain from driving or operating machinery. Furthermore, dose reduction or discontinuation of treatment should be considered. Due to possible additive effects, caution is recommended when patients are taking other sedative medicinal products or alcohol in combination with pramipexole (see sections "Interaction with other medicinal products and other forms of interaction", "Ability to influence 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 treatment with dopamine agonists, including MIRAPLEX PD, may lead to symptoms of impulse control disorders such as pathological gambling, increased libido, hypersexuality, compulsive spending or shopping, binge eating, and compulsive eating. If such symptoms occur, 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 develop, 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 monitoring at consistent intervals or whenever visual disturbances occur is recommended.

Severe cardiovascular disorders. Caution should be exercised in patients with severe cardiovascular disorders. 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 following abrupt withdrawal 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 in patients with Parkinson's disease, the dose of pramipexole should be gradually reduced (see section "Dosage and administration"). Limited data suggest that patients with impulse control disorders and those receiving high daily 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 or discontinuing pramipexole, patients should be informed about possible withdrawal symptoms. Patients should be closely monitored during dose reduction and discontinuation of pramipexole. In cases of severe and/or persistent dopamine agonist withdrawal syndrome symptoms, temporary reinitiation of pramipexole at the lowest effective dose may be considered.

Residues in feces. Some patients have reported the presence of residues in feces resembling intact prolonged-release tablets of MIRAPLEX PD. In case of such a report from a patient, the physician should reassess the patient's response to therapy.

Use during pregnancy or breastfeeding.

Pregnancy. The effect on pregnancy and lactation in humans has not been studied. Pramipexole did not show teratogenic effects in studies in rats and rabbits, but it exerted embryotoxic effects in rats at doses that were toxic to pregnant females. MIRAPLEX PD should not be used during pregnancy unless clearly necessary, i.e., when the potential benefit justifies the potential risk to the fetus.

Breastfeeding period. 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 milk was higher than in plasma. Due to the lack of adequate human data, MIRAPLEX PD should not be used during breastfeeding. However, if use of this medicinal product cannot be avoided, breastfeeding should be discontinued.

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

Ability to influence reaction speed when driving or operating machinery.

MIRAPLEX PD may have a significant effect on the ability to drive or operate machinery. Hallucinations or somnolence may occur.

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

Dosage and Administration

MIRAPEX PD prolonged-release tablets are a pharmaceutical form of pramipexole intended for oral administration once daily.

Initial Therapy

Dosages should be increased gradually, starting with a dose of 0.375 mg pramipexole dihydrochloride monohydrate (0.26 mg pramipexole) per day. Subsequent dose increases should be performed every 5–7 days. If patients do not experience intolerable adverse reactions, dose titration should be performed to achieve the maximum therapeutic effect.

If necessary, the daily dose should be increased at weekly intervals by 0.75 mg of pramipexole dihydrochloride monohydrate (0.52 mg pramipexole) up to the maximum dose of 4.5 mg pramipexole dihydrochloride monohydrate (3.15 mg pramipexole) per day.

However, it should be noted that the likelihood of somnolence increases with doses exceeding 1.5 mg pramipexole dihydrochloride monohydrate (1.05 mg pramipexole) per day (see section "Side Effects").

Patients already taking MIRAPREX tablets may be switched to prolonged-release MIRAPREX PD tablets. This is best done at night, maintaining the same daily dose. After switching to prolonged-release MIRAPREX PD tablets, the dose may be adjusted according to the patient's response to treatment (see subsection "Pharmacodynamics").

Maintenance treatment.

The individual dose of pramipexole dihydrochloride monohydrate should range from 0.375 mg pramipexole dihydrochloride monohydrate (0.26 mg pramipexole) to a maximum of 4.5 mg pramipexole dihydrochloride monohydrate (3.15 mg pramipexole) per day. In clinical trials, efficacy was observed starting with a daily dose of 1.5 mg pramipexole dihydrochloride monohydrate (1.05 mg pramipexole). Further dose adjustments should be made based on clinical response and consideration of adverse reactions. During clinical studies, approximately 5% of patients were treated with doses lower than 1.5 mg pramipexole dihydrochloride monohydrate (1.05 mg pramipexole). For patients with progressive Parkinson's disease, doses exceeding 1.5 mg pramipexole dihydrochloride monohydrate (1.05 mg pramipexole) per day may be beneficial, especially when planning to reduce levodopa dosage. It is recommended to reduce the levodopa dose during dose escalation of MIRAPREX PD and also during maintenance therapy with this drug, depending on individual patient response (see section "Interaction with other medicinal products and other forms of interaction").

Missed dose.

If a dose is missed, the prolonged-release MIRAPREX PD tablet should be taken within 12 hours of the usual dosing time. If more than 12 hours have passed since the missed dose, the tablet should not be taken; instead, the next dose should be taken the following day at the usual time.

Discontinuation of treatment.

Sudden interruption of dopaminergic therapy may lead to the development of neuroleptic malignant syndrome or dopamine agonist withdrawal syndrome. The pramipexole dose should be gradually reduced by 0.75 mg pramipexole dihydrochloride monohydrate (0.52 mg pramipexole) per day until the daily dose is reduced to 0.75 mg pramipexole dihydrochloride monohydrate (0.52 mg pramipexole). After that, the dose should be further reduced to 0.375 mg pramipexole dihydrochloride monohydrate (0.26 mg pramipexole) per day (see section "Special precautions"). 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").

Dosing in patients with renal impairment

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

• Patients with creatinine clearance above 50 mL/min do not require dose reduction or adjustment of dosing frequency;
• Patients with creatinine clearance between 30 and 50 mL/min should start treatment with a dose of 0.375 mg pramipexole dihydrochloride monohydrate (0.26 mg pramipexole) every other day. Caution should be exercised before increasing the daily dose after one week of treatment, and careful evaluation of treatment response and tolerability should be performed. If necessary, the dose should be increased at weekly intervals by 0.375 mg pramipexole dihydrochloride monohydrate (0.26 mg pramipexole) up to a maximum dose of 2.25 mg pramipexole dihydrochloride monohydrate (1.57 mg pramipexole) per day;
• Treatment with prolonged-release MIRAPREX PD tablets is not recommended in patients with creatinine clearance below 30 mL/min due to lack of data in this patient population. Consideration should be given to using MIRAPREX tablets instead.

If renal function deteriorates during maintenance therapy, the above recommendations should be followed.

Dosing in patients with hepatic impairment

Dose adjustment is unlikely to be 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 MIRAPREX PD has not been studied.

Method of administration.

Tablets should be swallowed whole with water, without chewing, dividing, or crushing. Food intake does not affect administration of the drug. MIRAPREX PD should be taken every day at approximately the same time.

Children.

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

Overdose.

There is no significant clinical experience with 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 fluids, activated charcoal, and ECG monitoring.

Adverse Reactions

Expected Adverse Reactions

An analysis of pooled placebo-controlled trials involving a total of 1778 Parkinson’s disease patients treated with pramipexole and 1297 patients treated with placebo showed that adverse reactions were frequently reported in both groups. Adverse reactions were reported in 67% of patients treated with pramipexole and in 54% of patients treated with placebo.

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

Adverse reactions are listed below by system organ class according to 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 (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data).

The most frequently reported adverse reactions (≥ 5%) in Parkinson’s disease patients treated with pramipexole (more common with pramipexole 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"). Dyskinesia was the most common adverse reaction when the drug was administered in combination with levodopa. Hypotension may occur at the beginning of treatment, particularly if titration of pramipexole is performed too rapidly.

1 This adverse reaction was observed during the post-marketing period. With 95 % certainty, its frequency was determined as "uncommon", but it may be lower. Establishing the exact frequency is impossible, as the adverse reaction was not observed during clinical trials in 2762 patients with Parkinson's disease 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 precautions").

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

Impulse control disorders. During treatment with dopamine agonists, including MIRAPEX PD, 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 precautions").

During a cross-sectional retrospective screening and a case-control study involving 3090 patients with Parkinson's disease, 13.6 % of all patients receiving dopaminergic or non-dopaminergic therapy exhibited symptoms of impulse control disorders during the past six months. Observed manifestations included pathological gambling, compulsive shopping, excessive eating, and compulsive sexual behavior (hypersexuality). Possible independent risk factors for 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 upon dose reduction or discontinuation of dopamine agonists (including pramipexole). Symptoms include apathy, anxiety, depression, fatigue, sweating, and pain (see section "Special precautions").

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

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store in the original packaging in a dry place protected from moisture, at a temperature not exceeding 25 °C. Keep out of reach of children!

Packaging.

10 prolonged-release tablets per blister; 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Boehringer Ingelheim Pharma GmbH & Co.KG, Germany.

or

Rottendorf Pharma GmbH, Germany

Manufacturer's address and location of operations.

Binger Strasse 173, 55216 Ingelheim am Rhein, Germany.

Binger Strasse 173, 55216 Ingelheim am Rhein, Germany.

or

Ostenfelder Strasse 51–61, 59320 Ennigerloh, Germany /

Ostenfelder Strasse 51–61, 59320 Ennigerloh, Germany.